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

作　　者：Kai Sun Nan-lin Zhu Su-ling Huang Hui Qu Yi-pei Gu Li Qin Jia Liu Ying Leng 

机构地区：[1]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [2]University of Chinese Academy of Sciences,Beijing,100049,China [3]Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China

出　　处：《Acta Pharmacologica Sinica》2024年第10期2134-2148,共15页中国药理学报（英文版）

基　　金：supported by Shanghai Municipal Science and Technology Major Project and the Foundation of Shanghai Science and Technology Committee(Grant No.21DZ2291100).

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 receptorβ(THRβ)agonist and the first approved drug for NASH treatment.It is well known that the THRβactivation 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 CCl_(4)(HFD+CCl_(4))-induced NASH mice were used to evaluate the effects of resmetirom on lipid and BA composition.We showed that resmetirom administration(10 mg·kg^(-1)·d^(-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 THRβactivation 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 P4508B1(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 THRβagonists on NASH treatment by inhibiting intestinal lipid absorption through remodeling BAs composition,which highlights the multiple regulation of THRβactivation on lipid metabolis

关 键 词：nonalcoholic steatohepatitis THRβagonists resmetirom bile acids composition CYP8B1 intestinal lipid absorption 

分 类 号：R575[医药卫生—消化系统]