Control of liver fibrosis and failure by insulin resistance and FoxO signaling
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abstract
Overnutrition and excess alcohol intake induce in insulin resistance, a hallmark of type 2 diabetes mellitus, promoting liver fibrosis and failure, of which the mechanisms remain unclear. Insulin receptor substrate --1 and --2 (IRS1, 2) are key mediators of insulin action through activation of protein kinase B (PKB/Akt) to maintain liver function. PKB suppresses a transcription factor Foxo1, inhibiting hepatic glucose production. The mouse liver develops fibrosis and failure when IRS1 and IRS2 are suppressed during insulin resistance and subsequently Akt inactivated and Foxo1 activated. We found that Foxo1 activation promotes liver fibrosis and failure, and stimulates expression and secretion of a cytokine- transforming growth factor ?1 (TGF-?1), a key factor resulting in liver fibrosis and failure. This proposal will test the role of Foxo1 in control of liver fibrosis and failure in animals subject to overnutrition of high fat-diet (HFD), excess alcohol intake, and liver injury, through TGF-?1. We will use genetic approaches to suppress Foxo1 in liver of mice and assess the effect of Foxo1 inhibition on HFD-, excess alcohol-, and liver injury-induced fibrosis and failure. Moreover, we generated a genetically engineered mouse model expressing active Foxo1 to induce liver fibrosis and then examine whether suppression of TGF-?1 blocks the Foxo1-induced liver fibrosis. By inhibiting Foxo1 and its target gene TGF-?1 in hepatocyte and cell-cell communication in liver, we will establish that suppression of Foxo1?TGF-?1 can be developed as a strategy for treating liver fibrosis and failure induced by type 2 diabetes, excess alcohol intake and liver injury.
