Discovery of a novel, liver-targeted thyroid hormone receptor-ß agonist, CS271011, in the treatment of lipid metabolism disorders.
Front Endocrinol (Lausanne)
; 14: 1109615, 2023.
Article
in En
| MEDLINE
| ID: mdl-36742393
ABSTRACT
Introduction:
Thyroid hormone receptor ß (THR-ß) plays a critical role in metabolism regulation and has become an attractive target for treating lipid metabolism disorders in recent years. Thus, in this study, we discovered CS271011, a novel THR-ß agonist, and assessed the safety and efficiency of CS271011 compared to MGL-3196 in vitro and in vivo.Methods:
We conducted luciferase reporter gene assays to assess the activation of THR-ß and α in vitro. C57BL/6J mice were fed a high-fat diet for 12 weeks, CS271011 was administered by gavage at the dose of 1 mg/kg and 3 mg/kg, and MGL-3196 was administered at the dose of 3 mg/kg for 10 weeks. Body weight, food intake, serum and hepatic parameters, histological analysis, pharmacokinetic studies, RNA sequencing of the liver and heart, and expression of hepatic lipid-metabolic genes were determined to evaluate the safety and efficiency of CS271011.Results:
Compared with MGL-3196, CS271011 showed higher THR-ß activation in vitro. In the diet-induced obesity mice model, CS271011 demonstrated favourable pharmacokinetic properties in mice and was enriched in the liver. Finally, CS271011 improved dyslipidaemia and reduced liver steatosis in the diet-induced obesity murine model. Mechanistically, CS271011 and MGL-3196 showed potent regulation of lipid metabolism-related genes.Conclusions:
CS271011 is a potent and liver-targeted THR-ß agonist for treating lipid metabolism disorders.Key words
Full text:
1
Database:
MEDLINE
Main subject:
Thyroid Hormone Receptors beta
/
Dyslipidemias
Limits:
Animals
Language:
En
Journal:
Front Endocrinol (Lausanne)
Year:
2023
Type:
Article
Affiliation country:
China