Nouvelles fonctions du co-activateur transcriptionnel PGC1A dans le foie
The inability of the liver to respond to metabolic stresses such as high fat diets causes the development of non-alcoholic fatty liver disease (NAFLD). It is a liver disease that affects 25% of the population of industrialized countries. It can progress to a more severe stage: steatohepatitis, characterized by inflammation, oxidative stress and fibrosis. Non-alcoholic fatty liver disease is strongly associated with the development of insulin resistance, that is, the body's inability to respond to insulin, and with type 2 diabetes. NAFLD is difficult to diagnose early and we lack tools to understand molecular mechanisms underlying its progression. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is a transcriptional coactivator, able to bind to transcription factors to regulate their function in response to metabolic stresses. Reduction of PGC1A expression in the liver has been associated with the development of insulin resistance and NAFLD. Moreover, genetic variants of PGC1A are also associated with the development of type diabetes and NASH. However, the causal role of PGC1A in the development of these diseases, and its role in molecular mechanisms of hepatic insulin response are unclear. We hypothesized that lack of PGC1A expression in the liver aggravates the progression of NAFLD to steatohepatitis and affects the liver's response to insulin. In this thesis, we show that PGC1A is necessary for the hepatic response to oxidative stress - especially in female mice. Indeed, PGC1A is able to bind to the estrogen receptor to induce the cellular antioxidant response. Lack of PGC1A causes liver damage and the appearance of severe steatohepatitis. We also show that PGC1A controls the hepatic response to insulin during fasting by modifying the adapter proteins Insulin Receptor Substrate 1 and Insulin Receptor Substrate 2. Finally, by proteomic methods, we have discovered potential biomarkers of NAFLD. This would allow the development of an early diagnosis method of the disease.  In conclusion, this thesis sheds new light on the activity of PGC1A in the liver in response to metabolic stress and its importance for liver health.
Pgc1a Glucagon Ppargc1a Biomarker Steatosis Liver Steatohepatitis Insulin Diabetes