Usp21 Knockout Causes Abnormal Lipid Metabolism in Mouse and Its Polymorphism Correlates with Hypercholesterolemia in Outpatients

TL;DR

This study shows that Usp21 knockout in mice leads to elevated cholesterol and fatty acids, and a genetic variant near USP21 is linked to high cholesterol in humans.

Contribution

The novel finding is that Usp21 influences lipid metabolism in mice and that a USP21-related SNP correlates with hypercholesterolemia in humans.

Findings

Usp21 knockout mice had elevated total cholesterol and free fatty acids.

Genes Fabp7, Nlrc5, and Ppargc1a were upregulated in Usp21 KO mice.

The rs11421 SNP near USP21 is significantly associated with hypercholesterolemia in outpatients.

Abstract

Usp21, a member of the ubiquitin protease family, plays a vital role in various biological functions. However, the effects of Usp21 dysfunction remain incompletely understood. In this study, we generated Usp21 knockout (KO) mice. Blood tests showed no impairment of liver function but did reveal elevated levels of total cholesterol (T-CHOL) and free fatty acid (FFA) in Usp21 KO mice compared to wild-type (WT) mice. Next, we performed RNA-sequencing (RNA-seq) to identify genes that Usp21 regulates. The results highlighted several candidate genes based on their biological relevance, and their expression levels were validated by RT-qPCR. The Usp21 KO mice exhibited significant elevations in the expression of the genes Fabp7, Nlrc5, and Ppargc1a, which play an important role in lipid metabolism, compared to WT. These data suggest that Usp21 may play roles in lipid metabolism in association with Fabp7, Nlrc5 and Ppargc1a. To clarify the involvement of USP21 in human hypercholesterolemia, we examined single-nucleotide polymorphisms (SNPs) around USP21 in non-hypercholesterolemic and hypercholesterolemic outpatients. We found that the rs11421 SNP downstream of USP21 was significantly associated with hypercholesterolemia. These data suggest that Usp21 plays a role in mice and human lipid metabolism and that its polymorphism may be a diagnostic marker for human hypercholesterolemia.

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