Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emer ging Role of Lipin-1.
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.
4209 State Route 44, Rootstown OH 44272. United States.
Min
M
You
Department of Pharmaceutical Sciences. 0.
Alvin
A
Jogasuria
Department of Pharmaceutical Sciences. 0.
Kwangwon
K
Lee
Department of Pharmaceutical Sciences. 0.
Jiashin
J
Wu
Department of Integrative Medical Sciences, Northeast Ohio Medical University, College of Pharmacy and College of Medicine, Rootstown OH 44272. United States.
Yanqiao
Y
Zhang
Department of Integrative Medical Sciences, Northeast Ohio Medical University, College of Pharmacy and College of Medicine, Rootstown OH 44272. United States.
Yoon Kwang
YK
Lee
Department of Pharmaceutical Sciences. 0.
Prabodh
P
Sadana
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000431:Ethanol / Q000737:chemistry / Q000378:metabolism*; D005235:Fatty Liver, Alcoholic / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D010711:Phosphatidate Phosphatase / Q000378:metabolism*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism
D000431:Ethanol; D055372:AMP-Activated Protein Kinases; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase; D056564:Sirtuin 1
Lipin-1; alcoholic fatty liver disease; inflammation; lipid metabolism; signal
transduction; transcriptional regulators