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.
复制标题
肝因子 ERAP1 通过抑制 USP33 介导的 ADRB2 去泛素化扰乱骨骼肌胰岛素敏感性。
作者：
Yuguo Niu;Haizhou Jiang;Hanrui Yin;Fenfen Wang;Ronggui Hu;Xiaoming Hu;B. Peng;Yousheng Shu;Zhigang Li;Shanghai Chen;Feifan Guo
肝脏的慢性炎症在系统和其他组织中诱导胰岛素抵抗，包括骨骼肌(SM)；然而，其潜在的机制在很大程度上仍不清楚。通过对长期高脂饮食(HFD)且存在严重慢性炎症和胰岛素抵抗的野生型小鼠原代肝细胞进行RNA-SEQ分析，发现HFD可上调肝细胞内质网氨基肽酶1(ERAP1)的表达。在干扰素-γ处理的原代肝细胞中也观察到ERAP1水平的增加。此外，肝脏ERAP1过表达降低了全身和SM的胰岛素敏感性，而肝脏ERAP1基因敲除则有相反的作用，血清ERAP1水平也发生了相应的变化。机制上，ERAP1作为一种拮抗剂样因子与β2肾上腺素能受体(ADRB2)相互作用，通过抑制泛素特异肽酶33(USP33)介导的去泛素化来减少ADRB2的表达，从而阻断ADRB2刺激的SM胰岛素信号转导。综上所述，ERAP1是一种炎症诱导的肝细胞因子，会损害SM的胰岛素敏感性。它的抑制可能为胰岛素抵抗相关疾病提供一种治疗策略，如2型糖尿病。
Chronic inflammation in liver induces insulin resistance systemically and in other tissues, including the skeletal muscle (SM); however, the underlying mechanisms remain largely unknown. By performing RNA-seq of primary hepatocytes from wild-type mice fed long term high-fat diet (HFD), which have severe chronic inflammation and insulin resistance, we found that the expression of hepatokine endoplasmic reticulum aminopeptidase 1 (ERAP1) was upregulated by 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 (USP33)-mediated deubiquitination, and thereby interrupts ADRB2-stimulated insulin signaling in the SM. Taken together, 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.