State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2024 Oct;45(10):2134-2148. doi: 10.1038/s41401-024-01303-x. Epub 2024 May 24.
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 CCl (HFD+CCl)-induced NASH mice were used to evaluate the effects of resmetirom on lipid and BA composition. We showed that resmetirom administration (10 mg·kg·d, 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.
过量的膳食卡路里会导致全身代谢紊乱，扰乱肝脏脂质代谢，并加重非酒精性脂肪性肝炎（NASH）。胆汁酸（BAs）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，也是首个获批用于 NASH 治疗的药物。众所周知，THRβ 激活可促进肝内脂质分解代谢并改善线粒体功能，但其对肠道脂质吸收和 BA 组成的影响尚不清楚。在本研究中，使用胆碱缺乏、L-氨基酸定义的高脂肪饮食（CDAHFD）和高脂肪饮食加 CCl（HFD+CCl）诱导的 NASH 小鼠来评估 resmetirom 对脂质和 BA 组成的影响。我们发现，resmetirom 给药（10mg·kg·d，ig）显著改变了肝脂质组成，特别是在两种 NASH 小鼠模型中降低了含有 C18:2 脂肪酸链的甘油三酯（TG）和磷脂酰胆碱（PC），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。BA 的靶向分析表明，resmetirom 通过抑制两种 NASH 小鼠模型中的细胞色素 P450 8B1（CYP8B1）表达，显著降低了肝和肠 12-OH 与非 12-OH BAs 的比值。通过 BODIPY 灌胃和口服脂肪耐量试验进一步证实了 resmetirom 对肠道脂质吸收的直接抑制作用。此外，外源性胆酸（CA）补充对改变的 BA 谱的干扰消除了 resmetirom 对正常和 CDAHFD 喂养小鼠肠道脂质吸收的抑制作用，表明 resmetirom 通过降低 12-OH BAs 含量抑制肠道脂质吸收。总之，我们通过重塑 BA 组成发现了 THRβ 激动剂治疗 NASH 的新机制，通过抑制肠道脂质吸收来治疗 NASH，这突显了 THRβ 激活对脂质代谢的多种调节作用，并扩展了 THRβ 激动剂在 NASH 治疗中的作用机制的现有知识。
