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

Iodothyronines influence lipid metabolism and energy homeostasis. Previous studies demonstrated that 3,5-L-diiodothyronine (T-2), as well as 3,30,5-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 TR alpha 1 and TR beta 1 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-alpha, -gamma, -delta) 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, PPAR gamma mRNA expression, and a decrease in PPAR delta 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 PPAR alpha, PPAR gamma, and AOX expression; iii) increase in PPARd 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. Journal of Endocrinology (2011) 210, 59-69