北京大学庞艳莉等研究人员合作发现，一种微生物代谢物抑制HIF-2α-神经酰胺通路来介导限时进食对MASH的有益影响。这一研究成果于2024年7月29日在线发表在国际学术期刊《细胞—代谢》上。

研究人员表示，限时进食（TRF）是一种有效的饮食干预方法，可改善代谢疾病，包括代谢功能障碍相关的脂肪肝病/代谢功能障碍相关的脂肪性肝炎（MASLD/MASH）。然而，这种疗效的机制仍不清楚。

研究人员发现TRF能改善MASLD，并与Ruminococcus torques的显著富集相关。从机制上讲，R. torques通过产生2-羟基-4-甲基戊酸（HMP）抑制肠道HIF-2α-神经酰胺途径。研究人员确定了rtMor作为一种4-甲基-2-氧戊酸还原酶，负责在R. torques中合成HMP。最后，研究人员展示了R. torques的定植或口服HMP补充剂可以改善MASH小鼠模型中的炎症和纤维化。这些发现将R. torques和HMP确定为潜在的TRF模拟物，可用于治疗代谢性疾病。

附：英文原文

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

Author: Yi Zhang, Xuemei Wang, Jun Lin, Jia Liu, Kai Wang, Qixing Nie, Chuan Ye, Lulu Sun, Yanpeng Ma, Ruize Qu, Yuejian Mao, Xuguang Zhang, Hua Lu, Pengyan Xia, Dongyu Zhao, Guang Wang, Zhipeng Zhang, Wei Fu, Changtao Jiang, Yanli Pang

Issue&Volume: 2024-07-29

Abstract: Time-restricted feeding (TRF) is a potent dietary intervention for improving metabolicdiseases, including metabolic dysfunction-associated steatotic liver disease/metabolicdysfunction-associated steatohepatitis (MASLD/MASH). However, the mechanism of thisefficacy has remained elusive. Here, we show that TRF improves MASLD, which is associatedwith 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-methylpentanoicacid (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 mousemodel. These findings identify R. torques and HMP as potential TRF mimetics for the treatment of metabolic disorders.

DOI: 10.1016/j.cmet.2024.07.004

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00275-4