A microbial metabolite inhibits the HIF-2α-ceramide pathway to mediate the beneficial effects of time-restricted feeding on MASH

IF 27.7 1区 生物学 Q1 CELL BIOLOGY
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Abstract

Time-restricted feeding (TRF) is a potent dietary intervention for improving metabolic diseases, including metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH). However, the mechanism of this efficacy has remained elusive. Here, we show that TRF improves MASLD, which is associated with a significant enrichment of Ruminococcus torques (R. torques). Mechanistically, R. torques suppresses the intestinal HIF-2α-ceramide pathway via the production of 2-hydroxy-4-methylpentanoic acid (HMP). We identify rtMor as a 4-methyl-2-oxopentanoate reductase that synthesizes HMP in R. torques. Finally, we show that either the colonization of R. torques or oral HMP supplementation can ameliorate inflammation and fibrosis in a MASH mouse model. These findings identify R. torques and HMP as potential TRF mimetics for the treatment of metabolic disorders.

Abstract Image

一种微生物代谢物抑制 HIF-2α 神经酰胺通路,从而介导限时进食对 MASH 的有益影响
限时喂养(TRF)是一种有效的饮食干预措施,可改善代谢性疾病,包括代谢功能障碍相关性脂肪肝/代谢功能障碍相关性脂肪性肝炎(MASLD/MASH)。然而,这种疗效的机理仍然难以捉摸。在这里,我们发现 TRF 可改善 MASLD,而 MASLD 与瘤胃球菌(R. torques)的显著富集有关。从机理上讲,R. torques 通过产生 2-hydroxy-4-methylpentanoic acid (HMP) 来抑制肠道 HIF-2α 神经酰胺通路。我们发现 rtMor 是一种合成 HMP 的 4-甲基-2-氧代戊酸还原酶。最后,我们还发现,在 MASH 小鼠模型中,定殖 R. torques 或口服 HMP 补充剂都能改善炎症和纤维化。这些研究结果表明,扭角菌和 HMP 是治疗代谢性疾病的潜在 TRF 模拟物。
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来源期刊
Cell metabolism
Cell metabolism 生物-内分泌学与代谢
CiteScore
48.60
自引率
1.40%
发文量
173
审稿时长
2.5 months
期刊介绍: Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others. Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.
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