Type 1 Deiodinase Regulates ApoA-I Gene Expression and ApoA-I Synthesis Independent of Thyroid Hormone Signaling

Arterioscler Thromb Vasc Biol. 2016 Jul;36(7):1356-66. doi: 10.1161/ATVBAHA.116.307330. Epub 2016 May 5.

Abstract

Objective: Plasma levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) are reduced in individuals with defective insulin signaling. Initial studies using liver-specific insulin receptor (InsR) knockout mice identified reduced expression of type 1 deiodinase (Dio1) as a potentially novel link between defective hepatic insulin signaling and reduced expression of the ApoA-I gene. Our objective was to examine the regulation of ApoA-I expression by Dio1.

Approach and results: Acute inactivation of InsR by adenoviral delivery of Cre recombinase to InsR floxed mice reduced HDL-C and expression of both ApoA-I and Dio1. Overexpression of Dio1 in InsR knockout mice restored HDL-C and ApoA-I levels and increased the expression of ApoA-I. Dio1 knockout mice had low expression of ApoA-I and reduced serum levels of HDL-C and ApoA-I. Treatment of C57BL/6J mice with antisense to Dio1 reduced ApoA-I mRNA, HDL-C, and serum ApoA-I. Hepatic 3,5,3'-triiodothyronine content was normal or elevated in InsR knockout mice or Dio1 knockout mice. Knockdown of either InsR or Dio1 by siRNA in HepG2 cells decreased the expression of ApoA-I and ApoA-I synthesis and secretion. siRNA knockdown of InsR or Dio1 decreased activity of a region of the ApoA-I promoter lacking thyroid hormone response elements (region B). Electrophoretic mobility shift assay demonstrated that reduced Dio1 expression decreased the binding of nuclear proteins to region B.

Conclusions: Reductions in Dio1 expression reduce the expression of ApoA-I in a 3,5,3'-triiodothyronine-/thyroid hormone response element-independent manner.

Keywords: apolipoprotein A-I; cholesterol, HDL; electrophoretic mobility shift assay; mice, knockout; response element; type 1 deiodinase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apolipoprotein A-I / blood
  • Apolipoprotein A-I / deficiency
  • Apolipoprotein A-I / genetics
  • Apolipoprotein A-I / metabolism*
  • Cholesterol, HDL / blood
  • Gene Expression Regulation
  • Genotype
  • Hep G2 Cells
  • Humans
  • Iodide Peroxidase / deficiency
  • Iodide Peroxidase / genetics
  • Iodide Peroxidase / metabolism*
  • Liver / enzymology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligonucleotides, Antisense / genetics
  • Oligonucleotides, Antisense / metabolism
  • Phenotype
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, Insulin / deficiency
  • Receptor, Insulin / genetics
  • Response Elements
  • Signal Transduction*
  • Transfection
  • Triiodothyronine / metabolism*

Substances

  • APOA1 protein, human
  • Apolipoprotein A-I
  • Cholesterol, HDL
  • Oligonucleotides, Antisense
  • RNA, Messenger
  • Triiodothyronine
  • Iodide Peroxidase
  • selenodeiodinase type 1, mouse
  • Receptor, Insulin