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

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.

Roles of silent information regulator 1–serine/arginine-rich splicing factor 10–lipin 1 axis in the pathogenesis of alcohol fatty liver disease

“…8,35,36 LPIN1 gene can encode three diverse isoforms, namely lipin-1 a, b, and g, by alternative splicing of pre-mRNA in human. 1,37 Lipin-1a and lipin-1b have been found principally settling in liver and skeletal muscle, while lipin-1g primarily in brain tissue regulating lipid metabolism. 37 Lipin1b, chiefly in the cytoplasm, transforms phosphatidate to DAG fostering TG synthesis and excessive hepatic fat accumulation by its PAP enzyme activity.…”

“…38 Furthermore, lipin1a restrains SREBP-1 expression and activity, resulting in weakened hepatic lipogenesis by downregulating lipid and cholesterol biosynthetic enzymes expression, 1,35,36 including FAS, mitochondrial glycerol-3-phosphate acyltransferase1, ACC, stearoyl-CoA desaturase, ATP citrate lyase, and malic enzyme. 1,39 In hepatocytes, ethanol may interdict lipin1 nuclear entry and upregulate SREBP-1 activity via triggering mammalian target of rapamycin complex 1-phosphorylated lipin1 signaling. 1,36,40 Moreover, lipin-1-PAP activity plays important role on SREBP-1 activation and the exacerbation of hepatic lipid accumulation.…”

“…1,36,40 Moreover, lipin-1-PAP activity plays important role on SREBP-1 activation and the exacerbation of hepatic lipid accumulation. 1,8 Paradoxically, chronic ethanol consumption to lipin1 LKO mice, which can abrogate the elevation of ethanol-induced intrahepatic PAP activity, has showed a significantly augmented lipid accumulation in liver, suggesting that lipin1 PAP activity might prevent from AFLD. 41 Lipin1 PAP activity may exert a protective role on AFLD via mediating autophagy, urging lipid storage, normalizing phosphatidic acid levels, regulating fatty acid catabolism or restraining inflammation.…”

“…41 Lipin1 PAP activity may exert a protective role on AFLD via mediating autophagy, urging lipid storage, normalizing phosphatidic acid levels, regulating fatty acid catabolism or restraining inflammation. 1,42,43 Under the physiology condition, it is the lipoprotein of VLDL which carries TG migration to plasma from liver. 44 Perturbations of VLDL assembly and secretion affect lipid homeostasis of liver and plasma lipoprotein profile.…”

“…6,8 Furthermore, post-translational modifications of lipin1 largely control its nucleocytoplasmic localization such as sumoylation, acetylation or phosphorylation of lipin-1. 1,8 Lipin1a is localized in both the cytoplasm and the nucleus of hepatocytes, 6 but its transcriptional co-activator activity works mainly in nucleus. 8 Both lipin1a and b are bedecked with sumoylation at two same sumoylation sites (K566/596).…”