Roles Of Silent Information Regulator 1-serine/arginine-rich Splicing Factor 10-lipin1 Axis In The Pathogenesis Of Alcoholic Fatty Liver Disease

Ethanol administration is a principal factor of alcoholic liver disease(ALD),with multiple detrimental clinical outcomes.Alcoholic fatty liver disease(AFLD)is the earliest feature of ALD and reversible.While AFLD can further progress to the severer liver lesions,such as alcoholic steatohepatitis,fibrosis or sclerosis and even liver cancer and liver failure,with the persistent ethanol exposure.The ethanol-mediated hepatic fat over-deposition,which is tightly linked with the gather of fatty acids,synthesis of triglyceride(TG),weakening of mitochondrial fatty acids β-oxidation and collection of very-low-density lipoprotein(VLDL),is the chief feature of AFLD.It seems to be tightly related to various signal pathways,although little is known about mechanisms of AFLD in cellular and molecular level.Lots of researches have verified that fatty degeneration of liver is closely linked to the ethanol-induced silent information regulator 1(SIRT1)impairment and lipin1β/α ratio increase.Presently,serine/arginine-rich splicing factor 10(SFRS10),a splicing factor specifically targeting to lipin1 pre-m RNAs,has been found as the crucial bridge between SIRT1 and lipin1 protein.Ethanol can downregulate hepatic SIRT1 expression and its deacetylation activity in multifarious manners,to disturb the regulation of SFRS10 acetylation state,reducing SFRS10 protein stability and expression in the liver,and then promote the inclusion of exon 6of LPIN1 gene,increasing lipin1β expression while reducing the expression of lipin1α.Finally,it results in the disturbance of lipid metabolism and excessive hepatic fat accumulation,promoting the occurrence and progress of the AFLD.