Targeting hepatic serine-arginine protein kinase 2 ameliorates alcohol-associated liver disease by alternative splicing control of lipogenesis
Targeting hepatic serine-arginine protein kinase 2 ameliorates alcohol-associated liver disease by alternative splicing control of lipogenesis
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DOI：
10.1097/hep.0000000000000433
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发表时间：
2023-05
期刊：
影响因子：
13.5
通讯作者：
Guannan Li;Hanqing Chen;Feng Shen;Steven Blake Smithson;Gavyn Lee Shealy;Q. Ping;Zerong Liang;Jingyan Han;A. Adams;Y. Li;D. Feng;Bin Gao;M. Morita;Xianlin Han;T. Huang;N. Musi;Mengwei Zang
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文献类型：
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作者：
Guannan Li;Hanqing Chen;Feng Shen;Steven Blake Smithson;Gavyn Lee Shealy;Q. Ping;Zerong Liang;Jingyan Han;A. Adams;Y. Li;D. Feng;Bin Gao;M. Morita;Xianlin Han;T. Huang;N. Musi;Mengwei Zang
背景和目标：饮酒引起的脂质蓄积不仅是酒精相关性肝病（ALD）的早期病理生理反应，也是ALD进展的先决条件。选择性剪接调节基因表达和蛋白质多样性;这一过程的失调与人类肝脏疾病有关。然而，如何选择性剪接调节脂质代谢有助于ALD的发病机制仍不清楚。方法和结果：富含丝氨酸-精氨酸的蛋白激酶2（SRPK 2）是一种控制选择性剪接的关键激酶，在酒精刺激下，在长期饮酒的小鼠和ALD患者的肝细胞中被激活。这种诱导激活固醇调节元件结合蛋白1并促进ALD中的脂肪生成。FGF 21在转基因小鼠中的过表达消除了酒精介导的SRPK 2诱导及其相关的脂肪变性、脂毒性和炎症;这些酒精诱导的病理在FGF 21敲除小鼠中加重。从机制上讲，SRPK 2是酒精介导的丝氨酸-精氨酸剪接因子10受损所必需的，丝氨酸-精氨酸剪接因子10产生Lipin 1中的外显子7包含物，并触发脂肪生成调节因子-Lipin 1β和固醇调节元件结合蛋白1的同时诱导。FGF 21通过雷帕霉素复合物1的哺乳动物靶点抑制SRPK 2的依赖性降解来抑制酒精诱导的SRPK 2积累。沉默SRPK 2拯救FGF 21敲除小鼠中酒精诱导的剪接失调和肝损伤结论：这些研究表明：（1）SRPK 2对选择性剪接的调节与ALD患者的脂肪生成有关;（2）FGF 21是一种关键的肝细胞因子，主要通过抑制SRPK 2来改善ALD病理;（3）FGF 21靶向SRPK 2信号传导可能提供对抗ALD的潜在治疗方法。
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.