β-hydroxybutyrate inhibits ferroptosis-mediated pancreatic damage in acute liver failure through the increase of H3K9bhb

Yufan Zheng; Wenrui Sun; Cong Shan; Borui Li; Jiaying Liu; Hao Xing; Qingling Xu; Baiping Cui; Wenjia Zhu; Jia Chen; Liyan Liu; Tian Yang; Ning Sun; Xiaobo Li

doi:10.1016/j.celrep.2022.111847

β-hydroxybutyrate inhibits ferroptosis-mediated pancreatic damage in acute liver failure through the increase of H3K9bhb

Cell Rep. 2022 Dec 20;41(12):111847. doi: 10.1016/j.celrep.2022.111847.

Authors

Yufan Zheng¹, Wenrui Sun², Cong Shan³, Borui Li¹, Jiaying Liu¹, Hao Xing⁴, Qingling Xu⁵, Baiping Cui¹, Wenjia Zhu¹, Jia Chen¹, Liyan Liu⁶, Tian Yang⁷, Ning Sun⁸, Xiaobo Li⁹

Affiliations

¹ Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
² Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
³ Wuxi School of Medicine, Jiangnan University, Jiangsu 214122, China.
⁴ Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai 200438, China.
⁵ Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China.
⁶ General Practice/International Medical Care Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
⁷ Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai 200438, China. Electronic address: yangtianehbh@smmu.edu.cn.
⁸ Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Wuxi School of Medicine, Jiangnan University, Jiangsu 214122, China. Electronic address: sunning@fudan.edu.cn.
⁹ Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: xbli@fudan.edu.cn.

PMID: 36543135
DOI: 10.1016/j.celrep.2022.111847

Abstract

Acute pancreatitis and hyperamylasemia are often seen in patients with acute liver failure (ALF). However, the underlying mechanisms remain elusive. This study describes pancreatic tissue damage and exocrine dysfunction in a mouse model of major-liver-resection-induced ALF. The analysis of 1,264 clinical cases of liver failure (LF) showed that the incidence of hyperamylasemia and hyperlipasemia in patients with LF is 5.5% and 20%, respectively. Metabolomic studies indicate that glutathione (GSH)-deficiency-caused ferroptosis contributes to pancreatic damage in mouse ALF. β-hydroxybutyrate (β-HB) is the only metabolite downregulated in the liver, serum, and pancreas. Our data suggest that β-HB protects pancreatic cells and tissues from GSH-deficiency-caused ferroptosis. β-HB administration in ALF mice restores the expression of ferroptosis-suppressor genes through histone H3 lysine 9 β-hydroxybutyrylation (H3K9bhb)-mediated chromatin opening. Our findings highlight β-HB as an endogenous metabolite regulating ferroptosis in the pancreas and extend our understanding of the pathophysiology of ALF-induced pancreatitis.

Keywords: CP: Metabolism; CP: Molecular biology; H3K9bhb; acute liver failure; chromatin opening; epigenetic regulation; ferroptosis; pancreatitic damage; β-hydroxybutyrate; β-hydroxybutyrylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3-Hydroxybutyric Acid / pharmacology
Acute Disease
Animals
Ferroptosis*
Hyperamylasemia*
Liver Failure, Acute* / chemically induced
Liver Failure, Acute* / metabolism
Mice
Pancreas / metabolism
Pancreatitis*

Substances

3-Hydroxybutyric Acid