Islr regulates insulin sensitivity by interacting with Psma4 to control insulin receptor alpha levels in obese mice
Islr regulates insulin sensitivity by interacting with Psma4 to control insulin receptor alpha levels in obese mice
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DOI：
10.1016/j.biocel.2023.106420
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发表时间：
2023-05-04
影响因子：
4
通讯作者：
Meng，Qingyong
中科院分区：
文献类型：
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作者：
Zhang，Yuying;Lan，Miaomiao;Meng，Qingyong
胰岛素抵抗是2型糖尿病（T2D）的主要原因，而胰岛素受体信号失调是这种胰岛素抵抗的主要表现。在T2D中，相应的胰岛素受体水平异常下调，这是肥胖诱导脂肪组织胰岛素抵抗的主要因素之一。然而，肥胖个体胰岛素受体损伤的确切机制尚不清楚。在本研究中，我们确定了高脂饮食小鼠脂肪细胞中含有富亮氨酸重复序列（Islr）的免疫球蛋白超家族高表达。我们进一步证明，通过特异性地与蛋白酶体亚基α 4 （Psma4）相互作用，Islr介导胰岛素受体α (Insrα)的泛素非依赖性蛋白酶体降解。敲除Islr增加了相应的Insrα亚基水平，增强了脂肪细胞的胰岛素敏感性，最终改善了全身代谢。此外，sirna介导的肥胖小鼠白色脂肪组织中Islr表达的下调增加了胰岛素敏感性。总体而言，在肥胖小鼠中，Islr通过与Psma4相互作用来调节胰岛素敏感性，从而控制Insrα的泛素非依赖性蛋白酶体降解，这表明Islr可能是改善胰岛素抵抗的潜在治疗靶点。
Insulin resistance is the leading cause of type 2 diabetes (T2D), and dysfunctional insulin receptor signaling is a major manifestation of this insulin resistance. In T2D, the corresponding insulin receptor levels are aberrantly down-regulated, which is one of the major factors underlying obesity-induced insulin resistance in adipose tissue. However, the precise mechanism of insulin receptor impairment in obese individuals remains unclear. In the current study, we established that immunoglobulin superfamily containing leucine-rich repeat (Islr) is highly expressed in adipocytes of mice fed a high-fat diet. We further demonstrated that Islr mediates the ubiquitin-independent proteasomal degradation of insulin receptor alpha (Insrα) by specifically interacting with proteasome subunit alpha type 4 (Psma4). Islr knockout increased the corresponding Insrα subunit levels and enhanced insulin sensitivity in adipocytes, ultimately improving systemic metabolism. Further, siRNA-mediated down-regulation of Islr expression in the white adipose tissue of obese mice increased insulin sensitivity. Overall, Islr regulates insulin sensitivity by interacting with Psma4 to control the ubiquitin-independent proteasomal degradation of Insrα in obese mice, indicating that Islr may be a potential therapeutic target for ameliorating insulin resistance.