The Role Of Lipin-1 In The Pathogenesis Of Alcoholic Fatty Liver

Objective : Clinically, alcoholic liver disease(ALD) is caused by long-term heavy drinking. Alcohol fatty liver disease(AFLD) is the early phase, which is characterized by increased accumulation of lipid in the liver of patients. Ethanol could cause lipid metabolic disturbance in many ways, and the development of AFLD has been attributed to a combined increase in the rate of de novo lipogenesis and a decrease in the rate of fatty acid oxidation in animal liver. Growing evidence has demonstrated that lipin-1 plays an important role in lipid metabolism, which is regulated by ethanol in ALD. Recent studies indicate that lipin-1 exhibits dual distinct functions in lipid metabolism depending on its subcellular localization. In the cytoplasm, lipin-1 functions as a Mg2+-dependent phosphatidic acid phosphohydrolase(PAP) enzyme in the triglyceride synthesis pathway. When lipin-1 enters the nucleus after sumoylation, it acts as a transcriptional co-regulator to regulate lipid metabolism. More importantly, ample experimental evidence has suggested that ethanol could induce the expression of lipin-1 through the AMPK- SREBP-1 signaling and dramatically induce the ratio of Lpin1β to Lpin1α by SIRT1-SFRS10- Lpin1β/α axis in the liver. This review aims to integrate the current research findings of ethanol-mediated dysregulation of lipin-1 and to provide a viewpoint for understanding the role of lipin-1 in the pathogenesis of ALD.Methods: We bought 50 male depuratory grade Wistar rats that weighting about 200士20g. First they were acclimatized for one week. Ten rats were chosen as the normal control group. Other 40 rats were to develop the model of ALD. The model were treated by intragastric alcohol of increasing concentration 30%-60%,5-9g·Kg-1·d-1. At 4th, 10 rats were sacrificed, at 8th, 9 rats were sacrificed, at 12 th, 8 rats were sacrificed, and at 16 th, 8 rats were sacrificed. The hepatic tissue were frozen in liquid nitrogen,then in-80℃ fridge. In the end, we detect the expression of SFRS10、lipin-1α、 lipin-1β、 lipin-1 protein by Western blot and m RNA by RT-q PCR.Results: 1 Changes of m RNA expression of SFRS10 in the liver of rats by RT-q PCR:There were a lot expression of SFRS10, lipin-1, lipin-1β and lipin-1α in hepatic tissue of rats in normal control group. 1.1 The expression of SFRS10 decreased gradually with the progress of ALD,and compared with those of the normal control group(0.64±0.04 VS 0.54±0.03, 0.42±0.05, 0.35±0.03, 0.20±0.05; 0.20±0.05 VS 0.64±0.04, 0.54±0.03, 0.42±0.05, 0.35±0.03, all P<0.01). 1.2 The expression of lipin-1 and lipin-1β m RNA in the liver of rats by RT-q PCR:There were a little expression of lipin-1 and lipin-1β in hepatic tissue of rats in normal control group.The expression of lipin-1 and lipin-1β up- regulated gradually with the progress of ALD,and compared with those of the normal control group, lipin-1 : 0.20±0.03 VS 0.29±0.04, 0.42±0.04, 0.48±0.03, 0.55±0.04; 0.55±0.04 VS 0.20±0.03 0.29±0.04, 0.42±0.04, 0.48±0.03, all P<0.01; lipin-1β: 0.11±0.02 VS 0.32±0.02, 0.39±0.02, 0.44±0.02, 0.54±0.03; 0.54±0.03 VS 0.11±0.02, 0.32±0.02, 0.39±0.02, 0.44±0.02,all P<0.01; In contrast, the expression of lipin-1α m RNA in the liver of rats by RT-q PCR:There were a lot expression of lipin-1α in hepatic tissue of rats in normal control group.The expression of lipin-1α decreased gradually with the progress of ALD,and compared with those of the normal control group(0.54±0.02 VS 0.47±0.03, 0.32±0.03, 0.23±0.03, 0.18±0.02; 0.18±0.02 VS 0.54±0.02, 0.47±0.03, 0.32± 0.03, 0.23±0.03, all P<0.01). 1.3 The ratio of lipin-1β to lipin-1α up-regulated gradually with the progress of ALD,and compared with those of the normal control group, all P<0.05. 2 Changes of protein expression of SFRS10, lipin-1, lipin-1β and lipin-1α in the liver of rats by Western blot. 2.1 There were a lot expression of SFRS10 in hepatic tissue of rats in normal control group.The expression of SFRS10 decreased gradually with the progress of ALD,and compared with those of the normal control group(0.84±0.07 VS 0.58±0.07, 0.42±0.09, 0.28±0.05; 0.28±0.05 VS 0.84±0.07, 0.75±0.08, 0.58±0.07, 0.42±0.09,all P<0.01), but 4th compared with normal group(0.84±0.07 VS 0.75±0.08, P<0.05). 2.2 The expression of all lipin-1 and lipin-1β protein in the liver of rats by Western blot:There were a little expression of all lipin-1 and lipin-1β in hepatic tissue of rats in normal control group.The expression of all lipin-1 and lipin-1β increased gradually with the progress of ALD,and compared with those of the normal control group : lipin-1:(0.25±0.06 VS 0.41±0.07, 0.52±0.05, 0.77±0.10, 0.85±0.05; 0.85±0.05 VS 0.25±0.06, 0.41±0.07, 0.52±0.05, all P<0.01), but the 12 th compared with 16th(0.85±0.05 VS 0.77±0.10, P<0.05); lipin-1β: 0.13±0.03 VS 0.25±0.05, 0.39±0.03, 0.69±0.05, 0.74±0.05; 0.74±0.05 VS 0.13±0.03 VS 0.25±0.05, 0.39±0.03,all P<0.01),but the 12 th compared with 16th(0.74±0.05 VS 0.69±0.05, P<0.05).In contrast, the expression of lipin-1α protern in the liver of rats by Western blot:There were a lot expression of lipin-1α in hepatic tissue of rats in normal control group. The expression of lipin-1α decreased gradually with the progress of ALD,and compared with those of the normal control group(0.59±0.05 VS 0.44±0.05, 0.31±0.03, 0.17±0.02, 0.10±0.03; 0.10±0.03 VS 0.59±0.05, 0.44±0.05, 0.31±0.03, 0.17±0.02, all P<0.01).Conclusions:1 In the process of ALD, the consumption of ethanol increase, ethanol could induced the ratio of Lpin1β/α compared with controls though nhibiting the level of SFRS10 expression, an a result, the expression of lipin-1α is more and more decreased in nucleus, the expression of lipin-1β is more and more increased in cytoplasm.2 It is the redistribution of lipin-1 that induce the fat accumulation in hepatocyte. So it may be one of the pathogenesis of ALD.