SLC7A11-ROS/αKG-AMPK axis regulates liver inflammation through mitophagy and impairs liver fibrosis and NASH progression
Tingting Lv,
Xiude Fan,
Chang He,
Suwei Zhu,
Xiaofeng Xiong,
Wei Yan,
Mei Liu,
Hongwei Xu,
Ruihua Shi,
Qin He
Affiliations
Tingting Lv
Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Department of Cancer Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu, 210009, China
Xiude Fan
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
Chang He
Medical College, Nantong University, Nantong, Jiangsu, 226001, China
Suwei Zhu
Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
Xiaofeng Xiong
Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
Wei Yan
Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
Mei Liu
Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
Hongwei Xu
Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Corresponding author.
Ruihua Shi
Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu, 210009, China; Corresponding author.
Qin He
Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu, 210009, China; Corresponding author. Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
The changes of inflammation and metabolism are two features in nonalcoholic steatohepatitis (NASH). However, how they interact to regulate NASH progression remains largely unknown. Our works have demonstrated the importance of solute carrier family 7 member 11 (SLC7A11) in inflammation and metabolism. Nevertheless, whether SLC7A11 regulates NASH progression through mediating inflammation and metabolism is unclear. In this study, we found that SLC7A11 expression was increased in liver samples from patients with NASH. Upregulated SLC7A11 level was also detected in two murine NASH models. Functional studies showed that SLC7A11 knockdown or knockout had augmented steatohepatitis with suppression of inflammatory markers in mice. However, overexpression of SLC7A11 dramatically alleviated diet-induced NASH pathogenesis. Mechanically, SLC7A11 decreased reactive oxygen species (ROS) level and promoted α-ketoglutarate (αKG)/prolyl hydroxylase (PHD) activity, which activated AMPK pathway. Furthermore, SLC7A11 impaired expression of NLRP3 inflammasome components through AMPK-mitophagy axis. IL-1β release through NLRP3 inflammasome recruited myeloid cells and promoted hepatic stellate cells (HSCs) activation, which contributed to the progression of liver injury and fibrosis. Anti-IL-1β and anakinra might attenuate the hepatic inflammatory response evoked by SLC7A11 knockdown. Moreover, the upregulation of SLC7A11 in NASH was contributed by lipid overload-induced JNK-c-Jun pathway. In conclusions, SLC7A11 acts as a protective factor in controlling the development of NASH. Upregulation of SLC7A11 is protective by regulating oxidation, αKG and energy metabolism, decreasing inflammation and fibrosis.
