1580-P: FoxO1 Functions to Suppress Hepatic Stellate Cell Activation and Protect against Nonalcoholic Steatohepatitis

Nonalcoholic steatohepatitis (NASH) is characterized by hepatic inflammation, steatosis and fibrosis. NASH concomitant with its cardiometabolic comorbidities is an underlying cause for the liver-associated mortalities. Critical for the etiology of NASH is the activation of hepatic stellate cells, liver-resident pericytes that account for 5-10% of the cell population in liver. HSCs remain quiescent in normal physiology, but become activated in response to hepatic inflammation and steatosis. Activated HSCs are primed for increased synthesis and secretion of collagen, contributing to the formation of extracellular matrix in the liver. This effect catalyzes the conversion of nonalcoholic fatty liver (NAFL) to NASH. To gain mechanistic insights into HSC activation, we investigated hepatic regulation of HSC homeostasis by FoxO1, a key transcription factor that mediates insulin and cytokine action on hepatic inflammation and steatosis (PMID:35700043). We found that FoxO1 expression, which remains at a baseline in quiescent HSCs in normal mice, is markedly upregulated in activated HSCs in mice with diet-induced NAFL. We generated HSC-conditional FoxO1-knockout mice, revealing that FoxO1-deficient HSCs, relative to wild-type HSCs, were more susceptible to undergoing HSC activation in response to hepatic inflammation and steatosis. This effect contributed to the development of severe liver fibrosis in HSC-FoxO1-knockout vs. wild-type mice, when fed a NASH-inducing diet. Mechanistically, FoxO1 acts to suppress HSC activation by counteracting TGF-beta, a multifunctional cytokine whose paracrine action on HSCs contributes to HSC activation in NASH. We conclude that FoxO1 is pivotal for safeguarding HSCs against abnormal activation to stem the evolution of NAFL to NASH.