People with low levels of high density lipoprotein cholesterol (HDLC) and apolipoprotein A-I (ApoA-I) have a higher risk of cardiovascular disease. Low levels of HDLC are common in individuals who are insulin resistant (IR), e.g., with metabolic syndrome and type 2 diabetes mellitus (T2DM). Despite the high prevalence of these two disorders, very little work has been reported regarding the molecular pathways linking insulin signaling or action and the levels of either HDLC or ApoA-1. We reported previously that liver specific insulin receptor (InsR) knockout mice (LIRKO) have markedly reduced plasma HDLC levels that increase after restoration of hepatic Akt signaling. In the present study, we created acute LIRKO mice by injecting an albumin-Cre adenovirus (Ad) into InsR floxed mice and observed marked reductions in HDLC, the expression of ApoA-I, and the expression of the gene coding Type1 iodothyronine deiodinase1, a selenoenzyme expressed highly in the liver that converts thyroxine to 3,5,3’-triiodothyronine (T3) or reverse T3. Deiodinase 1 knockout mice also had significantly reduced hepatic ApoA-I mRNA levels. Overexpression of Dio1 in LIRKO restored HDLC and significantly increased the expression of ApoA-I mRNA. In vitro studies showed that the expression of ApoA-I was significantly reduced after knockdown of either InsR or Dio1 expression in HepG2 cells. Moreover, overexpression of Dio1 restored ApoA-I promoter activity that had been decreased by knockdown of InsR. Deletion analysis of ApoAI promoter regions showed that insulin signaling regulated ApoA-I expression by acting on a region which does not contain any thyroid response elements. Pulse-chase experiments in HepG2 cells showed that deficiency of insulin signaling resulted in decreased synthesis and secretion of ApoAI. Our results indicates that defective hepatic insulin signaling results in reduced expression of Dio1 which, in turn, leads to reduced expression of ApoA-I and decreased synthesis and secretion of ApoA-I from hepatocytes. We believe our studies have defined a novel pathway from insulin signaling to ApoA-I synthesis that may lead to new approaches for increasing HDL levels in people with defective insulin signaling.
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