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

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

doi:10.1016/j.cmet.2024.07.004

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

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

Authors

Yi Zhang¹, Xuemei Wang², Jun Lin³, Jia Liu⁴, Kai Wang², Qixing Nie², Chuan Ye², Lulu Sun⁵, Yanpeng Ma¹, Ruize Qu¹, Yuejian Mao⁶, Xuguang Zhang⁷, Hua Lu⁸, Pengyan Xia⁹, Dongyu Zhao¹⁰, Guang Wang¹¹, Zhipeng Zhang¹², Wei Fu¹³, Changtao Jiang¹⁴, Yanli Pang¹⁵

Affiliations

¹ 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.
² 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.
³ 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; Department of Endocrinology, Capital Medical University Chaoyang Hospital, Beijing, China.
⁴ Department of Endocrinology, Capital Medical University Chaoyang Hospital, Beijing, China.
⁵ Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; State Key Laboratory of Female Fertility Preservation, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
⁶ Mengniu Institute of Nutrition Science, Shanghai, China.
⁷ Mengniu Institute of Nutrition Science, Shanghai, China; Shanghai Institute of Nutrition and Health, The Chinese Academy of Sciences, Shanghai, China.
⁸ National Laboratory for Molecular Sciences, Center for Soft Matter Science and Engineering, Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
⁹ Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China.
¹⁰ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China; Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
¹¹ Department of Endocrinology, Capital Medical University Chaoyang Hospital, Beijing, China. Electronic address: wangguangcy@ccmu.edu.cn.
¹² 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. Electronic address: zhangzhipeng06@126.com.
¹³ 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. Electronic address: fuwei@bjmu.edu.cn.
¹⁴ 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; Department of Immunology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Peking University, Beijing, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China. Electronic address: jiangchangtao@bjmu.edu.cn.
¹⁵ State Key Laboratory of Female Fertility Preservation, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China; National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. Electronic address: yanlipang@bjmu.edu.cn.

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

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.

Keywords: MASLD/MASH; bacterial metabolites; gut microbiota; time-restricted feeding.

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors* / metabolism
Ceramides* / metabolism
Fatty Liver / metabolism
Gastrointestinal Microbiome / drug effects
Humans
Male
Metabolic Diseases / metabolism
Mice
Mice, Inbred C57BL*
Signal Transduction / drug effects

Substances

Basic Helix-Loop-Helix Transcription Factors
endothelial PAS domain-containing protein 1
Ceramides