Universität zu Köln

Matsushita, Maya, Awazawa, Motoharu, Kobayashi, Naoki, Ikushima, Yoshiko Matsumoto, Soeda, Kotaro, Tamura-Nakano, Miwa, Muratani, Masafumi, Kobayashi, Kenta, Blueher, Matthias, Bruening, Jens C. and Ueki, Kohjiro (2022). An antisense transcript transcribed from Irs2 locus contributes to the pathogenesis of hepatic steatosis in insulin resistance. Cell Chem. Biol., 29 (4). S. 680 - 697. CAMBRIDGE: CELL PRESS. ISSN 2451-9448

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Abstract

During insulin resistance, lipid uptake by the liver is promoted by peroxisome proliferator-activated protein (PPAR) gamma 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 similarto 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Matsushita, Maya UNSPECIFIED UNSPECIFIED UNSPECIFIED Awazawa, Motoharu UNSPECIFIED UNSPECIFIED UNSPECIFIED Kobayashi, Naoki UNSPECIFIED UNSPECIFIED UNSPECIFIED Ikushima, Yoshiko Matsumoto UNSPECIFIED UNSPECIFIED UNSPECIFIED Soeda, Kotaro UNSPECIFIED UNSPECIFIED UNSPECIFIED Tamura-Nakano, Miwa UNSPECIFIED UNSPECIFIED UNSPECIFIED Muratani, Masafumi UNSPECIFIED UNSPECIFIED UNSPECIFIED Kobayashi, Kenta UNSPECIFIED UNSPECIFIED UNSPECIFIED Blueher, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruening, Jens C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ueki, Kohjiro UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-691336
DOI:	10.1016/j.chembiol.2021.12.008
Journal or Publication Title:	Cell Chem. Biol.
Volume:	29
Number:	4
Page Range:	S. 680 - 697
Date:	2022
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	2451-9448
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PPAR-GAMMA; FATTY LIVER; EXPRESSION; PROTEIN; MICE Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69133