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A new mechanism of thyroid hormone receptor β agonists ameliorating nonalcoholic steatohepatitis by inhibiting intestinal lipid absorption via remodeling bile acid profiles

文献类型：期刊论文

作者Sun, Kai2,3; Zhu, Nan-lin1; Huang, Su-ling3; Qu, Hui3; Gu, Yi-pei3; Qin, Li3; Liu, Jia1; Leng, Ying2,3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2024-05-24
页码15
关键词nonalcoholic steatohepatitis THR beta agonists resmetirom bile acids composition intestinal lipid absorption
ISSN号1671-4083
DOI10.1038/s41401-024-01303-x
通讯作者Liu, Jia(jia.liu@simm.ac.cn) ; Leng, Ying(yleng@simm.ac.cn)
英文摘要Excessive dietary calories lead to systemic metabolic disorders, disturb hepatic lipid metabolism, and aggravate nonalcoholic steatohepatitis (NASH). Bile acids (BAs) play key roles in regulating nutrition absorption and systemic energy homeostasis. Resmetirom is a selective thyroid hormone receptor beta (THR beta) agonist and the first approved drug for NASH treatment. It is well known that the THR beta activation could promote intrahepatic lipid catabolism and improve mitochondrial function, however, its effects on intestinal lipid absorption and BA compositions remain unknown. In the present study, the choline-deficient, L-amino acid defined, high-fat diet (CDAHFD) and high-fat diet plus CCl4 (HFD+CCl4)-induced NASH mice were used to evaluate the effects of resmetirom on lipid and BA composition. We showed that resmetirom administration (10 mgkg-1d-1, i.g.) significantly altered hepatic lipid composition, especially reduced the C18:2 fatty acyl chain-containing triglyceride (TG) and phosphatidylcholine (PC) in the two NASH mouse models, suggesting that THR beta activation inhibited intestinal lipid absorption since C18:2 fatty acid could be obtained only from diet. Targeted analysis of BAs showed that resmetirom treatment markedly reduced the hepatic and intestinal 12-OH to non-12-OH BAs ratio by suppressing cytochrome P450 8B1 (CYP8B1) expression in both NASH mouse models. The direct inhibition by resmetirom on intestinal lipid absorption was further verified by the BODIPY gavage and the oral fat tolerance test. In addition, disturbance of the altered BA profiles by exogenous cholic acid (CA) supplementation abolished the inhibitory effects of resmetirom on intestinal lipid absorption in both normal and CDAHFD-fed mice, suggesting that resmetirom inhibited intestinal lipid absorption by reducing 12-OH BAs content. In conclusion, we discovered a novel mechanism of THR beta agonists on NASH treatment by inhibiting intestinal lipid absorption through remodeling BAs composition, which highlights the multiple regulation of THR beta activation on lipid metabolism and extends the current knowledge on the action mechanisms of THR beta agonists in NASH treatment.
WOS关键词CHOLESTEROL ; CYP8B1 ; ROLES ; FXR
资助项目Shanghai Municipal Science and Technology Major Project ; Foundation of Shanghai Science and Technology Committee[21DZ2291100]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001236331500002
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/311764]  
专题新药研究国家重点实验室
通讯作者Liu, Jia; Leng, Ying
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Sun, Kai,Zhu, Nan-lin,Huang, Su-ling,et al. A new mechanism of thyroid hormone receptor β agonists ameliorating nonalcoholic steatohepatitis by inhibiting intestinal lipid absorption via remodeling bile acid profiles[J]. ACTA PHARMACOLOGICA SINICA,2024:15.
APA Sun, Kai.,Zhu, Nan-lin.,Huang, Su-ling.,Qu, Hui.,Gu, Yi-pei.,...&Leng, Ying.(2024).A new mechanism of thyroid hormone receptor β agonists ameliorating nonalcoholic steatohepatitis by inhibiting intestinal lipid absorption via remodeling bile acid profiles.ACTA PHARMACOLOGICA SINICA,15.
MLA Sun, Kai,et al."A new mechanism of thyroid hormone receptor β agonists ameliorating nonalcoholic steatohepatitis by inhibiting intestinal lipid absorption via remodeling bile acid profiles".ACTA PHARMACOLOGICA SINICA (2024):15.

入库方式： OAI收割

来源：上海药物研究所

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