Sphingosine d18:1 promotes nonalcoholic steatohepatitis by inhibiting macrophage HIF-2α

Jialin Xia; Hong Chen; Xiaoxiao Wang; Weixuan Chen; Jun Lin; Feng Xu; Qixing Nie; Chuan Ye; Bitao Zhong; Min Zhao; Chuyu Yun; Guangyi Zeng; Yuejian Mao; Yongping Wen; Xuguang Zhang; Sen Yan; Xuemei Wang; Lulu Sun; Feng Liu; Chao Zhong; Pengyan Xia; Changtao Jiang; Huiying Rao; Yanli Pang

doi:10.1038/s41467-024-48954-2

Sphingosine d18:1 promotes nonalcoholic steatohepatitis by inhibiting macrophage HIF-2α

Nat Commun. 2024 Jun 4;15(1):4755. doi: 10.1038/s41467-024-48954-2.

Authors

Jialin Xia^#^{1

2

3

4

5}, Hong Chen^#^{1

2

3

4

5}, Xiaoxiao Wang^#⁶, Weixuan Chen^{4

5}, Jun Lin^{1

2

3}, Feng Xu^{1

2

3}, Qixing Nie^{1

2

3}, Chuan Ye^{1

2

3}, Bitao Zhong¹, Min Zhao^{4

5}, Chuyu Yun^{4

5}, Guangyi Zeng^{1

2

3

4

5}, Yuejian Mao⁵, Yongping Wen⁷, Xuguang Zhang^{7

8}, Sen Yan^{4

5}, Xuemei Wang^{1

2

3}, Lulu Sun^{5

9}, Feng Liu⁶, Chao Zhong¹⁰, Pengyan Xia¹⁰, Changtao Jiang^{1

2

3

10}, Huiying Rao¹¹, Yanli Pang^{12

13

14}

Affiliations

¹ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China.
² Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
³ Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China.
⁴ State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
⁵ Institute of Advanced Clinical Medicine, Peking University, Beijing, China.
⁶ Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China.
⁷ Mengniu Institute of Nutrition Science, Shanghai, China.
⁸ Shanghai Institute of Nutrition and Health, The Chinese Academy of Sciences, Shanghai, China.
⁹ Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China.
¹⁰ Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing, China.
¹¹ Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China. [email protected].
¹² Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China. [email protected].
¹³ State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. [email protected].
¹⁴ Institute of Advanced Clinical Medicine, Peking University, Beijing, China. [email protected].

^# Contributed equally.

Abstract

Non-alcoholic steatohepatitis (NASH) is a severe type of the non-alcoholic fatty liver disease (NAFLD). NASH is a growing global health concern due to its increasing morbidity, lack of well-defined biomarkers and lack of clinically effective treatments. Using metabolomic analysis, the most significantly changed active lipid sphingosine d18:1 [So(d18:1)] is selected from NASH patients. So(d18:1) inhibits macrophage HIF-2α as a direct inhibitor and promotes the inflammatory factors secretion. Male macrophage-specific HIF-2α knockout and overexpression mice verified the protective effect of HIF-2α on NASH progression. Importantly, the HIF-2α stabilizer FG-4592 alleviates liver inflammation and fibrosis in NASH, which indicated that macrophage HIF-2α is a potential drug target for NASH treatment. Overall, this study confirms that So(d18:1) promotes NASH and clarifies that So(d18:1) inhibits the transcriptional activity of HIF-2α in liver macrophages by suppressing the interaction of HIF-2α with ARNT, suggesting that macrophage HIF-2α may be a potential target for the treatment of NASH.

MeSH terms

Animals
Aryl Hydrocarbon Receptor Nuclear Translocator / genetics
Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
Basic Helix-Loop-Helix Transcription Factors* / genetics
Basic Helix-Loop-Helix Transcription Factors* / metabolism
Disease Models, Animal
Humans
Liver / drug effects
Liver / metabolism
Liver / pathology
Liver Cirrhosis / drug therapy
Liver Cirrhosis / genetics
Liver Cirrhosis / metabolism
Liver Cirrhosis / pathology
Macrophages* / drug effects
Macrophages* / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout*
Non-alcoholic Fatty Liver Disease* / drug therapy
Non-alcoholic Fatty Liver Disease* / genetics
Non-alcoholic Fatty Liver Disease* / metabolism
Non-alcoholic Fatty Liver Disease* / pathology
Sphingosine* / analogs & derivatives
Sphingosine* / metabolism

Substances

endothelial PAS domain-containing protein 1
Basic Helix-Loop-Helix Transcription Factors
Sphingosine
Aryl Hydrocarbon Receptor Nuclear Translocator