Hepatic IL22RA1 deficiency promotes hepatic steatosis by modulating oxysterol in the liver

Author:

Huang Yeping1,Yu Fan1,Ding Yue2,Zhang Hong1,Li Xinyue1,Wang Xiao1,Wu Xiaoshan3,Xu Jie1,Wang Liang4,Tian Chenxu4,Jiang Min2,Zhang Rong1,Yan Chenyan56,Song Yingxiang56,Huang Haijun7,Xu Guangzhong4,Ding Qiurong3,Ye Xiao56,Lu Yan8ORCID,Hu Cheng19ORCID

Affiliation:

1. Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

2. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China

3. CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

4. Surgery Centre of Diabetes Mellitus, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China

5. Department of Endocrinology, Center for General Practice Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College. Hangzhou, Zhejiang, China

6. Key Laboratory for Diagnosis and Treatment of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China

7. Department of Infectious Diseases, Center for General Practice Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China

8. Institute of Metabolism and Regenerative Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

9. Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, China

Abstract

Background and Aims: An imbalance in lipid metabolism is the main cause of NAFLD. While the pathogenesis of lipid accumulation mediated by extrahepatic regulators has been extensively studied, the intrahepatic regulators modulating lipid homeostasis remain unclear. Previous studies have shown that systemic administration of IL-22 protects against NAFLD; however, the role of IL-22/IL22RA1 signaling in modulating hepatic lipid metabolism remains uncertain. Approach and Results: This study shows that hepatic IL22RA1 is vital in hepatic lipid regulation. IL22RA1 is downregulated in palmitic acid-treated mouse primary hepatocytes, as well as in the livers of NAFLD model mice and patients. Hepatocyte-specific Il22ra1 knockout mice display diet-induced hepatic steatosis, insulin resistance, impaired glucose tolerance, increased inflammation, and fibrosis compared with flox/flox mice. This is attributed to increased lipogenesis mediated by the accumulation of hepatic oxysterols, particularly 3 beta-hydroxy-5-cholestenoic acid (3β HCA). Mechanistically, hepatic IL22RA1 deficiency facilitates 3β HCA deposition through the activating transcription factor 3/oxysterol 7 alpha-hydroxylase axis. Notably, 3β HCA facilitates lipogenesis in mouse primary hepatocytes and human liver organoids by activating liver X receptor-alpha signaling, but IL-22 treatment attenuates this effect. Additionally, restoring oxysterol 7 alpha-hydroxylase or silencing hepatic activating transcription factor 3 reduces both hepatic 3β HCA and lipid contents in hepatocyte-specific Il22ra1 knockout mice. Conclusions: These findings indicate that IL22RA1 plays a crucial role in maintaining hepatic lipid homeostasis in an activating transcription factor 3/oxysterol 7 alpha-hydroxylase-dependent manner and establish a link between 3β HCA and hepatic lipid homeostasis.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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