Nutrients

Dec

Published

online

Dec

doi

PMCID

Does

Vitamin

C

Deficiency

Promote

Fatty

Liver

Disease

Development

David

Højland

Ipsen

Pernille

TvedenNyborg

and

Jens

Lykkesfeldt

Author

information

Article

notes

Copyright

and

License

information

This

article

has

been

cited

by

other

articles

in

PMC

Go

to

Abstract

Obesity

and

the

subsequent

reprogramming

of

the

white

adipose

tissue

are

linked

to

human

diseasecomplexes

including

metabolic

syndrome

and

concurrent

nonalcoholic

fatty

liver

disease

NAFLD

and

nonalcoholic

steatohepatitis

NASH

The

dietary

imposed

dyslipidemia

promotes

redox

imbalance

by

the

generation

of

excess

levels

of

reactive

oxygen

species

and

induces

adipocyte

dysfunction

and

reprogramming

leading

to

a

low

grade

systemic

inflammation

and

ectopic

lipid

deposition

eg

in

the

liver

hereby

promoting

a

vicious

circle

in

which

dietary

factors

initiate

a

metabolic

change

that

further

exacerbates

the

negative

consequences

of

an

adverse

lifestyle

Large

epidemiological

studies

and

findings

from

controlled

in

vivo

animal

studies

have

provided

evidence

supporting

an

association

between

poor

vitamin

C

VitC

status

and

propagation

of

lifestyle

associated

diseases

In

addition

overweight

per

se

has

been

shown

to

result

in

reduced

plasma

VitC

and

the

distribution

of

body

fat

in

obesity

has

been

shown

to

have

an

inverse

relationship

with

VitC

plasma

levels

Recently

a

number

of

epidemiological

studies

have

indicated

a

VitC

intake

below

the

recommended

daily

allowance

RDA

in

NAFLDpatients

suggesting

an

association

between

dietary

habits

disease

and

VitC

deficiency

In

the

general

population

VitC

deficiency

defined

as

a

plasma

concentration

below

μM

affects

around

Keywords

antioxidants

obesity

oxidative

stress

nonalcoholic

fatty

liver

disease

nonalcoholic

steatohepatitis

reactive

oxygen

species

vitamin

C

vitamin

C

deficiency

Go

to

Introduction

Obesity

has

become

an

epidemic

with

detrimental

effects

on

health

and

wellbeing

In

more

than

onethird

of

the

worlds

adult

population

could

be

characterized

as

being

overweight

or

obese

body

mass

index

BMI

kgm

Obesity

has

been

found

to

result

in

dysfunctional

adipose

tissue

lowgrade

systemic

inflammation

and

redox

imbalance

with

increased

oxidative

stress

As

part

of

the

socalled

metabolic

syndrome

known

associations

with

obesity

include

a

wide

range

of

diseases

eg

atherosclerosis

insulin

resistance

IR

type

diabetes

and

nonalcoholic

fatty

liver

disease

NAFLD

The

development

of

NAFLD

is

closely

linked

to

increased

levels

of

circulating

lipids

IR

inflammation

and

oxidative

stress

In

agreement

with

a

putative

role

of

oxidative

stress

in

the

etiology

of

NAFLD

important

antioxidant

enzymes

and

vitamins

are

decreased

in

obese

and

NAFLD

patients

Vitamin

C

VitC

is

a

watersoluble

chainbreaking

antioxidant

capable

of

scavenging

essentially

all

physiologically

relevant

free

radicals

Additionally

it

serves

as

donor

of

reducing

equivalents

in

multiple

enzymatic

reactions

of

which

its

role

in

proline

and

lysine

hydroxylation

during

collagen

synthesis

is

probably

most

widely

known

Humans

and

a

few

other

species

are

unable

to

synthesize

VitC

and

must

instead

acquire

it

through

dietary

means

Inadequate

dietary

intake

results

in

VitC

deficiency

defined

as

plasma

levels

below

μM

Crosssectional

population

studies

have

shown

that

about

of

the

western

population

can

be

diagnosed

with

VitC

deficiency

and

that

poor

VitC

status

is

associated

with

increased

allcause

mortality

Moreover

the

prevalence

of

VitC

deficiency

in

specific

subgroups

may

be

considerably

higher

potentially

enhancing

susceptibility

to

oxidative

stress

and

disease

Accordingly

VitC

status

correlates

inversely

with

eg

BMI

and

is

significantly

decreased

in

obese

compared

with

lean

individuals

Thus

the

apparent

link

between

obesity

NAFLD

and

oxidative

stress

suggests

that

NAFLD

progression

may

be

accelerated

by

poor

VitC

status

The

aim

of

this

review

is

to

discuss

the

current

data

from

human

and

animal

studies

in

relation

to

a

putative

role

of

VitC

in

the

development

of

NAFLD

Go

to

Obesity

Systemic

Inflammation

and

NAFLD

Obesity

and

Systemic

Inflammation

Obesity

is

primarily

a

consequence

of

a

sedentary

lifestyle

and

the

intake

of

an

excess

amount

of

calories

As

a

result

unused

resources

are

accumulated

as

fat

in

adipose

tissue

facilitating

adipocyte

hypertrophy

and

hyperplasia

alongside

increased

production

of

chemokines

cytokines

reactive

oxygen

species

ROS

hypoxia

and

cell

death

ultimately

leading

to

macrophage

infiltration

and

adipocyte

dysfunction

Macrophages

initiate

and

maintain

inflammation

by

secreting

a

variety

of

cytokines

such

as

tumor

necrosis

factor

α

TNFα

and

interleukin

IL

At

the

same

time

dysfunctional

adipocytes

increase

their

secretion

of

proinflammatory

cytokines

while

decreasing

secretion

of

antiinflammatory

cytokines

Decreased

secretion

of

adiponectin

by

adipocytes

and

concurrent

interference

with

the

insulin

signaling

pathway

by

inflammatory

cytokines

promotes

the

development

of

IR

Furthermore

inflammation

of

the

adipose

tissue

may

participate

in

the

induction

of

hepatic

IR

as

well

Inflammation

IR

and

adipocyte

hypertrophy

per

se

can

increase

the

rate

of

lipolysis

and

subsequent

release

of

free

fatty

acids

FFA

FFAs

have

been

shown

to

directly

activate

macrophages

through

Tolllike

receptors

and

and

enhance

the

production

of

inflammatory

cytokines

Thus

a

vicious

cycle

is

established

Adipocyte

dysfunction

induces

a

lowgrade

inflammation

which

increases

the

release

of

FFA

In

turn

the

FFAs

stimulate

macrophage

activation

and

additional

production

of

inflammatory

cytokines

Figure

Ultimately

this

may

result

in

a

state

of

chronic

lowgrade

systemic

inflammation

and

oxidative

stress

Low

levels

of

antioxidants

may

enhance

oxidative

stress

aggravating

an

already

vulnerable

state

of

redox

imbalance

Figure

Propagation

of

lowgrade

systemic

inflammation

from

adipose

tissues

Dietary

induced

dyslipidemia

leads

to

increased

fat

deposition

and

promotes

hypertrophy

and

hyperplasia

of

adipocytes

as

well

as

cellular

reprogramming

leading

to

altered

secretory

functions

of

adipocytes

The

tissue

expansion

and

associated

adipocyte

dysfunction

increases

the

release

of

inflammatory

cytokines

such

as

and

TNFα

and

activates

macrophages

Furthermore

release

of

the

antiinflammatory

adipokines

eg

adiponectin

is

decreased

This

induces

a

state

of

lowgrade

systemic

inflammation

which

in

turn

compromises

insulin

sensitivity

and

increases

lipolysis

in

adipose

tissues

increasing

the

release

of

free

fatty

acids

FFA

and

exacerbating

the

dietary

induced

dyslipidemia

Moreover

FFAs

also

promote

macrophage

activation

by

binding

Multiple

crosssectional

studies

have

found

decreased

levels

of

VitC

and

several

other

antioxidants

in

obese

men

and

women

and

observed

an

inverse

correlation

between

VitC

levels

and

BMI

waist

circumference

and

body

fat

percentage

The

third

Glasgow

MONICA

population

survey

investigated

the

plasma

VitC

status

of

men

and

women

aged

years

and

found

of

the

participants

n

to

be

VitC

deficient

with

a

VitC

plasma

concentration

below

μM

Additionally

using

data

from

US

adult

men

and

women

participating

in

the

Third

National

Health

and

Nutrition

Examination

Survey

NHANES

III

Ford

et

al

reported

that

the

metabolic

syndrome

was

associated

with

decreased

levels

of

VitC

and

other

antioxidants

such

as

vitamin

E

VitE

Dietary

habits

may

be

an

important

factor

contributing

to

the

poor

VitC

status

in

obesity

