2. Academic Validation
  3. Hepatokine ERAP1 Disturbs Skeletal Muscle Insulin Sensitivity Via Inhibiting USP33-Mediated ADRB2 Deubiquitination

Hepatokine ERAP1 Disturbs Skeletal Muscle Insulin Sensitivity Via Inhibiting USP33-Mediated ADRB2 Deubiquitination

  • Diabetes. 2022 May 1;71(5):921-933. doi: 10.2337/db21-0857.
Yuguo Niu 1 2,  Haizhou Jiang 2,  Hanrui Yin 2,  Fenfen Wang 2,  Ronggui Hu 3,  Xiaoming Hu 1,  Bo Peng 1,  Yousheng Shu 1,  Zhigang Li 2,  Shanghai Chen 1,  Feifan Guo 1 2 4
Affiliations

Affiliations

  • 1 Zhongshan Hospital, State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, Ministry of Education Frontiers Center for Brain Science, Fudan University, Shanghai, China.
  • 2 Chinese Academy of Sciences (CAS) Key Laboratory of Nutrition, Metabolism and Food Safety, Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 3 Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
  • 4 Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
PMID: 35192681 DOI: 10.2337/db21-0857
Abstract

Chronic inflammation in liver induces Insulin resistance systemically and in other tissues, including the skeletal muscle (SM); however, the underlying mechanisms remain largely unknown. RNA Sequencing of primary hepatocytes from wild-type mice fed long-term high-fat diet (HFD), which have severe chronic inflammation and Insulin resistance revealed that the expression of hepatokine endoplasmic reticulum Aminopeptidase 1 (ERAP1) was upregulated by a HFD. Increased ERAP1 levels were also observed in interferon-γ-treated primary hepatocytes. Furthermore, hepatic ERAP1 overexpression attenuated systemic and SM Insulin sensitivity, whereas hepatic ERAP1 knockdown had the opposite effects, with corresponding changes in serum ERAP1 levels. Mechanistically, ERAP1 functions as an antagonist-like factor, which interacts with β2 Adrenergic Receptor (ADRB2) and reduces its expression by decreasing ubiquitin-specific peptidase 33-mediated deubiquitination and thereby interrupts ADRB2-stimulated Insulin signaling in the SM. The findings of this study indicate ERAP1 is an inflammation-induced hepatokine that impairs SM Insulin sensitivity. Its inhibition may provide a therapeutic strategy for Insulin resistance-related diseases, such as type 2 diabetes.

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