The Samm50 Genetic Variant rs3761472 Causes Mitochondrial Dysfunction and the Progression of Non-Alcoholic Fatty Liver Disease

Abstract

A Genome-Wide Association Study on 8,842 Korean subjects as a part of a Korea Association Resource project at the Korea National Institute of Health identified 23 single nucleotide polymorphisms (SNPs) associated with liver and lipid metabolism. Among them, SAMM50 genetic variant rs3761472 has been also reported to be associated with Non-Alcoholic Fatty Liver Disease (NAFLD) in the Asian population. SAMM50 is a component of the mitochondrial outer membrane that involves in the sorting and assembly of beta-barrel proteins in mitochondria. However, the genuine biological function of this single nucleotide change has never been elucidated in vivo. To investigate the impact of Samm50 rs3761472 in mice, we converted D110 to G110 in the Samm50 gene by CRISPR-Cas9 genome editing. Our study clearly demonstrated that Samm50 rs3761472 induced mitochondrial dysfunction by downregulating the expression of essential mitochondrial genes in SAMM50 knock-in (KI) mice. To further determine the association between SAMM50 rs3761472 and NAFLD progression, SAMM50 KI mice were fed a high-fat diet (HFD). Our study revealed that Samm50 rs3761472 increased the expression of de novo lipogenesis genes. In addition, HFD administration remarkably increased the lipid accumulation in Samm50 KI mouse liver than wild-type liver and elevated the alanine aminotransferase (ALT) and total cholesterol (TC) levels in Samm50 KI mice. Altogether, our findings suggest that SAMM50 rs3761472 impairs mitochondrial function and causes NAFLD susceptibility. These results will provide the basic knowledge needed to understand the biological function of the SAMM50 genetic variant rs3761472 and contribute to the design of NAFLD therapies for precision medicine.