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

• DOI: 10.2337/db21-0857
• Publication Date: 2022-02-22T20:36:22Z
• Authors: Yuguo Niu; Haizhou Jiang; Hanrui Yin; Fenfen Wang; Ronggui Hu; Xiaoming Hu; Bo Peng; Yousheng Shu; Zhigang Li; Shanghai Chen; Feifan Guo
• Keywords: Inflammation; 0301 basic medicine; Diet, High-Fat; Aminopeptidases; 3. Good health; Mice, Inbred C57BL; Minor Histocompatibility Antigens; Mice; 03 medical and health sciences; 0302 clinical medicine; Diabetes Mellitus, Type 2; Animals; Insulin Resistance; Muscle, Skeletal

Chronic inflammation in liver induces insulin resistance systemically and other tissues, including the skeletal muscle (SM); however, 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 revealed that expression hepatokine endoplasmic reticulum aminopeptidase 1 (ERAP1) was upregulated by a HFD. Increased ERAP1 levels were also observed interferon-γ–treated hepatocytes. Furthermore, hepatic overexpression attenuated systemic SM sensitivity, whereas knockdown had opposite effects, with corresponding changes serum levels. Mechanistically, functions as an antagonist-like factor, interacts β2 adrenergic receptor (ADRB2) reduces its decreasing ubiquitin-specific peptidase 33–mediated deubiquitination thereby interrupts ADRB2-stimulated signaling SM. The findings this study indicate is inflammation-induced impairs sensitivity. Its inhibition may provide therapeutic strategy for resistance–related diseases, such type 2 diabetes.