title: Non-receptor-mediated actions are responsible for the lipid-lowering effects of iodothyronines in FaO rat hepatoma cells.
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.
authors.affiliation: Dipartimento di Biologia, Università di Genova, Corso Europa 26, Genova 16132, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Grasselli
authors.forename: Adriana
authors.initials: A
authors.lastname: Voci
authors.forename: Laura
authors.initials: L
authors.lastname: Canesi
authors.forename: Fernando
authors.initials: F
authors.lastname: Goglia
authors.forename: Silvia
authors.initials: S
authors.lastname: Ravera
authors.forename: Isabella
authors.initials: I
authors.lastname: Panfoli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gallo
authors.forename: Laura
authors.initials: L
authors.lastname: Vergani
mesh_terms: D042931:Aldehyde Oxidase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D004104:Diiodothyronines / Q000494:pharmacology*; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism; D014285:Triiodothyronine, Reverse / Q000494:pharmacology*; D014475:Uncoupling Agents / Q000494:pharmacology*
chemical_list: D004104:Diiodothyronines; D000960:Hypolipidemic Agents; D047494:PPAR delta; D047495:PPAR gamma; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014475:Uncoupling Agents; D014285:Triiodothyronine, Reverse; D013230:Stearoyl-CoA Desaturase; D042931:Aldehyde Oxidase