tty acid like linolenic acid, oxidized fatty acid, eicosanoids (8S-HETE, LT B4||fatty acid catabolism - FA transport, FA oxidation in peroxisomes and mitochondria,|
|γ||adipose cells, some in colon||15-deoxy-D-prostaglandin J2||storage of fatty acids - lipoprotein lipase, adipocyte FA binding protein, FA transport; acyl CoA synthase|
Fatty acids are oxidized when food is scarce, but are stored as triacylglycerides when they are abundant. PPARs α and γ have differential effects in the fed and fasting states:
|Organ||Fed: Synthesize FA, triacylglycerides. CHO and fat in circulation Increased PPAR||Fasting: oxidize FA, break down triacylglycerides Increased PPAR|
Glc taken up by liver where it can be stored as glycogen. If glycogen reserves are high, Glc is funneled through glycolysis to pyruvate then to acetyl-CoA. Acetyl CoA then is used in the synthesis of fatty acid, which are esterifed to glycerol to form TAGs. These leave liver as VLDL (very low density lipoprotein). Sterol response element binding protein (SREBP) levels increase, leading to increase in transcription of genes involved in above processes.
FAs oxidized to Acetyl-CoA. Ketone bodies increase. Stimulated by increased expression of PPAR-α in fasting state. Increased FAs in liver (headed toward oxidation) might bind to PPAR-α and increase its activity. (αβcosθ)
|SREBP and PPAR-γ levels increases (from insulin signaling). Also SREBP activates PPAR-γgene transcription. Lead to uptake of Glc and FA into fat cells (through stimulation of breakdown of blood TAGs, to fatty acids which can be imported into fat cells. Glc through glycolysis to glyceraldehyde 3P which with FAs are converted to TAGs. Increased TAGs lead to leptin release by adipocytes. (This hormone leads to decreasing storage of TAGs. _(AG)||SREBP and PPAR-γ levels lows. TAGs converted to glycerol and FA, mostly for export; Some however reesterifies from FA and glycerol made reverse of glycolytic pathway, called gluconeogenesis; Transcription of an important enzyme in this pathway, PEPCK, is activated under control of PPAR-γ|
Drugs that bind to and either mimic (agonist) PPAR -αorγ effects are useful therapeutically in conditions characterized by lipid abnormalities (diabetes, cardiovascular disease). Drugs that bind to and activate PPAR-g (Rezulin, Avandia) can lower blood glucose levels and are used to treat type II diabetes. Drugs that activate PPAR-a (fibrates like gemfibrozil) can lower serum triglycerides (by stimulating liver fatty acid oxidation). Both drugs ultimately lower serum lipids.
PPARs also have an effect on plasma lipoprotein (LDL, HDL) levels. Both also might have a role in inflammation, which can promote cardiovascular disease. Fibrates, which interact with PPAR-a , appear to inhibit the inflammatory response mediated by the immune system by decreasing the release of protein "hormones" or cytokines, from stimulated immune cells.
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