Ethanol inhibits hepatocyte proliferation in insulin receptor substrate 1 transgenic mice

Background & Aims: Long-term ethanol consumption is known to impair the abi lity of the liver to regenerate, but the molecular mechanisms are poorly un derstood. Multiple growth factors promote hepatocyte proliferation, some of which involve the insulin receptor substrate 1 (IRS-1)-mediated signal tra nsduction pathway. To explore effects of ethanol on the IRS-1 signal liver growth in vivo, studies in transgenic mice overexpressing IRS-1 in the live r were performed because these mice show constitutive activation of the dow nstream signal transduction pathways leading to enhanced hepatocyte prolife ration. Methods: Tyrosyl phosphorylation of IRS-1 and subsequent protein-pr otein interactions were examined in liver lysates from animals fed ethanol or control diet. Activity of phosphatidylinositol-3 kinase (Pl3K) and mitog en-activated protein kinase (MAPK) was assessed by specific enzymatic assay s. Hepatocyte proliferation was measured by incorporation of [H-3]thymidine into liver DNA. Results: Tyrosyl phosphorylation of IRS-1, association of IRS-1 with Pl3K, and activation of downstream Pl3K and MAPK pathways were g reatly reduced as a result of long-term ethanol consumption, Ethanol virtua lly abolished the enhanced hepatocyte DNA synthesis induced by expression o f the IRS-1 transgene, Conclusions: Altered transmission of growth signals through the IRS-1-mediated signal transduction cascade may represent a mole cular mechanism of how ethanol inhibits hepatocyte proliferation.