脂肪生成
精氨酸
丝氨酸
选择性拼接
脂肪肝
化学
磷酸化
内科学
医学
生物化学
氨基酸
基因
外显子
疾病
作者
Guannan Li,Hanqing Chen,Feng Shen,Steven Blake Smithson,Gavyn Lee Shealy,Qinggong Ping,Zerong Liang,Jing‐Yan Han,Andrew C. Adams,Yu Liu,Dechun Feng,Bin Gao,Masahiro Morita,Xianlin Han,Tim H.M. Huang,Nicolas Musi,Mengwei Zang
出处
期刊:Hepatology
[Wiley]
日期:2023-05-03
卷期号:78 (5): 1506-1524
被引量:6
标识
DOI:10.1097/hep.0000000000000433
摘要
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.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.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.
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