1574-P: FoxO1 Links Insulin Resistance to Hepatic Inflammation and Catalyzes the Evolution of Benign Steatosis to Nonalcoholic Steatohepatitis

Abstract

Hepatic inflammation is intertwined with insulin resistance and is a causative factor for the transition of benign steatosis to nonalcoholic steatohepatitis (NASH). We found that FoxO1 was markedly upregulated in hepatic macrophages, coinciding with hepatic inflammation and steatosis in dietary obese mice. We generated myeloid-conditional FoxO1-transgenic and FoxO1-knockout mice, two complementary models for determining the effect of FoxO1 gain- vs. loss-of-function on macrophage activation in response to insulin resistance. We found that myeloid FoxO1 gain-of-function aggravated hepatic inflammation in mice in response to overnutrition or endotoxin. In contrast, myeloid FoxO1 loss-of-function skewed macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, accompanied by the reduction of macrophage infiltration in liver. This effect contributed to the suppression of hepatic inflammation and improvement of insulin sensitivity. Despite fat-induced obesity, myeloid-conditional FoxO1-deficient mice were protected from developing hyperglycemia, hyperinsulinemia and glucose intolerance. Furthermore, the improvement in hepatic inflammation and insulin resistance translated into a significant beneficial effect on NASH, culminating in the reduction of hepatic steatosis and fibrosis in myeloid FoxO1-deficient mice on NASH-inducing diet. Human FOXO1 expression was upregulated in inflammatory macrophages in liver, correlating with hepatic inflammation, steatosis and fibrosis in patients with NASH. Mechanistically, FoxO1 counteracts Stat6 to skew macrophage polarization from M2 toward M1 signatures with pro-inflammatory profiles. We concluded that myeloid FoxO1 dysregulation is culpable for linking insulin resistance to abnormal macrophage activation. This effect perpetuates hepatic inflammation and catalyzes the evolution of simple steatosis to NASH. Disclosure S.Lee: None. T.Usman: None. G.Chhetri: None. X.Wang: None. H.Dong: None.