An antisense transcript transcribed from Irs2 locus contributes to the pathogenesis of hepatic steatosis in insulin resistance
An antisense transcript transcribed from Irs2 locus contributes to the pathogenesis of hepatic steatosis in insulin resistance
复制标题
从 Irs2 位点转录的反义转录物有助于胰岛素抵抗中肝脂肪变性的发病机制
DOI：
10.1016/j.chembiol.2021.12.008
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发表时间：
2022
影响因子：
8.6
通讯作者：
Ueki Kohjiro
中科院分区：
文献类型：
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作者：
Matsushita Maya;Awazawa Motoharu;Kobayashi Naoki;Ikushima Yoshiko Matsumoto;Soeda Kotaro;Tamura-Nakano Miwa;Muratani Masafumi;Kobayashi Kenta;Bl?her Matthias;Br?ning Jens C.;Ueki Kohjiro
在胰岛素抵抗期间，过氧化物酶体增殖物激活蛋白（PPAR）γ上调促进肝脏的脂质摄取，导致肝脏脂肪变性。然而，胰岛素并不直接调节肝脏中脂肪形成基因的表达，其在肥胖症中上调的机制仍不清楚。在此，我们发现Irs2位点，胰岛素作用的关键调节因子，编码反义转录物ASIrs2，其在肥胖或再喂养后在肝脏中的表达增加，与Irs2的表达相反。ASIrs2调节肝脏Ppar g表达，其抑制可改善肥胖小鼠的脂肪变性。人类直系同源物AL162497.1的表达与肝PPARG的表达和非酒精性脂肪性肝炎（NASH）的严重程度相关，其基因组结构与ASIrs2相似。我们还鉴定了HARS2作为ASRS2的潜在结合蛋白，作为Pparg的调节剂发挥作用。总的来说，我们的数据揭示了Irs2基因位点的功能双重性，在肥胖中Irs2和ASIrs2的相互变化导致胰岛素抵抗和脂肪变性。
During insulin resistance, lipid uptake by the liver is promoted by peroxisome proliferator-activated protein (PPAR) γ upregulation, leading to hepatic steatosis. Insulin, however, does not directly regulate adipogenic gene expression in liver, and the mechanisms for its upregulation in obesity remain unclear. Here, we show that theIrs2locus, a critical regulator of insulin actions, encodes an antisense transcript,ASIrs2, whose expression increases in obesity or after refeeding in liver, reciprocal to that ofIrs2.ASIrs2regulates hepaticPpargexpression, and its suppression ameliorates steatosis in obese mice. The human orthologAL162497.1, whose expression is correlated with that of hepaticPPARGand the severity of non-alcoholic steatohepatitis (NASH), shows genomic organization similar to that ofASIrs2. We also identified HARS2 as a potential binding protein forASIrs2, functioning as a regulator ofPparg. Collectively, our data reveal a functional duality of theIrs2gene locus, where reciprocal changes ofIrs2andASIrs2in obesity cause insulin resistance and steatosis.