The role of SAMM50 in non‐alcoholic fatty liver disease: from genetics to mechanisms

Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. SAMM50 encodes Sam50, a mitochondrial outer membrane protein involved in the removal of reactive oxygen species, mitochondrial morphology, and regulation of mitophagy. Certain single nucleotide polymorphisms (SNPs) of SAMM50 have been reported to be correlated with NAFLD. However, the contribution of SAMM50 polymorphisms to the occurrence and severity of fatty liver in the Chinese Han cohort has rarely been reported. Here, we investigated the association between SAMM50 polymorphisms (rs738491 and rs2073082) and NAFLD in a Chinese Han cohort, as well as the mechanistic basis of this association. Clinical information and blood samples were collected from 380 NAFLD cases and 380 normal subjects for the detection of genotypes and biochemical parameters. Carriers of the rs738491 T-allele or rs2073082 G-allele of SAMM50 exhibit increased susceptibility to NAFLD (OR=1.39; 95% CI=1.14-1.71, P=0.001; OR=1.31; 95% CI=1.05-1.62, P=0.016, respectively) and are correlated with elevated serum TG, ALT, and AST levels. The presence of the T allele (TT+CT) of rs738491 (P<0.01) or G allele (AG+GG) of rs2073082 (P=0.03) is correlated with the severity of fatty liver in the NAFLD cohort. In vitro studies indicated that SAMM50 gene polymorphisms decrease its expression and SAMM50 deficiency results in increased lipid

Transcriptomic Analysis Reveals the Protective Effects of Empagliflozin on Lipid Metabolism in Nonalcoholic Fatty Liver Disease

“…Family with sequence similarity 131c (FAM131C) is a group of human N-myristoylated proteins; protein N-myristoylation is required for proper targeting of SAMM50 to mitochondria (Takamitsu et al, 2015). Some studies have shown that overexpression of SAMM50 enhances fatty acid oxidation and reduces intracellular lipid accumulation (Li et al, 2021). In contrast, we found that the Fam131c expression level increased in the HFD group but decreased in the EMP group.…”

Genetic Variation of SAMM50 Is Not an Independent Risk Factor for Alcoholic Hepatocellular Carcinoma in Caucasian Patients

“…However, the functional consequences of genetic variation of common SAMM50 polymorphisms remain poorly understood. It was suggested that SAMM50 is upregulated in patients with NAFLD, that this upregulation is impaired in the presence of genetic variants in polymorphisms associated with NAFLD and that experimental knock-down of SAMM50 leads to intracellular triglyceride accumulation [ 18 ]. In line with changed expression, both rs3761472 and rs3827385 were reported to affect the binding of transcription factors and were linked to SAMM50 mRNA expression level in adipose tissue [ 16 ].…”

“…Both polymorphisms are supposed to interfere with transcription factor binding, with SAMM50 expression being increased in the presence of the minor variant in adipocytes [ 16 ]. Rs3761472 [ 17 ] and rs738491/rs2073082 [ 18 ] in SAMM50 were associated with NAFLD before; another polymorphism in SAMM50 (rs2143571) was linked to the serum level of ALT at the population level [ 19 ]. Therefore, SAMM50 seems to be an interesting gene in relation to liver disease.…”

Chronic Inflammation—A Link between Nonalcoholic Fatty Liver Disease (NAFLD) and Dysfunctional Adipose Tissue

“…An observational study found that decreased SAMM50 in encoding Sam50 led to decreased FAO and increased lipid accumulation. The effects were reversed after increasing SAMM50 levels [ 96 ]. Some study evaluated the involvement of mitochondrial membrane potential (ΔΨm) in hyperglycemic status on HepaG2 cells.…”