中国科学院上海药物研究所Ying Leng等研究人员合作揭示，甲状腺激素受体β激动剂通过重塑胆汁酸谱抑制肠道脂质吸收从而改善非酒精性脂肪性肝炎的新机制。2024年5月24日，《中国药理学报》在线发表了这项成果。

研究人员表示，饮食热量过高会导致全身代谢紊乱，扰乱肝脏脂质代谢，加重非酒精性脂肪性肝炎（NASH）。胆汁酸（BA）在调节营养吸收和全身能量平衡方面发挥着关键作用。resmetirom是一种选择性甲状腺激素受体β（THRβ）激动剂，也是首个获准用于治疗NASH的药物。众所周知，THRβ激活可促进肝内脂质分解并改善线粒体功能，但其对肠道脂质吸收和BA组成的影响仍不清楚。

研究人员采用胆碱缺乏、L-氨基酸定义、高脂饮食（CDAHFD）和高脂饮食加CCl4（HFD+CCl4）诱导的NASH小鼠来评估了resmetirom对脂质和BA组成的影响。研究人员发现，在两种NASH小鼠模型中，resmetirom给药（10mg/kg每天，灌胃）显著改变了肝脏脂质组成，尤其是减少了含C18:2脂肪酰链的甘油三酯（TG）和磷脂酰胆碱（PC），这表明THRβ激活抑制了肠道脂质吸收，因为C18:2脂肪酸只能从饮食中获得。对BA的靶向分析表明，在两种NASH小鼠模型中，resmetirom通过抑制细胞色素P450 8B1（CYP8B1）的表达，显著降低了肝脏和肠道中12-OH与非12-OH BA的比例。BODIPY灌胃和口服脂肪耐受试验进一步验证了resmetirom对肠道脂质吸收的直接抑制作用。

此外，在正常小鼠和CDAHFD喂养小鼠中，通过补充外源性胆酸（CA）扰乱改变的BA谱可消除resmetirom对肠道脂质吸收的抑制作用，这表明resmetirom是通过减少12-OH BA含量来抑制肠道脂质吸收的。总之，研究人员发现了THRβ激动剂通过重塑BA组成抑制肠道脂质吸收治疗NASH的新机制，这突出了THRβ激活对脂质代谢的多重调控，扩展了目前对THRβ激动剂治疗NASH作用机制的认识。

附：英文原文

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

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

Issue&Volume: 2024-05-24

Abstract: 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 β (THRβ) agonist and the first approved drug for NASH treatment. It is well known that the THRβ 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 (10mg·kg1·d1, 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 THRβ 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 THRβ agonists on NASH treatment by inhibiting intestinal lipid absorption through remodeling BAs composition, which highlights the multiple regulation of THRβ activation on lipid metabolism and extends the current knowledge on the action mechanisms of THRβ agonists in NASH treatment.

DOI: 10.1038/s41401-024-01303-x

Source: https://www.nature.com/articles/s41401-024-01303-x