Loss of Insulin Signaling in Hepatocytes Leads to Severe Insulin Resistance and Progressive Hepatic Dysfunction

Abstract

The liver plays a central role in the control of glucose homeostasis and is subject to complex regulation by substrates, insulin, and other hormones. To investigate the effect of the loss of direct insulin action in liver, we have used the Cre-loxP system to inactivate the insulin receptor gene in hepatocytes. Liver-specific insulin receptor knockout (LIRKO) mice exhibit dramatic insulin resistance, severe glucose intolerance, and a failure of insulin to suppress hepatic glucose production and to regulate hepatic gene expression. These alterations are paralleled by marked hyperinsulinemia due to a combination of increased insulin secretion and decreased insulin clearance. With aging, the LIRKO liver exhibits morphological and functional changes, and the metabolic phenotype becomes less severe. Thus, insulin signaling in liver is critical in regulating glucose homeostasis and maintaining normal hepatic function.

Phosphoinositide 3-kinase regulatory subunit p85α suppresses insulin action via positive regulation of PTEN

“…Mice with a liver-specific deletion of Pik3r1 were generated via the Cre-loxP system by crossing animals carrying a floxed exon 7, which encodes the N-terminal SH2 domain common to all three transcripts, p85␣, p55␣, and p50␣ (16), with mice carrying the Cre transgene driven by the albumin promoter (17). The presence of loxP sites in the Pik3r1 gene did not affect expression of p85␣ in mice lacking albumin-Cre (16), nor did the presence of albumin-Cre affect p85 expression in mice lacking loxP sites (18). The L-Pik3r1KO mice were born in a normal Mendelian distribution and exhibited normal postnatal growth (data not shown).…”

Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse

“…Because liver is the primary site for insulin clearance (19,38), insulin resistance caused by increased SOCS proteins in liver may lead to persistent hyperinsulinemia that further exacerbates insulin resistance (19,38,39). Thus, increased SOCS proteins concordantly increase fatty acid synthesis by up-regulation of SREBP-1c expression presumably through suppression of STAT3 phosphorylation and persistent hyperinsulinemia even in the fasting state.…”

“…Polyclonal anti-SOCS-1, anti-SOCS-3, anti-STAT3, anti-STAT5, and anti-Akt1͞2 antibodies were purchased from Santa Cruz Biotechnology, whereas polyclonal antiphospho-STAT3 and antiphospho-STAT5 antibodies were purchased from Cell Signaling Technology (Beverly, MA). Polyclonal anti-IRS-1, anti-IRS-2, and antiinsulin receptor antibodies were generated as described (19). Monoclonal antiphosphotyrosine antibody was purchased from Upstate Biotechnology (Lake Placid, NY).…”

Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1

“…In particular, the liver functions as a major metabolic buffering system that controls macro-and micronutrient homeostasis, allowing other tissues to function normally under physiological stresses (1)(2)(3). Among its many functions, production of glucose by the liver is an essential process that contributes to normalization of systemic glucose levels (4,5), ensuring that glucose-dependent tissues such as brain and red blood cells will have access to an energy supply during periods of nutrient deprivation.…”