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Matsushita, M.* ; Awazawa, M.* ; Kobayashi, N.* ; Ikushima, Y.M.* ; Soeda, K.* ; Tamura-Nakano, M.* ; Muratani, M.* ; Kobayashi, K.* ; Blüher, M. ; Brüning, J.C.* ; Ueki, K.*

An antisense transcript transcribed from Irs2 locus contributes to the pathogenesis of hepatic steatosis in insulin resistance.

Cell Chem. Bio. 29, 680-689.e6 (2022)

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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 the Irs2 locus, a critical regulator of insulin actions, encodes an antisense transcript, ASIrs2, whose expression increases in obesity or after refeeding in liver, reciprocal to that of Irs2. ASIrs2 regulates hepatic Pparg expression, and its suppression ameliorates steatosis in obese mice. The human ortholog AL162497.1, whose expression is correlated with that of hepatic PPARG and the severity of non-alcoholic steatohepatitis (NASH), shows genomic organization similar to that of ASIrs2. We also identified HARS2 as a potential binding protein for ASIrs2, functioning as a regulator of Pparg. Collectively, our data reveal a functional duality of the Irs2 gene locus, where reciprocal changes of Irs2 and ASIrs2 in obesity cause insulin resistance and steatosis.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Pparg ; Fatty Liver ; Insulin Resistance ; Natural Antisense Transcript ; Non-coding Rna

ISSN (print) / ISBN 2451-9448

e-ISSN 2451-9456

Journal Cell Chemical Biology

Quellenangaben Volume: 29, Issue: 4, Pages: 680-689.e6

Publisher Cell Press

Publishing Place Cambridge, Massachusetts

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)