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一种微生物代谢物抑制 HIF-2α-神经酰胺通路,从而介导限时喂养对 MASH 的有益作用。

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

机构信息

Department of General Surgery, Cancer Center, Peking University Third Hospital, Beijing, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China.

出版信息

Cell Metab. 2024 Aug 6;36(8):1823-1838.e6. doi: 10.1016/j.cmet.2024.07.004. Epub 2024 Jul 29.


DOI:10.1016/j.cmet.2024.07.004
PMID:39079531
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.

摘要

限时喂养(TRF)是一种有效的饮食干预方法,可改善代谢性疾病,包括代谢功能障碍相关脂肪性肝病/代谢功能障碍相关脂肪性肝炎(MASLD/MASH)。然而,其疗效的机制仍不清楚。在这里,我们发现 TRF 可改善 MASLD,这与 Ruminococcus torques(R. torques)的显著富集有关。从机制上讲,R. torques 通过产生 2-羟基-4-甲基戊酸(HMP)来抑制肠道 HIF-2α-神经酰胺途径。我们鉴定出 rtMor 是一种 4-甲基-2-氧代戊酸还原酶,可在 R. torques 中合成 HMP。最后,我们表明,R. torques 的定植或口服 HMP 补充均可改善 MASH 小鼠模型中的炎症和纤维化。这些发现确定了 R. torques 和 HMP 是治疗代谢紊乱的潜在 TRF 模拟物。

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