Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emer ging Role of Lipin-1.
Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emer ging Role of Lipin-1.
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DOI：
10.2174/1874467208666150817112109
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发表时间：
2017
影响因子：
2.7
通讯作者：
Sadana P
中科院分区：
文献类型：
--
作者：
You M;Jogasuria A;Lee K;Wu J;Zhang Y;Lee YK;Sadana P
Lipin-1是一种哺乳动物磷脂酸磷酸酶（PAP），是一种双功能分子，通过其在甘油三酯合成途径中作为PAP酶的功能和在细胞核中作为转录共调节子的功能参与各种信号传导途径。在肝脏中，已知lipin-1在多个调节水平上控制脂质代谢和炎症过程中发挥重要作用。酒精性脂肪性肝病（AFLD）是最早的肝损伤形式之一，约8-20%的单纯性脂肪变性患者可发展为更严重的肝损伤形式，包括脂肪性肝炎、纤维化/肝硬化，最终发展为肝细胞癌（HCC）。酒精对肝脏损伤的信号转导机制涉及复杂的多条信号通路的改变，这些通路主要由一个中枢和上游信号系统，即sirtuin 1（SIRT 1）-AMP激活激酶（AMPK）轴控制。新出现的证据表明，lipin-1作为SIRT 1-AMPK信号系统的关键下游调节因子，可能最终导致AFLD的发生和进展。几条证据表明，乙醇暴露显着诱导lipin-1基因和蛋白质的表达水平在培养的肝细胞和啮齿动物的肝脏，诱导lipin-1-PAP活性，损害核lipin-1的功能活性，破坏lipin-1 mRNA选择性剪接和诱导lipin-1核质穿梭。这种响应于乙醇的损伤导致肝脏脂质代谢紊乱，以及啮齿动物和人类酗酒者肝脏中炎性细胞因子的过度产生。本文就Lipin-1在AFLD发病中的作用及其信号转导机制作一综述。
Lipin-1, a mammalian phosphatidic acid phosphatase (PAP), is a bi-functional molecule involved in various signaling pathways via its function as a PAP enzyme in the triglyceride synthesis pathway and in the nucleus as a transcriptional co-regulator. In the liver, lipin-1 is known to play a vital role in controlling the lipid metabolism and inflammation process at multiple regulatory levels. Alcoholic fatty liver disease (AFLD) is one of the earliest forms of liver injury and approximately 8–20% of patients with simple steatosis can develop into more severe forms of liver injury, including steatohepatitis, fibrosis/cirrhosis, and eventually hepatocellular carcinoma (HCC). The signal transduction mechanisms for alcohol-induced detrimental effects in liver involves alteration of complex and multiple signaling pathways largely governed by a central and upstream signaling system, namely, sirtuin 1 (SIRT1)-AMP activated kinase (AMPK) axis. Emerging evidence suggests a pivotal role of lipin-1 as a crucial downstream regulator of SIRT1-AMPK signaling system that is likely to be ultimately responsible for development and progression of AFLD. Several lines of evidence demonstrate that ethanol exposure significantly induces lipin-1 gene and protein expression levels in cultured hepatocytes and in the livers of rodents, induces lipin-1-PAP activity, impairs the functional activity of nuclear lipin-1, disrupts lipin-1 mRNA alternative splicing and induces lipin-1 nucleocytoplasmic shuttling. Such impairment in response to ethanol leads to derangement of hepatic lipid metabolism, and excessive production of inflammatory cytokines in the livers of the rodents and human alcoholics. This review summarizes current knowledge about the role of lipin-1 in the pathogenesis of AFLD and its potential signal transduction mechanisms.