Ketogenesis acts as an endogenous protective programme to restrain inflammatory macrophage activation during acute pancreatitis
Li Zhang,
Juanjuan Shi,
Dan Du,
Ningning Niu,
Shiyu Liu,
Xiaotong Yang,
Ping Lu,
Xuqing Shen,
Na Shi,
Linbo Yao,
Ruling Zhang,
Guoyong Hu,
Guotao Lu,
Qingtian Zhu,
Tao Zeng,
Tingting Liu,
Qing Xia,
Wei Huang,
Jing Xue
Affiliations
Li Zhang
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Centre, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai 200127 China
Juanjuan Shi
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Centre, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai 200127 China
Dan Du
Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu 610041, China; Advanced Mass Spectrometry Centre, Research Core Facility, Frontiers Science Centre for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
Ningning Niu
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Centre, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai 200127 China
Shiyu Liu
Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu 610041, China
Xiaotong Yang
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Centre, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai 200127 China
Ping Lu
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Centre, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai 200127 China
Xuqing Shen
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Centre, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai 200127 China
Na Shi
Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu 610041, China
Linbo Yao
Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu 610041, China
Ruling Zhang
Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
Guoyong Hu
Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
Guotao Lu
Department of Gastroenterology, Pancreatic Centre, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225001, China
Qingtian Zhu
Department of Gastroenterology, Pancreatic Centre, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225001, China
Tao Zeng
Zhangjiang Laboratory, Institute of Brain-Intelligence Technology, Shanghai, China
Tingting Liu
Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu 610041, China
Qing Xia
Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu 610041, China
Wei Huang
Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu 610041, China; Institutes for Systems Genetics & Immunology and Inflammation, Frontiers Science Centre for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; Corresponding author at: State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Centre, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd,Shanghai, 200127, China.
Jing Xue
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Centre, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai 200127 China; Corresponding author: Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu, 610041, China.
Summary: Background: Innate immunity and metabolites link to the pathogenesis and severity of acute pancreatitis (AP). However, liver metabolism and its role in immune response and AP progression remain elusive. We investigated the function of liver metabolism in the pathogenesis of AP. Methods: Circulating ketone body β-hydroxybutyrate (βOHB) levels were determined in AP clinical cohorts and caerulein-induced AP (CER-AP) mouse models receiving seven (Cer*7) or twelve (Cer*12) injection regimens at hourly intervals. Liver transcriptomics and metabolomics were compared between CER-AP (Cer*7) and CER-AP (Cer*12). Inhibition of fatty acid β-oxidation (FAO)-ketogenesis, or supplementation of βOHB was performed in mouse models of AP. The effect and mechanism of βOHB were examined in vitro. Findings: Elevated circulating βOHB was observed in patients with non-severe AP (SAP) but not SAP. These findings were replicated in CER-AP (Cer*7) and CER-AP (Cer*12), which manifested as limited and hyperactive immune responses, respectively. FAO-ketogenesis was activated in CER-AP (Cer*7), while impaired long-chain FAO and mitochondrial function were observed in the liver of CER-AP (Cer*12). Blockage of FAO-ketogenesis (Cpt1a antagonism or Hmgcs2 knockdown) worsened, while supplementation of βOHB or its precursor 1,3-butanediol alleviated the severity of CER-AP. Mechanistically, βOHB had a discernible effect on pancreatic acinar cell damage, instead, it greatly attenuated the activation of pancreatic and systemic proinflammatory macrophages via class I histone deacetylases. Interpretation: Our findings reveal that hepatic ketogenesis is activated as an endogenous protective programme to restrain AP progression, indicating its potential therapeutic value. Funding: This work was supported by the National Natural Science Foundation of China, Shanghai Youth Talent Support Programme, and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant.