Obese

individuals

have

been

shown

to

consume

less

dietary

VitC

Similarly

obese

women

were

found

to

consume

less

fruits

and

vegetables

compared

to

lean

controls

A

putative

role

of

VitC

in

inflammation

has

also

been

suggested

since

VitC

levels

have

been

found

to

be

inversely

associated

with

inflammatory

markers

such

as

Creactive

protein

CRP

and

myeloperoxidase

Furthermore

VitC

may

be

involved

in

the

regulation

of

the

key

adipokine

adiponectin

supported

by

a

recent

study

reporting

dietary

VitC

intake

to

correlate

with

adiponectin

levels

in

adolescent

girls

In

vitro

studies

have

suggested

that

VitC

increases

the

secretion

of

high

molecular

weight

HMW

adiponectin

in

fully

differentiated

human

adipocytes

without

changing

total

adiponectin

secretion

Contrary

to

this

however

supplementation

with

VitC

mgday

in

obese

patients

did

not

change

adiponectin

levels

Quantification

of

total

adiponectin

instead

of

the

bioactive

HMW

isomer

alone

may

account

for

the

conflicting

results

Alternatively

the

dose

of

VitC

might

have

been

too

low

as

mgday

was

shown

to

improve

several

other

metabolic

parameters

in

patients

with

type

diabetes

ie

fasting

blood

sugar

serum

insulin

triglycerides

TG

and

lowdensity

lipoprotein

LDL

Further

cell

studies

have

shown

that

increased

oxidative

stress

decrease

the

expression

of

adiponectin

mRNA

in

adipocytes

and

that

adiponectin

levels

are

inversely

correlated

with

a

maker

of

lipid

peroxidation

Adiponectin

levels

were

also

inversely

associated

with

the

severity

of

hepatic

steatosis

and

necroinflammation

Thus

a

role

of

VitC

in

adiponectin

regulation

could

have

important

effects

on

progression

of

inflammation

IR

and

NAFLD

NAFLD

NAFLD

is

estimated

to

affect

to

median

of

the

worlds

population

and

constitutes

the

most

common

liver

disease

in

the

western

world

NAFLD

comprises

a

cluster

of

hepatic

conditions

ranging

from

simple

initially

benign

and

reversible

steatosis

to

hepatocyte

ballooning

Mallory

bodies

fibrosis

and

inflammation

in

nonalcoholic

steatohepatitis

NASH

However

in

some

patients

hepatic

steatosis

progresses

to

NASH

increasing

the

risk

of

hepatic

cirrhosis

and

hepatocellular

carcinoma

NAFLD

is

strongly

associated

with

obesity

dyslipidemia

IR

oxidative

stress

inflammation

and

the

metabolic

syndrome

Indeed

the

prevalence

of

NAFLD

in

obese

patients

has

been

reported

to

be

the

amount

of

visceral

adipose

tissue

in

particular

being

highly

correlated

with

increased

risk

of

NAFLD

The

pathogenesis

of

NAFLD

is

not

yet

completely

understood

However

it

is

currently

believed

that

initial

hepatic

fat

accumulation

is

followed

by

multiple

parallel

hits

that

promote

inflammation

and

disease

progression

The

most

important

events

believed

to

be

involved

in

this

process

include

IR

increased

FFA

dietary

factors

cytokines

derived

from

the

adipose

tissue

and

ROS

formation

IR

is

a

key

mechanism

in

hepatic

dyslipidemia

Expectedly

diabetic

patients

have

an

increased

prevalence

of

NAFLD

compared

to

nondiabetic

individuals

supporting

the

link

between

IR

and

NAFLD

While

IR

increases

circulating

levels

of

FFAs

hyperinsulinemia

during

IR

paradoxically

apparently

inhibits

hepatic

lipid

oxidation

and

increases

de

novo

lipogenesis

Concurrently

saturation

of

verylowdensity

lipoprotein

VLDL

secretion

may

facilitate

lipid

accumulation

as

well

In

patients

with

NAFLD

the

majority

of

hepatic

lipids

originate

from

circulating

FFA

FFA

from

visceral

adipose

tissue

can

drain

directly

into

the

portal

vein

and

be

transported

straight

to

the

liver

As

hepatocytic

FFA

uptake

is

mediated

by

passive

diffusion

increased

FFA

levels

result

in

increased

FFA

uptake

which

is

subsequently

stored

as

TG

Interestingly

a

metaanalysis

of

clinical

trials

investigating

the

effect

of

VitC

intervention

on

LDL

highdensity

lipoprotein

HDL

and

TGs

in

patients

with

hypercholesterolemia

suggested

that

VitC

supplementation

can

reduce

the

concentration

of

lipids

in

circulation

TG

and

LDLC

Additionally

adipose

tissuederived

cytokines

may

contribute

to

the

development

of

NAFLD

and

inflammation

of

the

adipose

tissue

may

indeed

precede

hepatic

inflammation

Adiponectin

has

been

shown

to

reduce

ectopic

hepatic

lipid

accumulation

systemic

IR

and

inflammation

In

addition

TNFα

and

have

received

much

attention

as

putative

key

cytokines

involved

in

hepatic

lipid

accumulation

inflammation

and

IR

Dietary

factors

also

play

an

important

role

in

NAFLD

High

dietary

fructose

transfatty

acids

and

cholesterol

have

all

been

found

to

contribute

to

the

development

of

dyslipidemia

hepatic

fat

accumulation

and

subsequent

disease

progression

FFA

and

cholesterol

not

only

induce

hepatic

lipid

deposition

but

may

also

have

injurious

effects

in

the

liver

in

part

by

inducing

hepatocyte

apoptosis

lipotoxicity

mitochondrial

dysfunction

and

endoplasmic

reticulum

stress

with

subsequent

ROS

formation

and

inflammation

Furthermore

activation

of

hepatic

stellate

cells

and

Kupffer

cells

eg

by

hepatocyte

apoptosis

and

ROS

also

appear

to

promote

disease

progression

through

the

secretion

of

TNFα

transforming

growth

factor

β

and

collagen

which

induces

inflammation

and

fibrosis

Figure

Indeed

increased

generation

of

ROS

and

lipid

peroxidation

are

believed

to

be

key

pathogenic

components

in

NAFLD

perpetuating

inflammation

fibrogenesis

and

development

of

cirrhosis

and

hepatocellular

carcinoma

Oxidative

stress

alone

has

been

found

to

be

associated

with

NAFLD

both

in

patients

with

but

also

without

type

diabetes

VitC

has

been

shown

to

decrease

mitochondrial

ROS

formation

and

stimulate

the

activity

of

manganese

superoxide

dismutase

SOD

and

glutathione

peroxidase

GPx

in

isolated

rat

liver

mitochondria

However

dietary

intake

of

VitC

and

VitE

has

been

reported

to

be

lower

in

NAFLD

patients

potentially

predisposing

them

to

oxidative

stress

Figure

Putative

effects

of

vitamin

C

deficiency

on

the

progression

of

NAFLD

As

cofactor

for

the

catalyzing

the

conversion

of

cholesterol

to

VitC

deficiency

may

increase

circulating

levels

of

cholesterol

CHOL

by

reducing

its

excretion

through

the

bile

Systemic

inflammation

and

dyslipidemia

is

propagated

through

adipocyte

dysfunction

eg

releasing

fatty

acids

FFA

and

inflammatory

cytokines

to

the

blood

stream

Moreover

by

affecting

adiponectin

regulation

lack

of

VitC

may

further

increase

dyslipidemia

systemic

inflammation

and

oxidative

stress

As

VitC

is

also

a

powerful

antioxidant

deficiency

per

se

promotes

cellular

oxidative

stress

eg

in

the

liver

The

excess

lipids

induce

mitochondrial

dysfunction

and

stress

of

the

endoplasmic

reticulum

ER

further

propagating

hepatic

Consistent

with

this

notion

a

number

of

investigators

have

found

that

markers

of

oxidative

damage

such

as

malondialdehyde

MDA

and

protein

carbonyls

are

elevated

while

antioxidants

like

catalase

and

SOD

are

decreased

in

the

plasma

and

livers

of

animals

and

humans

with

NAFLD

This

has

led

to

the

hypothesis

that

VitC

therapy

could

prove

beneficial

in

the

treatment

of

NAFLD

Figure

Go

to

Does

Vitamin

C

Deficiency

Promote

NAFLD

Animal

Studies

of

Vitamin

C

Deficiency

Several

in

vivo

studies

have

investigated

the

role

of

poor

VitC

status

in

relation

to

dyslipidemia

and

NAFLD

Table

Like

humans

guinea

pigs

are

unable

to

synthesize

VitC

due

to

a

nonfunctional

gene

encoding

for

l

gulonolactone

oxidase

gulo

making

them

an

excellent

model

for

the

study

of

VitC

deficiency

Moreover

with

regards

to

eg

cholesterol

distribution

activity

of

enzymes

involved

in

lipoprotein

metabolism

