Tg68, a novel thyroid hormone receptor‐β agonist for the treatment of NAFLD

Caddeo A.

First

Methodology

;Kowalik M. A.

Second

Methodology

;Serra M.

Methodology

;Runfola M.;Bacci A.;Rapposelli S.;Columbano A.

Penultimate

Conceptualization

;Perra A.

Last

Conceptualization

2021-01-01

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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 triglycer-ides. 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.