TG68, a Novel Thyroid Hormone Receptor-β Agonist for the Treatment of NAFLD

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.

Understanding the Progression of Metabolic Dysfunction Asso-Ciated Fatty Liver Disease (MAFLD): Early Effect on Mitochon-Dria and Krebs Cycle Due to Type 3 Deiodinase Dysfunction

“…The results shown here also clarify the data described in recent studies that used THR-β analogues [48,49]. The study by Caddeo et al (2021) evaluated the effect of TG68 (new THR-β agonist) in an animal model of MAFLD.…”

Influence of Altered Thyroid Hormone Mechanisms in the Progression of Metabolic Dysfunction Associated with Fatty Liver Disease (MAFLD): A Systematic Review

“…The cell studies used the administration of FFAs [ 29 ] or palmitic and oleic acid [ 30 ]. The animal models show heterogeneity regarding the induction of the model, but the vast majority used ae high fat diet (HFD) [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]; one study used a pork-derived diet [ 41 ], while other models did not induce MAFLD but induced situations of hypo and hyperthyroidism [ 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ], subsequently evaluating its effects on the liver. Most of the selected articles included some type of hormone supplementation.…”

Cell-Specific Transport and Thyroid Hormone Receptor Isoform Selectivity Account for Hepatocyte-Targeted Thyromimetic Action of MGL-3196

“…These results cannot exclude a possible transport of MGL-3196 by other transporters, e.g., OATP1C1 and SLC17A4, into other cells outside the liver. However, no extrahepatic adverse effects of MGL-3196, e.g., on TSH serum concentrations in probands or patients [ 11 , 25 ] or the heart and kidney weight in mice have been reported so far [ 26 ].…”