LDL

receptor

binding

domain

characteristics

and

cholesterol

synthesis

guinea

pigs

are

comparable

to

humans

in

contrast

to

other

rodents

Contrary

to

the

guinea

pig

the

gulo

gene

is

functional

in

mice

and

rats

and

both

species

are

able

to

synthesize

VitC

However

the

effect

of

VitC

deficiency

can

be

examined

in

genetically

engineered

rodent

models

although

the

validity

and

human

relevance

of

such

models

may

be

difficult

to

assess

Table

Animal

studies

of

vitamin

C

deficiency

Guinea

pigs

kept

on

a

diet

without

VitC

for

weeks

showed

elevated

levels

of

hepatic

cholesterol

and

TG

compared

to

control

animals

on

a

VitC

supplemented

diet

Similarly

another

study

in

guinea

pigs

showed

increased

hepatic

triacylglycerol

and

cholesteryl

esters

after

weeks

of

VitC

deficiency

Scurvy

can

be

avoided

by

supplementing

the

diet

with

small

amounts

of

VitC

allowing

investigators

to

study

the

longterm

effects

of

nonscorbutic

VitC

deficiency

After

up

to

weeks

on

such

a

diet

guinea

pigs

had

elevated

levels

of

TG

in

the

liver

thoracic

aorta

and

serum

This

was

due

to

decreased

conversion

of

cholesterol

to

bile

acid

revealing

a

crucial

role

of

VitC

in

this

process

Specifically

VitC

is

a

cofactor

for

the

catalyzing

the

conversion

of

cholesterol

to

constituting

the

ratelimiting

step

in

bile

acid

formation

and

thus

VitC

deficiency

results

in

reduced

excretion

of

cholesterol

in

animals

The

addition

of

cholesterol

to

a

VitC

deficient

diet

exacerbated

the

effects

of

VitC

deficiency

per

se

by

increasing

the

amount

of

hepatic

TG

cholesterol

focal

fibrosis

and

proliferation

of

connective

tissue

Moreover

high

dose

mgday

po

of

VitC

significantly

diminished

these

changes

Interestingly

dietary

cholesterol

also

appears

to

have

effects

on

the

VitC

status

In

a

longterm

dietary

intervention

study

in

guinea

pigs

high

cholesterol

fed

animals

consistently

showed

range

lower

plasma

and

liver

VitC

concentrations

compared

to

control

animals

regardless

of

low

or

high

dietary

VitC

intake

In

the

osteogenic

disorder

shionogi

ODS

rata

mutant

rat

strain

unable

to

synthesize

VitCVitC

deficiency

with

or

without

cholesterol

and

cholic

acid

supplementation

for

days

increased

hepatic

cholesterol

and

total

lipids

Furthermore

regardless

of

the

amount

of

cholesterol

added

to

the

diet

Uchida

et

al

did

not

find

any

effect

of

VitC

relating

to

changes

in

hepatic

lipids

in

ODS

rats

These

discrepancies

may

reflect

the

significant

differences

between

guinea

pigs

and

rats

in

the

way

lipids

are

handled

and

stored

Collectively

the

above

results

suggest

that

VitC

is

involved

in

the

regulation

of

both

circulating

and

hepatic

lipid

homeostasis

supporting

VitC

as

an

important

factor

in

the

development

of

NAFLD

In

accordance

with

a

central

role

in

the

prevention

of

oxidative

stress

VitC

deficiency

has

been

shown

to

cause

a

reduction

in

both

expression

and

activity

of

various

antioxidant

enzymes

with

a

concurrent

rise

in

markers

of

oxidative

stress

Thus

weeks

of

VitC

deficiency

caused

increased

levels

of

thiobarbituric

acid

reactive

substance

TBARS

MDA

and

protein

carbonyls

in

the

liver

of

guinea

pigs

Oxidative

stress

was

also

evident

in

the

liver

of

gulo

mice

without

access

to

VitC

for

days

Protein

carbonyls

but

not

TBARS

were

increased

in

the

livers

of

these

animals

alongside

decreased

catalase

protein

expression

compared

to

WT

or

gulo

supplemented

controls

However

SOD

activity

was

increased

likely

as

a

compensatory

mechanism

Indeed

SOD

appears

to

play

an

important

role

in

NAFLD

as

increased

hepatic

fibrosis

is

found

in

NASH

patients

with

mutations

in

the

gene

coding

for

Pierce

et

al

found

increased

hepatic

MDA

in

VitC

deficient

gulo

mice

placed

on

a

western

diet

but

with

no

change

in

glutathione

or

isoprostanes

However

other

authors

report

an

increase

of

glutathione

a

long

with

increased

MDA

and

protein

carbonyls

in

livers

of

gulo

mice

deprived

of

VitC

for

similar

periods

of

time

These

differences

between

studies

may

be

attributed

to

different

diet

compositions

and

age

of

the

animals

ie

a

western

type

diet

and

weeks

old

animals

vs

normal

chow

and

newly

born

animals

respectively

The

considerable

number

of

studies

reporting

increased

protein

carbonyls

MDA

and

TBARS

in

VitC

deficient

animals

support

that

VitC

has

a

protective

effect

against

hepatic

protein

and

lipid

oxidation

This

may

be

of

significance

as

lipid

oxidation

has

been

shown

to

occur

in

NAFLD

and

even

correlate

with

the

severity

of

liver

necroinflammation

and

fibrosis

Furthermore

keeping

ODS

rats

on

a

VitC

free

diet

for

days

resulted

in

increased

cytokineinduced

neutrophil

a

potent

inflammatory

chemokine

in

serum

liver

and

spleen

Thus

VitC

deficiency

may

mediate

the

infiltration

and

accumulation

of

neutrophils

with

subsequent

inflammatory

damage

in

some

tissues

Animal

Studies

of

VitC

Intervention

and

NAFLD

Methionine

and

choline

are

essential

for

hepatic

βoxidation

and

VLDL

production

Expectedly

methionine

and

choline

deficient

MCD

diets

cause

accumulation

of

intrahepatic

lipids

and

decreased

VLDL

synthesis

Rezazadeh

and

coworkers

fed

rats

a

MCD

diet

for

weeks

and

randomized

animals

to

receive

VitC

or

no

supplementation

for

an

additional

eight

weeks

on

the

diet

While

VitC

supplementation

significantly

decreased

hepatocellular

ballooning

and

inflammation

liver

steatosis

still

persisted

At

the

same

time

hepatic

markers

of

oxidative

stress

were

decreased

while

SOD

and

catalase

were

increased

Similar

results

were

obtained

by

supplementing

rats

placed

on

a

MCD

diet

with

VitC

for

weeks

The

authors

also

found

that

VitC

treatment

significantly

increased

glutathione

reductase

GR

and

GPx

activity

Moreover

VitC

treatment

resulted

in

a

significant

decrease

in

circulating

liver

enzymes

TG

and

LDL

showing

a

protective

effect

of

VitC

supplementation

on

the

MCD

dietinduced

dyslipidemia

Conversely

rats

fed

a

choline

deficient

diet

for

weeks

with

concurrent

VitC

supplementation

did

not

show

any

improvements

in

serum

TG

or

aspartate

aminotransferase

even

though

hepatic

steatosis

was

ameliorated

and

oxidative

stress

reduced

However

the

studies

differ

considerably

in

diet

composition

duration

and

rat

strain

used

confounding

compatibility

between

findings

Imbalance

of

the

antioxidant

status

similar

to

that

observed

in

the

animal

studies

has

also

been

found

in

patients

with

steatosis

while

antioxidant

status

is

even

further

compromised

in

NASH

Animal

models

utilizing

MCD

or

choline

deficient

diets

to

induce

NAFLD

appear

to

present

a

similar

pathology

but

the

pathogenesis

is

different

from

the

human

situation

Additionally

most

animals

lose

weight

on

the

MCD

diet

contrary

to

the

human

situation

in

which

many

NAFLD

patients

are

obese

Results

may

therefore

not

be

directly

translatable

Guinea

pigs

placed

on

an

atherogenic

diet

high

in

fat

and

cholesterol

for

months

developed

dyslipidemia

with

elevated

serum

cholesterol

and

phospholipids

in

addition

to

elevated

hepatic

levels

of

cholesterol

phospholipids

and

TG

VitC

deficiency

exacerbated

the

dyslipidemia

and

hepatic

consequences

but

high

VitC

reduced

the

severity

of

both

dyslipidemia

and

hepatic

lipid

accumulation

It

is

noteworthy

that

extremely

high

doses

of

VitC

mgkg

diet

have

been

shown

to

decrease

hepatic

markers

of

oxidation

to

the

same

degree

as

normal

VitC

doses

in

guinea

pigs

but

also

cause

a

reduction

of

body

weight

and

GR

activity

similarly

to

what

was

observed

in

the

VitC

