ETA2023 45th Annual Meeting of the European Thyroid Association ETA 2023 Oral Session 5: Young Investigators / Basic (6 abstracts)
Distinguishing beneficial local from adverse systemic thyroid hormone action in alcoholic liver disease
Christoph Hoppe 1 , G. Sebastian Hönes 2 , Devon Siemes 3 , Christina Wenzek 4 , Frédéric Flamant 5 , Karine Gauthier 5 , Daniel R. Engel 3 , Denise Zwanziger 6 , Christian M. Lange 7 , Hideo Baba 8 , Dagmar Führer-Sakel 9 & Lars Christian Möller 10
1University Hospital Essen, Department of Endocrinology, Diabetes and Metabolism, Department of Endocrinology, Diabetes and Metabolism, Essen, Germany; 2University Hospital Essen, University of Duisburg Essen, Department of Endocrinology, Diabetes and Metabolism, Essen, Germany; 3University Hospital Essen, Institute of Experimental Immunology and Imaging, Essen, Germany; 4University Hospital Essen, Department for Endocrinology, Diabetology and Metabolism, Essen, Germany; 5University Lyon, Institut de Génomique Fonctionnelle de Lyon, Lyon, France; 6University of Duisburg-Essen, Department of Endocrinology, Diabetes and Metabolism, Essen, Germany; 7Ludwig-Maximilian-University Hospital Munich, Department of Internal Medicine II, Munich, Germany; 8University Hospital Essen, Institute of Pathology, Essen, Germany; 9Department of Endocrinology, University Hospital Essen, Essen, Germany; 10University Hospital Essen, University Hospital Essen, Department of Endocrinology, Diabetes and Metabolism, Essen, Germany
Thyroid hormones (TH) reduce liver steatosis. As steatosis is the initial step of alcoholic liver disease (ALD), we hypothesized that TH treatment could ameliorate ALD. Wildtype (WT) mice were treated with either ethanol (EtOH) or liquid control diet for 10 days followed by a single EtOH or maltose binge on day 11. In both groups, diet was supplemented with either T3 or solvent. Serum triglycerides (TG) were increased by EtOH and, surprisingly, further elevated by T3. Liver weight and hepatic lipid content were increased by T3 in the EtOH group. T3 treatment did not protect from ALD and rather aggravated EtOH-induced liver steatosis. White adipose tissue (WAT) weight was reduced by EtOH and T3 treatment. Furthermore, WAT expression of thermogenic genes (Ucp1, Pgc1a, Dio2) and lipases (ATGL, HSl) was upregulated by T3, indicating that T3 action in WAT led to lipolysis and subsequently fatty acid accumulation in the liver, explaining the more severe ALD phenotype. To distinguish hepatic from such extrahepatic T3 effects, we performed the same experiment in hepatocyte-specific TH receptor beta knockout (hepTRβKO) mice. Absence of TRβ in hepatocytes aggravated the phenotype of T3 and EtOH treated mice even further with increased liver weight and hepatic lipid content. RNA-Sequencing and pathway analysis showed that T3 and TRβ induced beta oxidation and oxidative phosphorylation and repressed lipid synthesis. CYP2E1 is induced by EtOH and metabolizes EtOH, which generates reactive oxygen species (ROS) and liver damage in ALD. CYP2E1 induction by EtOH was completely prevented by T3 treatment (RNA and protein expression). The comparison of WT with hepTRβKO mice demonstrates beneficial local hepatic effects of TH on lipid metabolism and CYP2E1 expression, which partially compensate the adverse effect of WAT lipolysis. Therefore, employing exclusively beneficial local TH action, avoiding extrahepatic adverse effects, is highly desirable. We next repeated the experiment in WT mice replacing T3 by MGL-3196 (Resmetirom), a hepatocyte-specific and TRβ-selective TH analog. Pituitary Tshb expression, heart weight/tibia length ratio and serum TH concentrations were not altered by MGL-3196. Compared to T3, MGL-3196 treatment led to reduced serum TG concentration and liver weight on control and EtOH diet. We conclude that systemic T3 effects (increased lipolysis) are adverse in ALD and override beneficial local hepatic T3 effects (increased beta oxidation, reduced lipid synthesis and ROS production), precluding T3 treatment in ALD. Yet, hepatocyte-specific TRβ agonists, such as MGL-3196, can harness the beneficial hepatic effects while avoiding extrahepatic effects, allowing therapeutic use of TH action.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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