Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emer ging Role of Lipin-1.
Humans; Animals; AMP-Activated Protein Kinases/metabolism; Signal Transduction; Lipid Metabolism; Fatty Liver; Liver/metabolism; lipid metabolism; alcoholic fatty liver disease; inflammation; Lipin-1; signal transduction; transcriptional regulators; Phosphatidate Phosphatase/*metabolism; Inflammation/metabolism; Ethanol/chemistry/*metabolism; Sirtuin 1/metabolism; Alcoholic/*metabolism/pathology
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
You Min; Jogasuria Alvin; Lee Kwangwon; Wu Jiashin; Zhang Yanqiao; Lee Yoon-Kwang; Sadana Prabodh
Current molecular pharmacology
2017
1905-7
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/1874467208666150817112109" target="_blank" rel="noreferrer noopener">10.2174/1874467208666150817112109</a>
Sirtuin 1 signaling and alcoholic fatty liver disease.
lipid metabolism; inflammation; signal transduction; transcriptional regulators; alcoholic fatty liver; Sirtuin 1 (SIRT1)
Alcoholic fatty liver disease (AFLD) is one of the most prevalent forms of liver disease worldwide and can progress to inflammation (hepatitis), fibrosis/cirrhosis, and ultimately lead to end stage liver injury. The mechanisms, by which ethanol consumption leads to AFLD, are complicated and multiple, and remain incompletely understood. Nevertheless, understanding its pathogenesis will facilitate the development of effective pharmacological or nutritional therapies for treating human AFLD. Chronic ethanol consumption causes steatosis and inflammation in rodents or humans by disturbing several important hepatic transcriptional regulators, including AMP-activated kinase (AMPK), lipin-1, sterol regulatory element binding protein 1 (SREBP-1), PPARgamma co-activator-1alpha (PGC-1alpha), and nuclear transcription factor-kappaB (NF-kappaB). Remarkably, the effects of ethanol on these regulators are mediated in whole or in part by inhibition of a central signaling molecule, sirtuin 1 (SIRT1), which is a nicotinamide adenine dinucleotide (NAD(+), NADH)-dependent class III protein deacetylase. In recent years, SIRT1 has emerged as a pivotal molecule controlling the pathways of hepatic lipid metabolism, inflammatory responses and in the development of AFLD in rodents and in humans. Ethanol-mediated SIRT1 inhibition suppresses or stimulates the activities of above described transcriptional regulators and co-regulators, thereby deregulating diverse lipid metabolism and inflammatory response pathways including lipogenesis, fatty acid beta-oxidation, lipoprotein uptake and secretion and expression of pro-inflammatory cytokines in the liver. This review aims to highlight our current understanding of SIRT1 regulatory mechanisms and its response to ethanol-induced toxicity, thus, affirming significant role of SIRT1 signaling in the development of AFLD.
You Min; Jogasuria Alvin; Taylor Charles; Wu Jiashin
Hepatobiliary surgery and nutrition
2015
2015-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3978/j.issn.2304-3881.2014.12.06" target="_blank" rel="noreferrer noopener">10.3978/j.issn.2304-3881.2014.12.06</a>