deficient

animals

It

is

possible

that

the

very

high

dose

of

VitC

caused

adverse

effects

in

the

guinea

pigs

eg

gastrointestinal

disturbances

and

osmotic

diarrhea

which

could

affect

bodyweight

and

general

physiology

however

this

was

not

reported

by

the

authors

Conversely

Roomi

et

al

did

not

report

any

adverse

effects

of

a

megadose

of

VitC

mg

VitCkg

diet

in

guinea

pigs

Contrary

to

guinea

pigs

supplementation

with

high

levels

of

VitC

in

ODS

rats

did

not

reduce

hepatic

cholesterol

to

a

greater

extent

that

normal

VitC

levels

did

Thus

VitC

treatment

seemingly

reduces

hepatic

oxidative

stress

but

have

variable

effect

on

hepatic

steatosis

likely

depending

on

the

employed

method

of

induction

ie

a

high

fat

diet

versus

a

MCD

or

MD

diet

Table

Table

Animal

studies

of

VitC

intervention

in

NAFLD

Epidemiological

Studies

of

VitC

Intake

and

NAFLD

A

number

of

cohort

studies

have

been

carried

out

investigating

the

dietary

habits

of

patients

with

NAFLD

Results

are

conflicting

some

studies

indicate

suboptimal

VitC

intake

by

NAFLD

patients

while

others

do

not

Table

Using

a

food

record

Musso

et

al

evaluated

dietary

habits

in

patients

with

NASH

and

healthy

controls

Among

other

differences

NASH

patients

consumed

significantly

less

VitC

compared

to

the

healthy

controls

vs

mg

Males

constituted

the

vast

majority

of

the

NASH

group

patients

and

though

below

that

of

healthy

controls

dietary

intakes

were

close

to

the

recommended

daily

intake

of

mg

VitCday

although

this

was

not

the

case

for

smokers

with

NASH

Contrary

to

this

Ferolla

and

colleagues

found

that

intake

of

VitC

in

NAFLD

patients

diagnosed

with

fatty

liver

did

not

meet

recommendations

when

assessed

in

men

and

women

using

dietary

recall

and

food

frequency

questionnaires

FFQ

Unfortunately

the

lack

of

a

control

group

impedes

investigation

as

to

whether

low

VitC

intake

was

also

prevalent

in

a

comparable

healthy

population

Different

methodology

ethnicity

and

patients

disease

stage

may

account

for

apparent

study

dissimilarities

Indeed

food

records

may

themselves

lead

patients

to

change

their

dietary

patterns

Table

Epidemiological

studies

of

VitC

status

in

NAFLD

patients

Han

and

coworkers

studied

the

dietary

intake

of

Korean

adults

and

reported

no

differences

in

dietary

VitC

intake

between

men

and

women

with

NAFLD

and

control

subjects

However

when

adjusted

for

age

job

education

level

exercise

frequency

smoking

status

energy

intake

and

n

fatty

acid

intake

VitC

intake

was

negatively

associated

with

the

risk

of

NAFLD

in

male

patients

OR

p

trend

In

children

with

steatosis

or

NASH

Vos

et

al

found

dietary

intakes

of

VitC

to

be

similar

However

while

differences

in

steatosis

grade

were

not

associated

with

differences

in

VitC

intake

significantly

increased

hepatocyte

ballooning

was

indeed

observed

in

children

with

decreased

VitC

consumption

In

another

study

Mager

et

al

reported

that

daily

recommendations

of

VitC

were

met

by

children

with

NAFLD

However

impaired

antioxidant

status

was

implied

as

measured

by

low

levels

of

red

blood

cellglutathione

compared

to

previous

reports

in

healthy

children

although

the

conclusion

is

weakened

by

the

lack

of

paired

controls

Da

Silva

and

associates

concluded

that

VitC

intake

was

not

different

between

healthy

controls

and

adults

with

either

steatosis

or

NASH

In

this

study

of

NASH

patients

and

healthy

controls

the

intake

correlated

with

median

VitC

plasma

concentrations

which

did

not

differ

between

groups

and

μM

respectively

Likewise

Madan

et

al

did

not

find

any

differences

in

VitC

plasma

levels

between

NAFLD

patients

and

healthy

controls

Also

the

VitC

plasma

concentrations

were

found

not

to

correlate

with

hepatic

inflammation

or

fibrosis

However

in

another

study

by

Cabakan

and

coworkers

NASH

patients

had

reduced

VitC

plasma

levels

alongside

increased

plasma

MDA

and

nitric

oxide

compared

with

steatosis

patients

It

is

possible

that

this

reflects

an

ability

of

VitC

to

slow

down

the

progression

of

NAFLD

The

conflicting

results

do

not

allow

a

definitive

conclusion

regarding

dietary

VitC

intake

However

the

NAFLD

patients

included

in

the

studies

mentioned

above

largely

seem

to

have

met

recommended

daily

allowance

of

VitC

Unfortunately

most

of

the

studies

only

examine

the

estimated

dietary

intake

of

VitC

and

have

not

actually

measured

plasma

VitC

concentrations

It

has

been

suggested

that

assessments

of

dietary

VitC

only

have

a

moderate

relationship

with

plasma

VitC

levels

thus

the

two

measures

may

not

describe

the

VitC

status

in

the

same

way

Moreover

dietary

questionnaires

have

certain

limitations

and

underreporting

is

known

to

occur

which

may

also

skew

results

As

noted

previously

oxidative

stress

is

increased

in

NAFLD

patients

As

such

they

may

have

an

increased

demand

of

antioxidants

like

VitC

and

inadequate

levels

are

not

likely

to

be

reflected

by

reports

of

dietary

intake

alone

Daily

doses

of

VitC

between

and

mg

do

not

result

in

plasma

saturation

leading

some

investigators

to

propose

that

the

daily

recommended

dose

of

VitC

be

increased

from

and

mgday

US

women

and

men

respectively

to

mgday

in

healthy

individuals

Furthermore

small

differences

in

dietary

intake

of

VitC

between

and

mgday

can

lead

to

vastly

different

plasma

concentrations

as

this

interval

represents

a

very

steep

part

of

the

plasma

concentration

vs

dose

curve

Therefore

patients

with

a

daily

VitC

intake

in

this

area

and

even

corresponding

to

the

current

recommendation

may

still

be

at

risk

of

having

plasma

VitC

concentrations

below

optimal

levels

While

they

may

not

strictly

be

VitC

deficient

plasma

VitC

levels

between

and

μM

may

still

leave

patients

vulnerable

to

disease

as

eg

the

relative

risk

of

heart

failure

has

been

shown

to

increase

significantly

by

every

μM

drop

in

VitC

plasma

concentrations

Clinical

Intervention

Studies

with

VitC

and

NAFLD

To

date

no

study

has

directly

examined

the

effect

of

VitC

treatment

alone

in

NAFLD

and

compared

it

to

a

placebotreated

control

group

However

studies

which

combine

VitC

with

other

treatment

forms

have

been

conducted

Table

A

month

doubleblinded

randomized

controlled

trial

RCT

examined

the

differences

between

placebo

and

combined

treatment

with

VitC

mgday

and

E

IUday

in

children

Both

groups

received

lifestyle

intervention

involving

increased

physical

activity

and

a

tailored

diet

aimed

at

inducing

weight

loss

or

maintaining

weight

in

overweight

and

normal

weight

children

respectively

Liver

brightness

as

a

measure

of

lipid

accumulation

examined

by

ultrasound

circulating

levels

of

liver

enzymes

cholesterol

and

TG

were

reduced

in

both

groups

compared

to

baseline

but

were

not

significantly

different

between

groups

Subsequently

the

study

was

continued

as

an

openlabel

study

for

an

additional

months

but

with

fewer

participants

and

the

inclusion

of

a

posttreatment

liver

biopsy

Compared

to

baseline

both

groups

exhibited

significant

improvements

in

steatosis

grade

lobular

inflammation

hepatocyte

ballooning

and

liver

enzymes

but

not

in

fibrosis

scores

However

again

there

were

no

differences

between

placebo

and

treatment

group

Thus

VitC

and

E

supplementation

are

seemingly

not

superior

to

lifestyle

intervention

in

children

with

NAFLD

However

due

to

the

study

design

it

is

not

possible

to

determine

if

vitamin

treatment

is

better

than

no

treatment

at

all

The

authors

rightfully

suggested

that

increased

fruit

and

vegetable

consumption

augmented

by

the

new

diet

may

