Non-receptor-mediated actions are responsible for the lipid-lowering effects of iodothyronines in FaO rat hepatoma cells

J Endocrinol. 2011 Jul;210(1):59-69. doi: 10.1530/JOE-11-0074. Epub 2011 Apr 20.

Abstract

Iodothyronines influence lipid metabolism and energy homeostasis. Previous studies demonstrated that 3,5-l-diiodothyronine (T(2)), as well as 3,3',5-L-triiodothyronine (T(3)), was able to both prevent and reverse hepatic steatosis in rats fed a high-fat diet, and this effect depends on a direct action of iodothyronines on the hepatocyte. However, the involvement of thyroid hormone receptors (TRs) in mediating the lipid-lowering effect of iodothyronines was not elucidated. In this study, we investigated the ability of T(2) and T(3) to reduce the lipid overloading using the rat hepatoma FaO cells defective for functional TRs. The absence of constitutive mRNA expression of both TRα1 and TRβ1 in FaO cells was verified by RT-qPCR. To mimic the fatty liver condition, FaO cells were treated with a fatty acid mixture and then exposed to pharmacological doses of T(2) or T(3) for 24 h. Lipid accumulation, mRNA expression of the peroxisome proliferator-activated receptors (PPAR-α, -γ, -δ) the acyl-CoA oxidase (AOX), and the stearoyl CoA desaturase (SCD1), as well as fuel-stimulated O(2) consumption in intact cells, were evaluated. Lipid accumulation was associated with an increase in triacylglycerol content, PPARγ mRNA expression, and a decrease in PPARδ and SCD1 mRNA expression. The addition of T(2) or T(3) to lipid-overloaded cells resulted in i) reduction in lipid content; ii) downregulation of PPARα, PPARγ, and AOX expression; iii) increase in PPARδ expression; and iv) stimulation of mitochondrial uncoupling. These data demonstrate, for the first time, that in the hepatocyte, the lipid-lowering actions of both T(2) and T(3) are not mediated by TRs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Oxidase / genetics
  • Aldehyde Oxidase / metabolism
  • Animals
  • Carcinoma, Hepatocellular / metabolism
  • Cell Line, Tumor
  • Diiodothyronines / pharmacology*
  • Fatty Liver / drug therapy*
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Gene Expression Regulation / drug effects
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Hypolipidemic Agents / pharmacology*
  • Liver Neoplasms / metabolism
  • PPAR delta / genetics
  • PPAR delta / metabolism
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Receptors, Thyroid Hormone / genetics
  • Receptors, Thyroid Hormone / metabolism
  • Stearoyl-CoA Desaturase / genetics
  • Stearoyl-CoA Desaturase / metabolism
  • Thyroid Hormone Receptors alpha / genetics
  • Thyroid Hormone Receptors alpha / metabolism
  • Thyroid Hormone Receptors beta / genetics
  • Thyroid Hormone Receptors beta / metabolism
  • Triiodothyronine, Reverse / pharmacology*
  • Uncoupling Agents / pharmacology*

Substances

  • Diiodothyronines
  • Hypolipidemic Agents
  • PPAR delta
  • PPAR gamma
  • RNA, Messenger
  • Receptors, Thyroid Hormone
  • Thyroid Hormone Receptors alpha
  • Thyroid Hormone Receptors beta
  • Uncoupling Agents
  • Triiodothyronine, Reverse
  • Stearoyl-CoA Desaturase
  • Aldehyde Oxidase