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Review
. 2017;10(3):226-236.
doi: 10.2174/1874467208666150817112109.

Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emer ging Role of Lipin-1

Min You  1 , Alvin Jogasuria  2 , Kwangwon Lee  2 , Jiashin Wu  2 , Yanqiao Zhang  3 , Yoon Kwang Lee  3 , Prabodh Sadana  2
Affiliations
Review

Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emer ging Role of Lipin-1

Min You et al. Curr Mol Pharmacol. 2017.

Abstract

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.

Keywords: Lipin-1; alcoholic fatty liver disease; inflammation; lipid metabolism; signal transduction; transcriptional regulators.

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Figures

Figure 1
Figure 1. Proposed role of lipin-1 in the development and progression of alcoholic fatty liver disease
Abbreviations: Ac, acetylated; ER, endoplasmic reticulum; NFATc4, nuclear factor of activated T cells c4; mTORC1, mammalian target of rapamycin complex 1; PAP, phosphatidate phosphatase; PPAR, peroxisome proliferator-activated receptor; PGC-1α, PPARγ co-activator-alpha; SREBP-1, sterol regulatory element-binding protein 1; TG, triglyceride; VLDL, very low-density lipoprotein.
Figure 2
Figure 2. Proposed mechanisms by which ethanol regulates hepatic lipin-1
Abbreviations: AMPK, AMP-activated kinase; GCs, glucocorticoids; mTOR, mammalian target of rapamycin; NF-Y; nuclear factor-Y; PAP, phosphatidate phosphatase;SIRT1, Sirtuin 1; ROS, reactive oxygen species; SREBP-1, sterol regulatory element-binding protein 1
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