well

have

minimized

the

effect

of

the

vitamin

treatment

Indeed

VitC

absorption

is

highly

dose

depended

and

excess

amounts

are

effectively

excreted

and

can

therefore

not

facilitate

additional

health

benefits

Harrison

et

al

examined

the

effect

of

VitC

mgday

in

combination

with

VitE

IUday

versus

placebo

after

months

treatment

of

NASH

patients

Lifestyle

interventions

in

both

groups

focused

on

exercise

and

a

lowcalorie

diet

Hepatic

inflammation

necrosis

fibrosis

and

liver

enzymes

were

not

significantly

different

between

the

groups

However

a

significant

albeit

clinically

modest

intragroup

improvement

was

observed

in

the

vitamin

treated

group

with

regards

to

hepatic

fibrosis

On

the

basis

of

this

result

the

authors

concluded

that

VitC

and

VitE

treatment

seemingly

improves

hepatic

fibrosis

in

NASH

patients

However

this

conclusion

has

been

criticized

emphasizing

that

valid

conclusion

in

placebocontrolled

trials

must

be

made

by

comparing

treatment

and

placebogroups

rather

than

with

historic

data

Interestingly

the

fibrosis

score

was

not

improved

in

children

with

NAFLD

when

compared

to

baseline

Both

studies

implemented

lifestyle

changes

but

doses

of

VitC

and

E

study

duration

and

participants

were

different

between

the

two

studies

Additionally

the

children

with

NAFLD

had

a

low

fibrosis

score

at

baseline

which

may

impede

detection

of

potential

improvements

Importantly

liver

physiology

development

and

the

features

of

NASH

may

differ

considerably

between

children

and

adults

which

could

affect

study

outcomes

Table

Clinical

intervention

studies

with

VitC

in

NAFLD

In

a

pilot

study

NASH

patients

were

treated

with

VitC

mgday

and

VitE

mgday

for

months

and

changes

were

compared

to

baseline

BMI

remained

unchanged

but

serum

alanine

aminotransferase

and

highsensitivityCRP

were

significantly

reduced

by

the

antioxidant

treatment

HighsensitivityCRP

has

been

shown

to

be

associated

with

the

severity

of

liver

pathology

in

NASH

Ten

of

the

study

participants

underwent

liver

biopsy

posttreatment

and

of

these

steatosis

improved

in

necroinflammation

in

and

fibrosis

in

However

the

lack

of

a

placebo

group

confounds

these

findings

with

timeinduced

changes

and

complicates

the

interpretation

of

the

potential

effect

of

the

combined

VitC

and

E

treatment

The

effect

of

ursodeoxycholic

acid

UDCA

mgkgday

compared

to

that

of

VitC

mgday

and

VitE

IUday

was

examined

in

a

month

openlabel

randomized

study

Compared

to

baseline

both

treatments

decreased

circulating

levels

of

liver

enzymes

without

inducing

changes

in

liver

echogenicity

Side

effects

were

reported

in

the

UDCA

treated

group

whereas

no

side

effects

were

reported

in

the

vitamin

treated

group

This

is

in

agreement

with

other

studies

reporting

that

VitC

and

E

are

well

tolerated

Foster

and

coworkers

evaluated

the

combination

of

atorvastatin

mgday

VitC

mgday

and

VitE

IUday

CTscans

were

used

to

identify

NAFLD

Subsequently

the

participants

were

divided

into

NAFLD

patients

and

normal

liver

patients

These

two

groups

were

further

allocated

to

either

the

treatment

combination

or

placebo

The

four

groups

were

reexamined

after

and

years

In

patients

without

NALFD

at

baseline

the

treatment

had

no

preventive

effect

However

in

patients

with

NAFLD

active

treatment

significantly

reduced

the

prevalence

of

fatty

liver

This

is

contrary

to

the

result

of

Ersöz

et

al

who

found

no

improvement

in

hepatic

echogenicity

after

months

of

treatment

However

considerably

lower

vitamin

doses

duration

and

different

radiological

methods

were

used

by

Ersöz

et

al

which

may

explain

the

conflicting

results

However

improvements

in

hepatic

steatosis

may

of

cause

in

part

be

contributed

to

atorvastatin

as

hepatic

steatosis

is

associated

with

dyslipidemia

Indeed

active

treatment

with

VitC

VitE

and

atorvastatin

did

reduce

plasma

levels

of

LDL

and

cholesterol

while

HDL

and

TG

levels

remained

unchanged

Furthermore

treatment

with

atorvastatin

mgday

alone

improved

ultrasound

echopatterns

in

NAFLD

patients

Unfortunately

radiological

techniques

are

not

able

to

detect

small

amounts

of

hepatic

steatosis

and

can

therefore

not

distinguish

between

the

different

forms

of

NAFLD

Consequently

the

effect

of

the

treatment

on

more

advanced

stages

of

NAFLD

is

unknown

Go

to

Conclusion

Controlled

animal

experiments

support

a

role

of

VitC

deficiency

in

the

elevation

of

plasma

and

hepatic

lipids

alongside

increased

hepatic

oxidative

stress

fibrosis

and

inflammation

In

agreement

VitC

treatment

of

liver

diseaseinduced

animals

has

been

shown

to

reduce

hepatic

markers

of

oxidative

stress

Clinical

studies

of

the

relationship

between

VitC

deficiency

and

NAFLD

have

not

been

conducted

and

studies

of

estimated

dietary

intakes

of

VitC

in

NAFLD

patients

are

conflicting

Some

studies

show

correlations

between

VitC

intake

and

NAFLD

progression

while

others

do

not

Importantly

only

a

few

studies

have

addressed

VitC

plasma

levels

in

NAFLD

patients

The

presently

available

RCTs

have

not

found

an

effect

of

VitC

superior

to

that

of

placebo

However

a

number

of

studies

do

demonstrate

hepatic

improvements

compared

with

baseline

but

the

use

of

treatmentcocktails

and

concurrent

lifestyle

interventions

seriously

confound

the

analysis

of

VitC

specific

effects

Additionally

most

RCTs

have

not

recorded

or

reported

baseline

VitC

concentrations

and

putative

effects

of

VitC

supplementation

can

not

be

assessed

in

patients

already

saturated

with

VitC

due

to

its

nonlinear

absorption

kinetics

Therefore

the

role

of

VitC

in

NAFLD

should

be

investigated

in

future

RCTs

in

which

plasma

VitC

status

is

controlled

for

Go

to

Acknowledgments

DHI

and

JL

are

supported

by

the

LifePharm

Centre

for

in

Vivo

Pharmacology

Go

to

Author

Contributions

The

manuscript

was

conceived

by

all

authors

DHI

wrote

the

draft

manuscript

which

was

subsequently

edited

by

all

authors

Go

to

Conflicts

of

Interest

The

authors

declare

no

conflict

of

interest

Go

to

References

Ng

M

Fleming

T

Robinson

M

Thomson

B

Graetz

N

Margono

C

Mullany

EC

Biryukov

S

Abbafati

C

Abera

SF

et

al

Global

regional

and

national

prevalence

of

overweight

and

obesity

in

children

and

adults

during

A

systematic

analysis

for

the

global

burden

of

disease

study

Lancet

doi

PMC

free

article

PubMed

Cross

Ref

Bastard

JP

Maachi

M

Lagathu

C

Kim

MJ

Caron

M

Vidal

H

Capeau

J

Feve

B

Recent

advances

in

the

relationship

between

obesity

inflammation

and

insulin

resistance

Eur

Cytokine

Netw

PubMed

Jankovic

A

Korac

A

SrdicGalic

B

Buzadzic

B

Otasevic

V

Stancic

A

Vucetic

M

Markelic

M

Velickovic

K

Golic

I

et

al

Differences

in

the

redox

status

of

human

visceral

and

subcutaneous

adipose

tissuesRelationships

to

obesity

and

metabolic

risk

Metabolism

doi

PubMed

Cross

Ref

Uzun

H

Zengin

K

Taskin

M

Aydin

S

Simsek

G

Dariyerli

N

Changes

in

leptin

plasminogen

activator

factor

and

oxidative

stress

in

morbidly

obese

patients

following

open

and

laparoscopic

swedish

adjustable

gastric

banding

Obes

Surg

doi

PubMed

Cross

Ref

Mathieu

P

Lemieux

I

Despres

JP

Obesity

inflammation

and

cardiovascular

risk

Clin

Pharmacol

Ther

doi

PubMed

Cross

Ref

Qureshi

K

Abrams

GA

Metabolic

liver

disease

of

obesity

and

role

of

adipose

tissue

in

the

pathogenesis

of

nonalcoholic

fatty

liver

disease

World

J

Gastroenterol

doi

PMC

free

article

PubMed

Cross

Ref

Tilg

H

Moschen

AR

Evolution

of

inflammation

in

nonalcoholic

fatty

liver

disease

The

multiple

parallel

hits

hypothesis

Hepatology

doi

PubMed

Cross

Ref

Horoz

M

Bolukbas

C

Bolukbas

FF

