Significance and mechanisms of hepatic ChREBPα induction via post-translational modifications in diet-induced NASH

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Abstract NAFLD is the most common chronic liver disease affecting 10-30% of the general population. Its transition from simple steatosis to non-alcoholic steatohepatitis (NASH) poses a serious health threat due to the eventual progression to cirrhosis and liver failure. Given the fact that liver transplant is the only treatment option for patients at the end stage of NASH, there is an urgent need to understand the molecular mechanisms underlying the development of NASH. So far, both human and animal studies have suggested that chronic suppression of FAO in the liver could be a critical driver in promoting fatty liver disease. Meanwhile, uncontrolled activation of hepatic stellate cells (HSCs) has been identified as the primary source of hepatic fibrogenesis. However, there is a significant knowledge gap regarding whether and how dysregulation of hepatic fatty acid oxidation promotes NASH. Moreover, whether and how hepatic lipid regulators contribute to HSCs activation and liver fibrosis remains unknown. We have gathered evidence hepatic ChREBPα as a novel regulator of fatty acid oxidation in contrast to its canonical role as lipogenic transcriptional factor. Hepatocyte-specific ChREBPα knockout mice are more sensitive to diet induced NASH, whereas hepatic over-expression of ChREBPα protects mice against diet-induced NASH. Our RNA-seq analysis revealed that hepatic deficiency of Chrebpα elevates a panel of pro-fibrogenic factors in the mouse liver after feeding with NASH diet. Our in vitro experiments further demonstrated that Chrebpα-deficient hepatocytes stimulate fibrogenesis of human hepatic stellate cells via secreting factors, suggesting that hepatocyte ChREBPα could influence the microenvironment around hepatic stellate cells and modulate their activities. Based on these intriguing observations, we hypothesize that hepatocyte ChREBPα protects against diet-induced NAFLD/NASH by promoting fatty acid oxidation in hepatocytes and suppressing hepatic stellate cells activation. In this study, we propose to test our hypothesis in three aims: Aim 1 is to examine whether hepatic Chrebpα protects against diet-induced NAFLD/NASH via maintaining fatty acid oxidation pathway. Aim 2 is to determine whether hepatocyte ChREBPα suppresses hepatic stellate cell activation via secreting profibrogenic factors. Aim 3 is to dissect out the signaling and degradation pathways that control ChREBPα expression and activity during NASH. The completion of the proposed study would elucidate in- depth molecular mechanisms of how ChREBPα protects against diet-induced NASH, identify ChREBPα-associated risk factors, and shed light on novel strategies for the prevention and treatment diet-induced NASH.