Hepatic Knockdown of Splicing Regulator Slu7 Ameliorates Inflammation and Attenuates Liver Injury in Ethanol-Fed Mice

Aberrant pre-mRNA splicing plays a pivotal role in liver diseases. However, roles of splicing regulators in alcoholic liver disease are unknown. Here, we investigated a splicing regulator Slu7 in the development of alcoholic steatohepatitis. Adenovirus (Ad)-mediated alteration of hepatic Slu7 expression in mice pair-fed either with or without (as control) ethanol in their diet was utilized. Knockdown of hepatic Slu7 by Ad-Slu7shRNA treatment ameliorated inflammation and attenuated liver injury in mice after ethanol administration. Mechanistically, reducing liver Slu7 expression increased the expression of sirtuin 1 (SIRT1) full-length gene and repressed the splicing of SIRT1 into SIRT1-¿Exon8 isoform in ethanol-fed mice. Knockdown of hepatic Slu7 in the ethanol-fed mice also ameliorated splicing of lipin-1 and serine/arginine–rich splicing factor 3 (Srsf3). In concordance with ameliorated splicing of SIRT1, lipin-1, and Srsf3, knockdown of hepatic Slu7 inhibited the activity of nuclear factor kappa B (NF-¿B), normalized iron and zinc homeostasis, reduced oxidative stress, and attenuated liver damage in ethanol-fed mice. Additionally, hepatic Slu7 were significantly elevated in patients with alcoholic steatohepatitis. Our present study illustrates a novel role of Slu7 in alcoholic liver injury and suggests that dysregulated Slu7 may contribute to the pathogenesis of human alcoholic steatohepatitis.