Abstract 16553: Hepatic Insulin Signaling Regulates ApoAI gene Expression via Deiodinase Type I

Abstract

High density lipoprotein (HDL) cholesterol (C) and apolipoprotein AI (apoAI) levels are strong predictors of risk for cardiovascular disease (CVD). Low plasma levels of HDLC and apoAI are common in individuals who are insulin resistant with metabolic syndrome or type 2 diabetes mellitus (T2DM), but little is known about the regulation of HDLC and apoAI levels by insulin signaling. In prior studies, we observed that liver insulin receptor (Insr) knockout mice (LIRKO) had very low plasma HDLC and apoAI levels compared with their controls. HDLC levels were normalized when we restored insulin signaling by expression of constitutively active (CA) AKT1. In the present studies, we found that acute knockdown of hepatic Insr by adenovirus-delivery of albumin-Cre in Insr^flox/flox mice resulted in a marked decrease in the levels of ApoAI and Dio1 mRNA in the liver. Dio1 encodes the Type 1 deiodinase (D1), which can convert thyroxine to 3,5,3’-triiodothyronine (T3). Adenovirus-delivery of Dio1 increased HDLC and apoAI levels in LIRKO mice. D1 knockout mice exhibited a significant reduction in hepatic ApoAI mRNA levels. Knockdown of Insr by siRNA reduced promoter activity of both hDio1 and hApoAI in HepG2 cells. Moreover, knockdown of Dio1 expression also decreased hApoAI promoter activity. Furthermore, overexpression of Dio1 rescued ApoAI promoter activity in HepG2 cells treated with siRNA-Insr. Deletion analysis of a 256 bp ApoAI promoter-luciferase construct indicated that T3 was not playing a role in the regulation of ApoAI gene expression by insulin signaling. Pulse-chase experiments in HepG2 cells showed that deficiency of insulin signaling resulted in decreased synthesis of apoAI. These findings indicate that insulin signaling regulates the expression of both Dio1 and ApoAI, and that Dio1 regulates ApoAI expression. Reductions in ApoAI gene expression may play a significant role in the etiology of low HDL cholesterol levels commonly present in states of insulin resistance or T2DM.