Sabuncu

T

Aslan

M

Sarifakiogullari

S

Gunaydin

N

Erel

O

Measurement

of

the

total

antioxidant

response

using

a

novel

automated

method

in

subjects

with

nonalcoholic

steatohepatitis

BMC

Gastroenterol

doi

PMC

free

article

PubMed

Cross

Ref

Da

Silva

VR

Moreira

EA

WilhelmFilho

D

de

Miranda

JX

Beninca

JP

Vigil

SV

Moratelli

AM

Garlet

TR

de

Souza

Meirelles

MS

Vannucchi

H

et

al

Proinflammatory

and

oxidative

stress

markers

in

patients

submitted

to

rouxeny

gastric

bypass

after

year

of

followup

Eur

J

Clin

Nutr

PubMed

Buettner

GR

The

pecking

order

of

free

radicals

and

antioxidants

Lipid

peroxidation

αtocopherol

and

ascorbate

Arch

Biochem

Biophys

doi

PubMed

Cross

Ref

Kivirikko

KI

Myllyla

R

Posttranslational

processing

of

procollagens

Ann

N

Y

Acad

Sci

doi

PubMed

Cross

Ref

Smith

JL

Hodges

RE

Serum

levels

of

vitamin

C

in

relation

to

dietary

and

supplemental

intake

of

vitamin

C

in

smokers

and

nonsmokers

Ann

N

Y

Acad

Sci

doi

PubMed

Cross

Ref

Simon

JA

Hudes

ES

Tice

JA

Relation

of

serum

ascorbic

acid

to

mortality

among

us

adults

J

Am

Coll

Nutr

doi

PubMed

Cross

Ref

Hampl

JS

Taylor

CA

Johnston

CS

Vitamin

C

deficiency

and

depletion

in

the

United

States

The

third

national

health

and

nutrition

examination

survey

to

Am

J

Public

Health

doi

PMC

free

article

PubMed

Cross

Ref

Wrieden

WL

Hannah

MK

BoltonSmith

C

Tavendale

R

Morrison

C

TunstallPedoe

H

Plasma

vitamin

C

and

food

choice

in

the

third

glasgow

monica

population

survey

J

Epidemiol

Commun

Health

doi

PMC

free

article

PubMed

Cross

Ref

Lykkesfeldt

J

Poulsen

HE

Is

vitamin

C

supplementation

beneficial

Lessons

learned

from

randomised

controlled

trials

Br

J

Nutr

doi

PubMed

Cross

Ref

Frei

B

BirlouezAragon

I

Lykkesfeldt

J

Authors

perspective

What

is

the

optimum

intake

of

vitamin

C

in

humans

Crit

Rev

Food

Sci

Nutr

doi

PubMed

Cross

Ref

TvedenNyborg

P

Lykkesfeldt

J

Does

vitamin

C

deficiency

increase

lifestyleassociated

vascular

disease

progression

Evidence

based

on

experimental

and

clinical

studies

Antioxid

Redox

Signal

doi

PubMed

Cross

Ref

Aasheim

ET

Hofso

D

Hjelmesaeth

J

Birkeland

KI

Bohmer

T

Vitamin

status

in

morbidly

obese

patients

A

crosssectional

study

Am

J

Clin

Nutr

PubMed

Canoy

D

Wareham

N

Welch

A

Bingham

S

Luben

R

Day

N

Khaw

KT

Plasma

ascorbic

acid

concentrations

and

fat

distribution

in

british

men

and

women

in

the

european

prospective

investigation

into

cancer

and

nutrition

norfolk

cohort

study

Am

J

Clin

Nutr

PubMed

Johnston

CS

Beezhold

BL

Mostow

B

Swan

PD

Plasma

vitamin

C

is

inversely

related

to

body

mass

index

and

waist

circumference

but

not

to

plasma

adiponectin

in

nonsmoking

adults

J

Nutr

PubMed

Mah

E

Matos

MD

Kawiecki

D

Ballard

K

Guo

Y

Volek

JS

Bruno

RS

Vitamin

C

status

is

related

to

proinflammatory

responses

and

impaired

vascular

endothelial

function

in

healthy

collegeaged

lean

and

obese

men

J

Am

Diet

Assoc

doi

PubMed

Cross

Ref

Sun

K

Kusminski

CM

Scherer

PE

Adipose

tissue

remodeling

and

obesity

J

Clin

Investig

doi

PMC

free

article

PubMed

Cross

Ref

Bano

G

Glucose

homeostasis

obesity

and

diabetes

Best

Pract

Res

Clin

Obstet

Gynaecol

doi

PubMed

Cross

Ref

Furukawa

S

Fujita

T

Shimabukuro

M

Iwaki

M

Yamada

Y

Nakajima

Y

Nakayama

O

Makishima

M

Matsuda

M

Shimomura

I

Increased

oxidative

stress

in

obesity

and

its

impact

on

metabolic

syndrome

J

Clin

Investig

doi

PMC

free

article

PubMed

Cross

Ref

Odegaard

JI

Chawla

A

Pleiotropic

actions

of

insulin

resistance

and

inflammation

in

metabolic

homeostasis

Science

doi

PMC

free

article

PubMed

Cross

Ref

Stumvoll

M

Goldstein

BJ

van

Haeften

TW

Type

diabetes

Principles

of

pathogenesis

and

therapy

Lancet

doi

PubMed

Cross

Ref

Wisse

BE

The

inflammatory

syndrome

The

role

of

adipose

tissue

cytokines

in

metabolic

disorders

linked

to

obesity

J

Am

Soc

Nephrol

doi

PubMed

Cross

Ref

Sabio

G

Das

M

Mora

A

Zhang

Z

Jun

JY

Ko

HJ

Barrett

T

Kim

JK

Davis

RJ

A

stress

signaling

pathway

in

adipose

tissue

regulates

hepatic

insulin

resistance

Science

doi

PMC

free

article

PubMed

Cross

Ref

Farnier

C

Krief

S

Blache

M

DiotDupuy

F

Mory

G

Ferre

P

Bazin

R

Adipocyte

functions

are

modulated

by

cell

size

change

Potential

involvement

of

an

integrinerk

signalling

pathway

Int

J

Obes

Relat

Metab

Disord

doi

PubMed

Cross

Ref

Mittelman

SD

van

Citters

GW

Kirkman

EL

Bergman

RN

Extreme

insulin

resistance

of

the

central

adipose

depot

in

vivo

Diabetes

doi

PubMed

Cross

Ref

Nguyen

MT

Favelyukis

S

Nguyen

AK

Reichart

D

Scott

PA

Jenn

A

LiuBryan

R

Glass

CK

Neels

JG

Olefsky

JM

A

subpopulation

of

macrophages

infiltrates

hypertrophic

adipose

tissue

and

is

activated

by

free

fatty

acids

via

tolllike

receptors

and

and

JNKdependent

pathways

J

Biol

Chem

doi

PubMed

Cross

Ref

Elnakish

MT

Hassanain

HH

Janssen

PM

Angelos

MG

Khan

M

Emerging

role

of

oxidative

stress

in

metabolic

syndrome

and

cardiovascular

diseases

Important

role

of

racnadph

oxidase

J

Pathol

PubMed

Ford

ES

Mokdad

AH

Giles

WH

Brown

DW

The

metabolic

syndrome

and

antioxidant

concentrations

Findings

from

the

third

national

health

and

nutrition

examination

survey

Diabetes

doi

PubMed

Cross

Ref

Lissner

L

Lindroos

AK

Sjostrom

L

Swedish

obese

subjects

SOS

An

obesity

intervention

study

with

a

nutritional

perspective

Eur

J

Clin

Nutr

doi

PubMed

Cross

Ref

Del

Mar

Bibiloni

M

Maffeis

C

Llompart

I

Pons

A

Tur

JA

Dietary

factors

associated

with

subclinical

inflammation

among

girls

Eur

J

Clin

Nutr

doi

PubMed

Cross

Ref

Rose

FJ

Webster

J

Barry

JB

Phillips

LK

Richards

AA

Whitehead

JP

Synergistic

effects

of

ascorbic

acid

and

thiazolidinedione

on

secretion

of

high

molecular

weight

adiponectin

from

human

adipocytes

Diabetes

Obes

Metab

doi

PubMed

Cross

Ref

AfkhamiArdekani

M

ShojaoddinyArdekani

A

Effect

of

vitamin

C

on

blood

glucose

serum

lipids

serum

insulin

in

type

diabetes

patients

Indian

J

Med

Res

PubMed

Soares

AF

Guichardant

M

Cozzone

D

BernoudHubac

N

BouzaidiTiali

N

Lagarde

M

Geloen

A

Effects

of

oxidative

stress

on

adiponectin

secretion

and

lactate

production

in

adipocytes

Free

Radic

Biol

Med

doi

PubMed

Cross

Ref

Hui

JM

Hodge

A

Farrell

GC

Kench

JG

Kriketos

A

George

J

Beyond

insulin

resistance

in

NASH

TNFα

or

adiponectin

Hepatology

doi

PubMed

Cross

Ref

Chalasani

N

Younossi

Z

Lavine

JE

Diehl

AM

Brunt

EM

Cusi

K

Charlton

M

Sanyal

AJ

The

diagnosis

and

management

of

nonalcoholic

fatty

liver

disease

Practice

guideline

by

the

american

gastroenterological

association

american

association

for

the

study

of

liver

diseases

and

american

college

of

gastroenterology

Gastroenterology

doi

PubMed

Cross

Ref

Bechmann

LP

Hannivoort

RA

Gerken

G

Hotamisligil

GS

Trauner

M

Canbay

A

The

interaction

of

hepatic

lipid

and

glucose

metabolism

in

liver

diseases

J

Hepatol

doi

PubMed

Cross

Ref

Hebbard

L

George

J

Animal

models

of

nonalcoholic

fatty

liver

disease

Nat

Rev

Gastroenterol

Hepatol

doi

PubMed

Cross

Ref

Adams

LA

Sanderson

S

Lindor

KD

Angulo

P

The

histological

course

of

nonalcoholic

fatty

liver

disease

A

longitudinal

study

of

patients

with

sequential

liver

biopsies

J

Hepatol

doi

PubMed

Cross

Ref

Ekstedt

M

Franzen

LE

Mathiesen

UL

Thorelius

L

Holmqvist

M

Bodemar

G

Kechagias

S

Longterm

followup

of

patients

with

NAFLD

and

elevated

liver

enzymes

Hepatology

doi

PubMed

Cross

Ref

Bugianesi

E

Leone

N

Vanni

E

Marchesini

G

Brunello

F

Carucci

P

Musso

A

de

Paolis

P

Capussotti

L

Salizzoni

M

et

al

Expanding

the

natural

history

of

nonalcoholic

steatohepatitis

From

cryptogenic

cirrhosis

to

hepatocellular

carcinoma

Gastroenterology

doi

PubMed

Cross

Ref

