Dataset Information

Discovery of a novel, liver-targeted thyroid hormone receptor-β agonist, CS271011, in the treatment of lipid metabolism disorders.

ABSTRACT:

Introduction

Thyroid hormone receptor β (THR-β) 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-β 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-β 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-β 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-β agonist for treating lipid metabolism disorders.

SUBMITTER: Lin S

PROVIDER: S-EPMC9896003 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Discovery of a novel, liver-targeted thyroid hormone receptor-β agonist, CS271011, in the treatment of lipid metabolism disorders.

Lin Suwen S Huang Shengjian S Deng Zhou Z Zhang Yu Y Huang Lin L Wu Yanyi Y Lv Shuyan S Wang Zhiyi Z Huang Ning N Wang Lan L Chen Ziqi Z Yu Guangyin G Yin Weihua W Zhou You Y Fang Zhengyu Z

Frontiers in endocrinology 20230120

<h4>Introduction</h4>Thyroid hormone receptor β (THR-β) 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-β agonist, and assessed the safety and efficiency of CS271011 compared to MGL-3196 <i>in vitro</i> and <i>in vivo</i>.<h4>Methods</h4>We conducted luciferase reporter gene assays to assess the activation of THR-β and α in vitro. C57BL/6J mice were ...[more]

PMID: 36742393

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Project description:The typical modern lifestyle contributes to the development of many metabolic-related disorders, as exemplified by metabolic syndrome. How to prevent, resolve, or avoid subsequent deterioration of metabolic disturbances and the development of more serious diseases has become an important and much-discussed health issue. Thus, the question of the physiological and pathological roles of thyroid hormones (THs) in metabolism has never gone out of fashion. Although THs influence almost all organs, the liver is one of the most important targets as well as the hub of metabolic homeostasis. When this homeostasis is out of balance, diseases may result. In the current review, we summarize the common features and actions of THs, first focusing on their effects on lipid metabolism in the liver. In the second half of the review, we turn to a consideration of non-alcoholic fatty liver disease (NAFLD), a disease characterized by excessive accumulation of fat in the liver that is independent of heavy alcohol consumption. NAFLD is a growing health problem that currently affects ~25% of the world's population. Unfortunately, there are currently no approved therapies specific for NAFLD, which, if left uncontrolled, may progress to more serious diseases, such as cirrhosis or liver cancer. This absence of effective treatment can also result in the development of non-alcoholic steatohepatitis (NASH), an aggressive form of NAFLD that is the leading cause of liver transplantation in the United States. Because THs play a clear role in hepatic fat metabolism, their potential application in the prevention and treatment of NAFLD has attracted considerable research attention. Studies that have investigated the use of TH-related compounds in the management of NAFLD are also summarized in the latter part of this review. An important take-home point of this review is that a comprehensive understanding of the physiological and pathological roles of THs in liver fat metabolism is possible, despite the complexities of this regulatory axis-an understanding that has clinical value for the specific management of NAFLD.

Dataset Information

Discovery of a novel, liver-targeted thyroid hormone receptor-β agonist, CS271011, in the treatment of lipid metabolism disorders.

Introduction

Methods

Results

Conclusions

Publications

Discovery of a novel, liver-targeted thyroid hormone receptor-β agonist, CS271011, in the treatment of lipid metabolism disorders.

Similar Datasets

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