Ethanol inhibits hepatocyte proliferation in insulin receptor substrate 1 transgenic mice.
OBJECTIVE
Long-term ethanol consumption is known to impair the ability of the liver to regenerate, but the molecular mechanisms are poorly understood. Multiple growth factors promote hepatocyte proliferation, some of which involve the insulin receptor substrate 1 (IRS-1)-mediated signal transduction pathway. To explore effects of ethanol on the IRS-1 signal liver growth in vivo, studies in transgenic mice overexpressing IRS-1 in the liver were performed because these mice show constitutive activation of the downstream signal transduction pathways leading to enhanced hepatocyte proliferation.


METHODS
Tyrosyl phosphorylation of IRS-1 and subsequent protein-protein interactions were examined in liver lysates from animals fed ethanol or control diet. Activity of phosphatidylinositol-3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) was assessed by specific enzymatic assays. Hepatocyte proliferation was measured by incorporation of [3H]thymidine into liver DNA.


RESULTS
Tyrosyl phosphorylation of IRS-1, association of IRS-1 with PI3K, and activation of downstream PI3K and MAPK pathways were greatly reduced as a result of long-term ethanol consumption. Ethanol virtually abolished the enhanced hepatocyte DNA synthesis induced by expression of the IRS-1 transgene.


CONCLUSIONS
Altered transmission of growth signals through the IRS-1-mediated signal transduction cascade may represent a molecular mechanism of how ethanol inhibits hepatocyte proliferation.
Mohr
L
L
Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, USA.
Tanaka
S
S
Wands
J R
JR
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division; D000431:Ethanol / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D008099:Liver / Q000166:cytology* / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000187:drug effects*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011972:Receptor, Insulin / Q000187:drug effects*
D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D000431:Ethanol; D011972:Receptor, Insulin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017027:Protein Tyrosine Phosphatases