Angelico

F

del

Ben

M

Conti

R

Francioso

S

Feole

K

Fiorello

S

Cavallo

MG

Zalunardo

B

Lirussi

F

Alessandri

C

et

al

Insulin

resistance

the

metabolic

syndrome

and

nonalcoholic

fatty

liver

disease

J

Clin

Endocrinol

Metab

doi

PubMed

Cross

Ref

Marchesini

G

Bugianesi

E

Forlani

G

Cerrelli

F

Lenzi

M

Manini

R

Natale

S

Vanni

E

Villanova

N

Melchionda

N

et

al

Nonalcoholic

fatty

liver

steatohepatitis

and

the

metabolic

syndrome

Hepatology

doi

PubMed

Cross

Ref

Luyckx

FH

Desaive

C

Thiry

A

Dewe

W

Scheen

AJ

Gielen

JE

Lefebvre

PJ

Liver

abnormalities

in

severely

obese

subjects

Effect

of

drastic

weight

loss

after

gastroplasty

Int

J

Obes

Relat

Metab

Disord

doi

PubMed

Cross

Ref

Mohan

V

Farooq

S

Deepa

M

Ravikumar

R

Pitchumoni

CS

Prevalence

of

nonalcoholic

fatty

liver

disease

in

urban

south

indians

in

relation

to

different

grades

of

glucose

intolerance

and

metabolic

syndrome

Diabetes

Res

Clin

Pract

doi

PubMed

Cross

Ref

Abdelmalek

MF

Diehl

AM

Nonalcoholic

fatty

liver

disease

as

a

complication

of

insulin

resistance

Med

Clin

N

Am

doi

PubMed

Cross

Ref

Gaggini

M

Morelli

M

Buzzigoli

E

deFronzo

RA

Bugianesi

E

Gastaldelli

A

Nonalcoholic

fatty

liver

disease

NAFLD

and

its

connection

with

insulin

resistance

dyslipidemia

atherosclerosis

and

coronary

heart

disease

Nutrients

doi

PMC

free

article

PubMed

Cross

Ref

Donnelly

KL

Smith

CI

Schwarzenberg

SJ

Jessurun

J

Boldt

MD

Parks

EJ

Sources

of

fatty

acids

stored

in

liver

and

secreted

via

lipoproteins

in

patients

with

nonalcoholic

fatty

liver

disease

J

Clin

Investig

doi

PMC

free

article

PubMed

Cross

Ref

Bardini

G

Rotella

CM

Giannini

S

Dyslipidemia

and

diabetes

Reciprocal

impact

of

impaired

lipid

metabolism

and

betacell

dysfunction

on

micro

and

macrovascular

complications

Rev

Diabet

Stud

doi

PMC

free

article

PubMed

Cross

Ref

McRae

MP

Vitamin

C

supplementation

lowers

serum

lowdensity

lipoprotein

cholesterol

and

triglycerides

A

metaanalysis

of

randomized

controlled

trials

J

Chiropr

Med

doi

PMC

free

article

PubMed

Cross

Ref

Moschen

AR

Molnar

C

Geiger

S

Graziadei

I

Ebenbichler

CF

Weiss

H

Kaser

S

Kaser

A

Tilg

H

Antiinflammatory

effects

of

excessive

weight

loss

Potent

suppression

of

adipose

interleukin

and

tumour

necrosis

factor

alpha

expression

Gut

doi

PubMed

Cross

Ref

Kamada

Y

Tamura

S

Kiso

S

Matsumoto

H

Saji

Y

Yoshida

Y

Fukui

K

Maeda

N

Nishizawa

H

Nagaretani

H

et

al

Enhanced

carbon

tetrachlorideinduced

liver

fibrosis

in

mice

lacking

adiponectin

Gastroenterology

doi

PubMed

Cross

Ref

Finelli

C

Tarantino

G

What

is

the

role

of

adiponectin

in

obesity

related

nonalcoholic

fatty

liver

disease

World

J

Gastroenterol

doi

PMC

free

article

PubMed

Cross

Ref

Kim

JY

van

de

Wall

E

Laplante

M

Azzara

A

Trujillo

ME

Hofmann

SM

Schraw

T

Durand

JL

Li

H

Li

G

et

al

Obesityassociated

improvements

in

metabolic

profile

through

expansion

of

adipose

tissue

J

Clin

Investig

doi

PMC

free

article

PubMed

Cross

Ref

Park

EJ

Lee

JH

Yu

GY

He

G

Ali

SR

Holzer

RG

Osterreicher

CH

Takahashi

H

Karin

M

Dietary

and

genetic

obesity

promote

liver

inflammation

and

tumorigenesis

by

enhancing

and

TNF

expression

Cell

doi

PMC

free

article

PubMed

Cross

Ref

Tappy

L

Le

KA

Does

fructose

consumption

contribute

to

nonalcoholic

fatty

liver

disease

Clin

Res

Hepatol

Gastroenterol

doi

PubMed

Cross

Ref

Podszun

MC

Grebenstein

N

Spruss

A

Schlueter

T

Kremoser

C

Bergheim

I

Frank

J

Dietary

αtocopherol

and

atorvastatin

reduce

highfatinduced

lipid

accumulation

and

downregulate

protein

in

the

liver

of

guinea

pigs

J

Nutr

Biochem

doi

PubMed

Cross

Ref

Ye

P

Cheah

IK

Halliwell

B

A

highfat

and

cholesterol

diet

causes

fatty

liver

in

guinea

pigs

The

role

of

iron

and

oxidative

damage

Free

Radic

Res

doi

PubMed

Cross

Ref

Coban

J

Evran

B

Ozkan

F

Cevik

A

DogruAbbasoglu

S

Uysal

M

Effect

of

blueberry

feeding

on

lipids

and

oxidative

stress

in

the

serum

liver

and

aorta

of

guinea

pigs

fed

on

a

highcholesterol

diet

Biosci

Biotechnol

Biochem

PubMed

Kim

JE

Clark

RM

Park

Y

Lee

J

Fernandez

ML

Lutein

decreases

oxidative

stress

and

inflammation

in

liver

and

eyes

of

guinea

pigs

fed

a

hypercholesterolemic

diet

Nutr

Res

Pract

doi

PMC

free

article

PubMed

Cross

Ref

Mari

M

Caballero

F

Colell

A

Morales

A

Caballeria

J

Fernandez

A

Enrich

C

FernandezCheca

JC

GarciaRuiz

C

Mitochondrial

free

cholesterol

loading

sensitizes

to

TNF

and

FASmediated

steatohepatitis

Cell

Metab

doi

PubMed

Cross

Ref

Feldstein

AE

Werneburg

NW

Canbay

A

Guicciardi

ME

Bronk

SF

Rydzewski

R

Burgart

LJ

Gores

GJ

Free

fatty

acids

promote

hepatic

lipotoxicity

by

stimulating

TNFα

expression

via

a

lysosomal

pathway

Hepatology

doi

PubMed

Cross

Ref

Basaranoglu

M

Basaranoglu

G

Senturk

H

From

fatty

liver

to

fibrosis

A

tale

of

second

hit

World

J

Gastroenterol

doi

PMC

free

article

PubMed

Cross

Ref

Pessayre

D

Role

of

mitochondria

in

nonalcoholic

fatty

liver

disease

J

Gastroenterol

Hepatol

doi

PubMed

Cross

Ref

Wei

Y

Wang

D

Topczewski

F

Pagliassotti

MJ

Saturated

fatty

acids

induce

endoplasmic

reticulum

stress

and

apoptosis

independently

of

ceramide

in

liver

cells

Am

J

Physiol

Endocrinol

Metab

doi

PubMed

Cross

Ref

Van

Rooyen

DM

Larter

CZ

Yeh

MM

Haigh

WG

Teoh

N

Farrell

GC

Ezetimibe

and

atorvastatin

ameliorate

liver

injury

in

fozfoz

mice

with

NASH

J

Gastroenterol

Hepatol

doi

Cross

Ref

Fujii

H

Kawada

N

Inflammation

and

fibrogenesis

in

steatohepatitis

J

Gastroenterol

doi

PubMed

Cross

Ref

Laurent

A

Nicco

C

Tran

van

Nhieu

J

Borderie

D

Chereau

C

Conti

F

Jaffray

P

Soubrane

O

Calmus

Y

Weill

B

et

al

Pivotal

role

of

superoxide

anion

and

beneficial

effect

of

antioxidant

molecules

in

murine

steatohepatitis

Hepatology

doi

PubMed

Cross

Ref

Farrell

GC

van

Rooyen

D

Gan

L

Chitturi

S

Nash

is

an

inflammatory

disorder

Pathogenic

prognostic

and

therapeutic

implications

Gut

Liver

doi

PMC

free

article

PubMed

Cross

Ref

Narasimhan

S

Gokulakrishnan

K

Sampathkumar

R

Farooq

S

Ravikumar

R

Mohan

V

Balasubramanyam

M

Oxidative

stress

is

independently

associated

with

nonalcoholic

fatty

liver

disease

NAFLD

in

subjects

with

and

without

type

diabetes

Clin

Biochem

doi

PubMed

Cross

Ref

Valdecantos

MP

PerezMatute

P

Quintero

P

Martinez

JA

Vitamin

C

resveratrol

and

lipoic

acid

actions

on

isolated

rat

liver

mitochondria

All

antioxidants

but

different

Redox

Rep

doi

PubMed

Cross

Ref

Musso

G

Gambino

R

de

Michieli

F

Cassader

M

Rizzetto

M

Durazzo

M

Faga

E

Silli

B

Pagano

G

Dietary

habits

and

their

relations

to

insulin

resistance

and

postprandial

lipemia

in

nonalcoholic

steatohepatitis

Hepatology

doi

PubMed

Cross

Ref

Ferolla

SM

Ferrari

TC

Lima

ML

Reis

TO

Tavares

WC

Jr

Couto

OF

Vidigal

PV

Fausto

MA

Couto

CA

Dietary

patterns

in

brazilian

patients

with

nonalcoholic

fatty

liver

disease

A

crosssectional

study

Clinics

doi

PMC

free

article

PubMed

Cross

Ref

Koruk

M

Taysi

S

Savas

MC

Yilmaz

O

Akcay

F

Karakok

M

Oxidative

stress

and

enzymatic

antioxidant

status

in

patients

with

nonalcoholic

steatohepatitis

Ann

Clin

Lab

Sci

PubMed

Videla

LA

Rodrigo

R

Orellana

M

Fernandez

V

Tapia

G

Quinones

L

Varela

N

Contreras

J

Lazarte

R

Csendes

A

et

al

Oxidative

stressrelated

parameters

in

the

liver

of

nonalcoholic

fatty

liver

disease

patients

Clin

Sci

doi

PubMed

Cross

Ref

FrikkeSchmidt

H

Lykkesfeldt

J

Role

of

marginal

vitamin

C

deficiency

in

atherogenesis

In

vivo

models

and

clinical

studies

Basic

Clin

Pharmacol

Toxicol

doi

PubMed

Cross

Ref

Roomi

MW

Association

between

hyperlipidemia

and

hepatic

cytochrome

in

guinea

pigs

Res

Commun

Mol

Pathol

Pharmacol

PubMed

Montano

CE

