Targeting hepatic serine-arginine protein kinase 2 ameliorates alcohol-associated liver disease by alternative splicing control of lipogenesis.

Autor:	Li G; Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging, University of Texas Health San Antonio, Texas, USA.; Department of Molecular Medicine, University of Texas Health San Antonio, Texas, USA., Chen H; Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging, University of Texas Health San Antonio, Texas, USA.; Department of Molecular Medicine, University of Texas Health San Antonio, Texas, USA., Shen F; Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging, University of Texas Health San Antonio, Texas, USA.; Department of Molecular Medicine, University of Texas Health San Antonio, Texas, USA., Smithson SB; Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging, University of Texas Health San Antonio, Texas, USA.; Department of Molecular Medicine, University of Texas Health San Antonio, Texas, USA., Shealy GL; Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging, University of Texas Health San Antonio, Texas, USA.; Department of Molecular Medicine, University of Texas Health San Antonio, Texas, USA., Ping Q; Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging, University of Texas Health San Antonio, Texas, USA.; Department of Molecular Medicine, University of Texas Health San Antonio, Texas, USA., Liang Z; Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging, University of Texas Health San Antonio, Texas, USA.; Department of Molecular Medicine, University of Texas Health San Antonio, Texas, USA., Han J; Boston University School of Medicine, Boston, Massachusetts, USA., Adams AC; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA., Li Y; CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China., Feng D; Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA., Gao B; Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA., Morita M; Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging, University of Texas Health San Antonio, Texas, USA.; Department of Molecular Medicine, University of Texas Health San Antonio, Texas, USA., Han X; Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging, University of Texas Health San Antonio, Texas, USA., Huang TH; Department of Molecular Medicine, University of Texas Health San Antonio, Texas, USA., Musi N; Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging, University of Texas Health San Antonio, Texas, USA.; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas, USA., Zang M; Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging, University of Texas Health San Antonio, Texas, USA.; Department of Molecular Medicine, University of Texas Health San Antonio, Texas, USA.; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas, USA.
Jazyk:	angličtina
Zdroj:	Hepatology (Baltimore, Md.) [Hepatology] 2023 Nov 01; Vol. 78 (5), pp. 1506-1524. Date of Electronic Publication: 2023 May 03.
DOI:	10.1097/HEP.0000000000000433
Abstrakt:	Background and Aims: Lipid accumulation induced by alcohol consumption is not only an early pathophysiological response but also a prerequisite for the progression of alcohol-associated liver disease (ALD). Alternative splicing regulates gene expression and protein diversity; dysregulation of this process is implicated in human liver diseases. However, how the alternative splicing regulation of lipid metabolism contributes to the pathogenesis of ALD remains undefined. Approach and Results: Serine-arginine-rich protein kinase 2 (SRPK2), a key kinase controlling alternative splicing, is activated in hepatocytes in response to alcohol, in mice with chronic-plus-binge alcohol feeding, and in patients with ALD. Such induction activates sterol regulatory element-binding protein 1 and promotes lipogenesis in ALD. Overexpression of FGF21 in transgenic mice abolishes alcohol-mediated induction of SRPK2 and its associated steatosis, lipotoxicity, and inflammation; these alcohol-induced pathologies are exacerbated in FGF21 knockout mice. Mechanistically, SRPK2 is required for alcohol-mediated impairment of serine-arginine splicing factor 10, which generates exon 7 inclusion in lipin 1 and triggers concurrent induction of lipogenic regulators-lipin 1β and sterol regulatory element-binding protein 1. FGF21 suppresses alcohol-induced SRPK2 accumulation through mammalian target of rapamycin complex 1 inhibition-dependent degradation of SRPK2. Silencing SRPK2 rescues alcohol-induced splicing dysregulation and liver injury in FGF21 knockout mice. Conclusions: These studies reveal that (1) the regulation of alternative splicing by SRPK2 is implicated in lipogenesis in humans with ALD; (2) FGF21 is a key hepatokine that ameliorates ALD pathologies largely by inhibiting SRPK2; and (3) targeting SRPK2 signaling by FGF21 may offer potential therapeutic approaches to combat ALD. (Copyright © 2023 American Association for the Study of Liver Diseases.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu