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

Author:

Cui Donghai1,Wang Zixiang1ORCID,Dang Qianli1,Wang Jing1,Qin Junchao1,Song Jianping1,Zhai Xiangyu1,Zhao Ling1,Lu Gang2,Liu Hongbin3,Liu Runping4,Shao Changshun5ORCID,Zhang Xiyu1ORCID,Liu Zhaojian1ORCID

Affiliation:

1. Shandong University

2. The Chinese University of Hong Kong

3. Shandong Provincial Hospital Affiliated to Shandong University

4. Beijing University of Chinese Medicine

5. Suzhou Medical College of Soochow University

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.

Publisher

Research Square Platform LLC

Reference43 articles.

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