Sakuma Ikki, Gaspar Rafael C, Nasiri Ali R, Dufour Sylvie, Kahn Mario, Zheng Jie, LaMoia Traci E, Guerra Mateus T, Taki Yuki, Kawashima Yusuke, Yimlamai Dean, Perelis Mark, Vatner Daniel F, Petersen Kitt Falk, Huttasch Maximilian, Knebel Birgit, Kahl Sabine, Roden Michael, Samuel Varman T, Tanaka Tomoaki, Shulman Gerald I
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520.
Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
Proc Natl Acad Sci U S A. 2025 May 6;122(18):e2502978122. doi: 10.1073/pnas.2502978122. Epub 2025 May 1.
Metabolic dysfunction-associated steatohepatitis (MASH) represents a progressive form of steatotic liver disease which increases the risk for fibrosis and advanced liver disease. The accumulation of discrete species of bioactive lipids has been postulated to activate signaling pathways that promote inflammation and fibrosis. However, the key pathogenic lipid species is a matter of debate. We explored candidates using various dietary, molecular, and genetic models. Mice fed a choline-deficient L-amino acid-defined high-fat diet (CDAHFD) developed steatohepatitis and manifested early markers of liver fibrosis associated with increased cholesterol content in liver lipid droplets within 5 d without any changes in total liver cholesterol content. Treating mice with antisense oligonucleotides against or treatment with bempedoic acid or atorvastatin decreased liver lipid droplet cholesterol content and prevented CDAHFD-induced MASH and the fibrotic response. All these salutary effects were abrogated with dietary cholesterol supplementation. Analysis of human liver samples demonstrated that cholesterol in liver lipid droplets was increased in humans with MASH and liver fibrosis and was higher in PNPLA3 I148M (variants rs738409) than in HSD17B13 variants (rs72613567). Together, these data identify cholesterol in liver lipid droplets as a critical mediator of MASH and demonstrate that Coenzyme A synthase knockdown and bempedoic acid are therapeutic approaches to reduce liver lipid droplet cholesterol content and thereby prevent the development of MASH and liver fibrosis.
代谢功能障碍相关脂肪性肝炎（MASH）是一种进行性脂肪性肝病，会增加纤维化和晚期肝病的风险。据推测，生物活性脂质离散种类的积累会激活促进炎症和纤维化的信号通路。然而，关键的致病脂质种类仍存在争议。我们使用各种饮食、分子和遗传模型探索了候选脂质。喂食胆碱缺乏的L-氨基酸限定高脂饮食（CDAHFD）的小鼠发生了脂肪性肝炎，并在5天内出现了与肝脂滴中胆固醇含量增加相关的肝纤维化早期标志物，而肝脏总胆固醇含量没有任何变化。用针对……的反义寡核苷酸处理小鼠，或用贝派地酸或阿托伐他汀处理，可降低肝脂滴胆固醇含量，并预防CDAHFD诱导的MASH和纤维化反应。补充膳食胆固醇可消除所有这些有益作用。对人类肝脏样本的分析表明，MASH和肝纤维化患者肝脏脂滴中的胆固醇增加，PNPLA3 I148M（rs738409变体）患者的胆固醇高于HSD17B13变体（rs72613567）患者。总之，这些数据确定肝脂滴中的胆固醇是MASH的关键介质，并表明敲低辅酶A合酶和使用贝派地酸是降低肝脂滴胆固醇含量从而预防MASH和肝纤维化发展的治疗方法。