Fernandez

ML

McNamara

DJ

Regulation

of

apolipoprotein

Bcontaining

lipoproteins

by

vitamin

C

level

and

dietary

fat

saturation

in

guinea

pigs

Metabolism

doi

PubMed

Cross

Ref

Ginter

E

Cerven

J

Nemec

R

Mikus

L

Lowered

cholesterol

catabolism

in

guinea

pigs

with

chronic

ascorbic

acid

deficiency

Am

J

Clin

Nutr

PubMed

Ginter

E

Ascorbic

acid

in

cholesterol

and

bile

acid

metabolism

Ann

N

Y

Acad

Sci

doi

PubMed

Cross

Ref

Sharma

P

Pramod

J

Sharma

PK

Sapra

M

Manorma

Kothari

LK

Effect

of

vitamin

C

deficiency

and

excess

on

the

liver

A

histopathological

and

biochemical

study

in

guinea

pigs

fed

normal

or

high

cholesterol

diet

Indian

J

Pathol

Microbiol

PubMed

FrikkeSchmidt

H

TvedenNyborg

P

Birck

MM

Lykkesfeldt

J

High

dietary

fat

and

cholesterol

exacerbates

chronic

vitamin

C

deficiency

in

guinea

pigs

Br

J

Nutr

doi

PubMed

Cross

Ref

Horio

F

Ozaki

K

Oda

H

Makino

S

Hayashi

Y

Yoshida

A

Effect

of

dietary

ascorbic

acid

cholesterol

and

PCB

on

cholesterol

concentrations

in

serum

and

liver

in

a

rat

mutant

unable

to

synthesize

ascorbic

acid

J

Nutr

PubMed

Uchida

K

Nomura

Y

Takase

H

Tasaki

T

Seo

S

Hayashi

Y

Takeuchi

N

Effect

of

vitamin

C

depletion

on

serum

cholesterol

and

lipoprotein

levels

in

ODS

odod

rats

unable

to

synthesize

ascorbic

acid

J

Nutr

PubMed

Fernandez

ML

Guinea

pigs

as

models

for

cholesterol

and

lipoprotein

metabolism

J

Nutr

PubMed

Yang

R

Guo

P

Song

X

Liu

F

Gao

N

Hyperlipidemic

guinea

pig

model

Mechanisms

of

triglyceride

metabolism

disorder

and

comparison

to

rat

Biol

Pharm

Bull

doi

PubMed

Cross

Ref

Barja

G

LopezTorres

M

PerezCampo

R

Rojas

C

Cadenas

S

Prat

J

Pamplona

R

Dietary

vitamin

C

decreases

endogenous

protein

oxidative

damage

malondialdehyde

and

lipid

peroxidation

and

maintains

fatty

acid

unsaturation

in

the

guinea

pig

liver

Free

Radic

Biol

Med

doi

PubMed

Cross

Ref

Mori

T

Kitamura

R

Imaoka

S

Funae

Y

Kitada

M

Kamataki

T

Examination

for

lipid

peroxidation

in

liver

microsomes

of

guinea

pigs

as

a

causal

factor

in

the

decrease

in

the

content

of

cytochrome

due

to

ascorbic

acid

deficiency

Res

Commun

Chem

Pathol

Pharmacol

PubMed

Amano

A

Sato

Y

Kishimoto

Y

Takahashi

K

Handa

S

Aigaki

T

Maruyama

N

Ishigami

A

Effects

of

ascorbic

acid

deficiency

on

protein

and

lipid

oxidation

in

livers

from

knockout

mice

J

Nutr

Sci

Vitaminol

doi

PubMed

Cross

Ref

Pierce

MR

Diasio

DL

Rodrigues

LM

Harrison

FE

May

JM

Combined

vitamin

C

and

E

deficiency

induces

motor

defects

in

gulo

mice

Nutr

Neurosci

doi

PMC

free

article

PubMed

Cross

Ref

Harrison

FE

Meredith

ME

Dawes

SM

Saskowski

JL

May

JM

Low

ascorbic

acid

and

increased

oxidative

stress

in

gulo

mice

during

development

Brain

Res

doi

PMC

free

article

PubMed

Cross

Ref

Horio

F

Kiyama

K

Kobayashi

M

Kawai

K

Tsuda

T

Ascorbic

acid

deficiency

stimulates

hepatic

expression

of

inflammatory

chemokine

cytokineinduced

neutrophil

in

scurvyprone

ODS

rats

J

Nutr

Sci

Vitaminol

doi

PubMed

Cross

Ref

AlSerri

A

Anstee

QM

Valenti

L

Nobili

V

Leathart

JB

Dongiovanni

P

Patch

J

Fracanzani

A

Fargion

S

Day

CP

et

al

The

polymorphism

influences

NAFLD

fibrosis

severity

Evidence

from

casecontrol

and

intrafamilial

allele

association

studies

J

Hepatol

doi

PubMed

Cross

Ref

Seki

S

Kitada

T

Yamada

T

Sakaguchi

H

Nakatani

K

Wakasa

K

In

situ

detection

of

lipid

peroxidation

and

oxidative

DNA

damage

in

nonalcoholic

fatty

liver

diseases

J

Hepatol

doi

PubMed

Cross

Ref

Rezazadeh

A

Yazdanparast

R

Molaei

M

Amelioration

of

dietinduced

nonalcoholic

steatohepatitis

in

rats

by

Mnsalen

complexes

via

reduction

of

oxidative

stress

J

Biomed

Sci

doi

PMC

free

article

PubMed

Cross

Ref

Rezazadeh

A

Yazdanparast

R

Prevention

of

nonalcoholic

steatohepatitis

in

rats

by

two

manganesesalen

complexes

Iran

Biomed

J

PMC

free

article

PubMed

Oliveira

CP

Gayotto

LC

Tatai

C

Della

Nina

BI

Lima

ES

Abdalla

DS

Lopasso

FP

Laurindo

FR

Carrilho

FJ

Vitamin

C

and

vitamin

E

in

prevention

of

nonalcoholic

fatty

liver

disease

NAFLD

in

choline

deficient

diet

fed

rats

Nutr

J

doi

PMC

free

article

PubMed

Cross

Ref

Nambisan

B

Kurup

PA

Ascorbic

acid

and

glycosaminoglycan

and

lipid

metabolism

in

guinea

pigs

fed

normal

and

atherogenic

diets

Atherosclerosis

doi

PubMed

Cross

Ref

Hathcock

JN

Azzi

A

Blumberg

J

Bray

T

Dickinson

A

Frei

B

Jialal

I

Johnston

CS

Kelly

FJ

Kraemer

K

et

al

Vitamins

E

and

C

are

safe

across

a

broad

range

of

intakes

Am

J

Clin

Nutr

PubMed

The

National

Academies

Institute

of

Medicine

Dietary

Reference

Intakes

for

Vitamin

C

Vitamin

E

Selenium

and

Carotenoids

The

National

Academies

Press

Washington

DC

USA

Monsen

ER

Dietary

reference

intakes

for

the

antioxidant

nutrients

Vitamin

C

vitamin

E

selenium

and

carotenoids

J

Am

Diet

Assoc

doi

PubMed

Cross

Ref

Johnson

RK

Dietary

intakeHow

do

we

measure

what

people

are

really

eating

Obes

Res

doi

PubMed

Cross

Ref

Han

JM

Jo

AN

Lee

SM

Bae

HS

Jun

DW

Cho

YK

Suk

KT

Yoon

JH

Ahn

SB

Cho

YJ

et

al

Associations

between

intakes

of

individual

nutrients

or

whole

food

groups

and

nonalcoholic

fatty

liver

disease

among

korean

adults

J

Gastroenterol

Hepatol

doi

PubMed

Cross

Ref

Vos

MB

Colvin

R

Belt

P

Molleston

JP

Murray

KF

Rosenthal

P

Schwimmer

JB

Tonascia

J

Unalp

A

Lavine

JE

Correlation

of

vitamin

E

uric

acid

and

diet

composition

with

histologic

features

of

pediatric

NAFLD

J

Pediatr

Gastroenterol

Nutr

doi

PMC

free

article

PubMed

Cross

Ref

Mager

DR

Patterson

C

So

S

Rogenstein

CD

Wykes

LJ

Roberts

EA

Dietary

and

physical

activity

patterns

in

children

with

fatty

liver

Eur

J

Clin

Nutr

doi

PubMed

Cross

Ref

Da

Silva

HE

Arendt

BM

Noureldin

SA

Therapondos

G

Guindi

M

Allard

JP

A

crosssectional

study

assessing

dietary

intake

and

physical

activity

in

canadian

patients

with

nonalcoholic

fatty

liver

disease

vs

healthy

controls

J

Acad

Nutr

Diet

doi

PubMed

Cross

Ref

Madan

K

Bhardwaj

P

Thareja

S

Gupta

SD

Saraya

A

Oxidant

stress

and

antioxidant

status

among

patients

with

nonalcoholic

fatty

liver

disease

NAFLD

J

Clin

Gastroenterol

doi

PubMed

Cross

Ref

Canbakan

B

Senturk

H

Tahan

V

Hatemi

I

Balci

H

Toptas

T

Sonsuz

A

Velet

M

Aydin

S

Dirican

A

et

al

Clinical

biochemical

and

histological

correlations

in

a

group

of

nondrinker

subjects

with

nonalcoholic

fatty

liver

disease

Acta

GastroEnterol

Belgica

PubMed

Dehghan

M

AkhtarDanesh

N

McMillan

CR

Thabane

L

Is

plasma

vitamin

C

an

appropriate

biomarker

of

vitamin

C

intake

A

systematic

review

and

metaanalysis

Nutr

J

doi

PMC

free

article

PubMed

Cross

Ref

Levine

M

ConryCantilena

C

Wang

Y

Welch

RW

Washko

PW

Dhariwal

KR

Park

JB

Lazarev

A

Graumlich

JF

King

J

et

al

Vitamin

C

pharmacokinetics

in

healthy

volunteers

Evidence

for

a

recommended

dietary

allowance

Proc

Natl

Acad

Sci

USA

doi

PMC

free

article

PubMed

Cross

Ref

Pfister

R

Sharp

SJ

Luben

R

Wareham

NJ

Khaw

KT

Plasma

vitamin

C

predicts

incident

heart

failure

in

men

and

women

in

european

prospective

investigation

into

cancer

and

nutritionnorfolk

prospective

study

Am

Heart

J

doi

PubMed

Cross

Ref

Nobili

V

Manco

M

Devito

R

Ciampalini

P

Piemonte

F

Marcellini

M

Effect

of

vitamin

E

on

aminotransferase

levels

and

insulin

resistance

in

children

with

nonalcoholic

fatty

liver

disease

Aliment

Pharmacol

Ther

doi

PubMed

Cross

Ref

Nobili

V

Manco

M

Devito

R

di

Ciommo

V

Comparcola

D

Sartorelli

MR

Piemonte

F

Marcellini

M

Angulo

P

Lifestyle

intervention

and

antioxidant

therapy

in

children

with

nonalcoholic

fatty

liver

disease

A

randomized

controlled

trial

Hepatology

vitamin c deficiency
fatty liver disease development
obesity