Spliceosome component Usp39 contributes to hepatic lipid homeostasis through the regulation of lipophagy

Abstract

Abstract Regulation of alternative splicing (AS) enables a single transcript to yield multiple isoforms that increase transcriptome and proteome diversity. Here, we report that spliceosome component Usp39 plays a critical role in the regulation of hepatocyte lipid homeostasis. We demonstrate that Usp39 expression is downregulated in hepatic tissues of NAFLD and non-alcoholic steatohepatitis (NASH) subjects. Hepatocyte-specific Usp39 deletion leads to increased lipid accumulation, spontaneous steatosis and impaired autophagy. Combined analysis of RIP-seq and RNA-seq data reveals that Usp39 regulates AS of several autophagy-related genes. For example, deletion of Usp39 results in alternative 5’ splice site selection of exon 6 in Heat shock transcription factor 1 (Hsf1) and consequently reduced expression. Importantly, overexpression of Hsf1 restores attenuated lipid accumulation caused by Usp39 deficiency. Taken together, our findings indicate that Usp39-mediated AS is crucial for sustaining lipophagy and lipid homeostasis in the liver.