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

摘要

Alcohol exposure is a major reason of morbidity and mortality all over the world, with much of detrimental consequences attributing to alcoholic liver disease (ALD). With the continued ethanol consumption, alcoholic fatty liver disease (AFLD, the earliest and reversible form of ALD) can further develop to more serious forms of alcoholic liver damage, including alcoholic steatohepatitis, fibrosis/cirrhosis, and even eventually progress to hepatocellular carcinoma and liver failure. Furthermore, cell trauma, inflammation, oxidative stress, regeneration, and bacterial translocation are crucial promoters of ethanol-mediated liver lesions. AFLD is characterized by excessive fat deposition in liver induced by excessive drinking, which is related closely to the raised synthesis of fatty acids and triglyceride, reduction of mitochondrial fatty acid β-oxidation, and the aggregation of very-low-density lipoprotein (VLDL). Although little is known about the cellular and molecular mechanisms of AFLD, it seems to be correlated to diverse signal channels. Massive studies have suggested that liver steatosis is closely associated with the inhibition of silent information regulator 1 (SIRT1) and the augment of lipin1 β/α ratio mediated by ethanol. Recently, serine/arginine-rich splicing factor 10 (SFRS10), a specific molecule functioning in alternative splicing of lipin 1 (LPIN1) pre-mRNAs, has emerged as the central connection between SIRT1 and lipin1 signaling. It seems a new signaling axis, SIRT1–SFRS10–LPIN1 axis, acting in the pathogenesis of AFLD exists. This article aims to further explore the interactions among the above three molecules and their influences on the development of AFLD.Impact statementALD is a major health burden in industrialized countries as well as China. AFLD, the earliest and reversible form of ALD, can progress to hepatitis, fibrosis/cirrhosis, even hepatoma. While the mechanisms, by which ethanol consumption leads to AFLD, are complicated and multiple, and remain incompletely understood. SIRT1, SFRS10, and LIPIN1 had been separately reported to participate in lipid metabolism and the pathogenesis of AFLD. Noteworthy, we found the connection among them via searching articles in PubMed and we had elaborated the connection in detail in this minireview. It seems a new signaling axis, SIRT1–SFRS10–LIPIN1 axis, acting in the pathogenesis of AFLD exists. Further study aimed at SIRT1–SFRS10–LIPIN1 signaling system will possibly offer a more effective therapeutic target for AFLD.