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Published on: April 16, 2019
TG68, a Novel Thyroid Hormone Receptor-β Agonist for the Treatment of NAFLD
Andrea Caddeo1, Marta Anna Kowalik1, Marina Serra1
1Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy.
Abstract:
Activation of thyroid hormone receptor β (THRβ) has shown beneficial effects on metabolic alterations, including non-alcoholic fatty liver disease (NAFLD). Here, we investigated the effect of TG68, a novel THRβ agonist, on fatty liver accumulation and liver injury in mice fed a high-fat diet (HFD). C57BL/6 mice fed HFD for 17 or 18 weeks, a time when all mice developed massive steatohepatitis, were then given TG68 at a dose of 9.35 or 2.8 mg/kg for 2 or 3 weeks, respectively. As a reference compound, the same treatment was adopted using equimolar doses of MGL-3196, a selective THRβ agonist currently in clinical phase III. The results showed that treatment with TG68 led to a reduction in liver weight, hepatic steatosis, serum transaminases, and circulating triglycerides. qRT-PCR analyses demonstrated activation of THRβ, as confirmed by increased mRNA levels of Deiodinase-1 and Malic enzyme-1, and changes in lipid metabolism, as revealed by increased expression of Acyl-CoA Oxidase-1 and Carnitine palmitoyltransferase-1. The present results showed that this novel THRβ agonist exerts an anti-steatogenic effect coupled with amelioration of liver injury in the absence of extra-hepatic side effects, suggesting that TG68 may represent a useful tool for the treatment of NAFLD.
Insights
A novel thyroid hormone receptor beta (THRβ) agonist, TG68, effectively reduced fatty liver accumulation and liver injury in mice with non-alcoholic fatty liver disease (NAFLD). TG68 demonstrated anti-steatogenic effects without extra-hepatic side effects.
Area of Science:
- Hepatology
- Endocrinology
- Pharmacology
Background:
- Thyroid hormone receptor beta (THRβ) activation shows promise for treating metabolic disorders like non-alcoholic fatty liver disease (NAFLD).
- High-fat diet (HFD) induced mouse models are crucial for studying NAFLD pathogenesis and therapeutic interventions.
Purpose of the Study:
- To investigate the efficacy of TG68, a novel THRβ agonist, in ameliorating fatty liver and liver injury in a mouse model of NAFLD.
- To compare the effects of TG68 with MGL-3196, a clinically relevant THRβ agonist.
Main Methods:
- C57BL/6 mice were fed a HFD to induce steatohepatitis.
- Mice received TG68 or MGL-3196 for 2-3 weeks.
- Liver weight, hepatic steatosis, serum markers, and gene expression related to THRβ activation and lipid metabolism were assessed.
Main Results:
- TG68 treatment significantly reduced liver weight, hepatic steatosis, serum transaminases, and triglyceride levels.
- qRT-PCR confirmed THRβ activation and altered expression of key genes involved in lipid metabolism (DIO1, ME1, ACOX1, CPT1).
- TG68 demonstrated anti-steatogenic and liver-protective effects comparable to MGL-3196.
Conclusions:
- TG68 is a potent THRβ agonist with significant anti-steatogenic and liver-ameliorating properties in a preclinical NAFLD model.
- The observed effects were achieved without apparent extra-hepatic side effects.
- TG68 holds potential as a therapeutic agent for treating NAFLD.
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