Recent genome-wide association studies have identified a missense variant p.A165T in mitochondrial amidoxime-reducing component 1 (mARC1) that is strongly associated with protection from all-cause cirrhosis and improved prognosis in nonalcoholic steatohepatitis. The precise mechanism of this protective effect is unknown. Substitution of alanine 165 with threonine is predicted to affect mARC1 protein stability and to have deleterious effects on its function. To investigate the mechanism, we have generated a knock-in mutant mARC1 A165T and a catalytically dead mutant C273A (as a control) in human hepatoma HepG2 cells, enabling characterization of protein subcellular distribution, stability, and biochemical functions of the mARC1 mutant protein expressed from its endogenous locus. Compared to WT mARC1, we found that the A165T mutant exhibits significant mislocalization outside of its traditional location anchored in the mitochondrial outer membrane and reduces protein stability, resulting in lower basal levels. We evaluated the involvement of the ubiquitin proteasome system in mARC1 A165T degradation and observed increased ubiquitination and faster degradation of the A165T variant. In addition, we have shown that HepG2 cells carrying the MTARC1 p.A165T variant exhibit lower N-reductive activity on exogenously added amidoxime substrates in vitro. The data from these biochemical and functional assays suggest a mechanism by which the MTARC1 p.A165T variant abrogates enzyme function which may contribute to its protective effect in liver disease.

The identification of genetic variants associated with fatty liver disease (FLD) from genome-wide association studies started in 2008 when single nucleotide polymorphisms in PNPLA3, the gene encoding patatin-like phospholipase domain-containing 3, were found to be associated with altered hepatic fat content. Since then, several genetic variants associated with protection from, or an increased risk of, FLD have been identified. The identification of these variants has provided insight into the metabolic pathways that cause FLD and enabled the identification of potential therapeutic targets. In this mini-review, we will examine the therapeutic opportunities derived from genetically validated targets in FLD, including oligonucleotide-based therapies targeting PNPLA3 and HSD17B13 that are currently being evaluated in clinical trials for the treatment of NASH (non-alcoholic steatohepatitis).

The growing prevalence of nonalcoholic fatty liver disease (NAFLD) has sparked interest in understanding genetics and epigenetics associated with the development and progression of the disease. A better understanding of the genetic factors related to progression will be beneficial in the risk stratification of patients. These genetic markers can also serve as potential therapeutic targets in the future. In this review, we focus on the genetic markers associated with the progression and severity of NAFLD.

Epidemiological studies have reported that the Mexican population is highly susceptible to dyslipidemia. The MARC1, ADCY5, and BCO1 genes have recently been involved in lipidic abnormalities. This study aimed to analyze the association of single nucleotide polymorphisms (SNPs) rs2642438, rs56371916, and rs6564851 on MARC1, ADCY5, and BCO1 genes, respectively, with the lipid profile in a cohort of Mexican adults. We included 1900 Mexican adults from the Health Workers Cohort Study. Demographic and clinical data were collected through a structured questionnaire and standardized procedures. Genotyping was performed using a predesigned TaqMan assay. A genetic risk score (GRS) was created on the basis of the three genetic variants. Associations analysis was estimated using linear and logistic regression. Our results showed that rs2642438-A and rs6564851-A alleles had a risk association for hypertriglyceridemia (OR = 1.57, p = 0.013; and OR = 1.33, p = 0.031, respectively), and rs56371916-C allele a trend for low HDL-c (OR = 1.27, p = 0.060) only in men. The GRS revealed a significant association for hypertriglyceridemia (OR = 2.23, p = 0.022). These findings provide evidence of an aggregate effect of the MARC1, ADCY5, and BCO1 variants on the risk of hypertriglyceridemia in Mexican men. This knowledge could represent a tool for identifying at-risk males who might benefit from early interventions and avoid secondary metabolic traits.

There is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) (\'MetComp\') and part by common modifiers of genetic risk (\'GenComp\'). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD.
We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D5-glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D2O (n = 61).
We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the \'MetComp\'. In contrast, the \'GenComp\' was not accompanied by any substrate excess but was characterized by an increased hepatic mitochondrial redox state, as determined by serum β-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum β-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD.
These data show that the mechanisms underlying \'Metabolic\' and \'Genetic\' components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD.
The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates.