Abstract 506: Hepatic Insulin Signaling Regulates ApoAI Expression Through Type I Deiodinase

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Low HDL cholesterol is a common feature of insulin resistant states such as type 2 diabetes, but little is known about the regulation of HDL cholesterol and apoAI levels by insulin signaling. In prior studies, we observed that liver insulin receptor (Insr) knockout mice (LIRKO) had very low plasma HDL cholesterol and apoAI levels compared with their controls. HDL cholesterol levels were normalized when we restored insulin signaling by expression of constitutively active (CA) AKT1. Acute knock down of hepatic Insr by adenovirus-mediated expression 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. Adenovirus mediated overexpression of Dio1 increased HDL cholesterol and apoAI levels in LIRKO mice. D1 knockout mice exhibited a significant reduction in hepatic ApoAI mRNA levels. In McArdle cells, short interfering (si) RNA-mediated knockdown of Insr reduced both Dio1 and ApoAI mRNA levels. Knockdown of Insr by siRNA reduced luciferase activity of both hDio1 and hApoAI promoter constructs in HepG2 cells. Furthermore, siRNA-mediated knockdown of Dio1 expression also decreased hApoAI luciferase activity. 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 role in the etiology of low HDL cholesterol levels commonly present in states of insulin resistance. Targeting D1 may be a novel way to increase apoAI and HDL cholesterol levels in people with insulin resistance or type 2 diabetes mellitus.