Cumulative number of genetic variants in the Mitochondrially Encoded Cytochrome B in the Liver Tissue is associated with Nonalcoholic Steatohepatitis (NASH) and a Deregulated Metabolic Profile

SILVIA C. SOOKOIAN; GUSTAVO O CASTAÑO; GARAYCOECHEA, MARTIN; DIEGO FLICHMAN; CARLA GAZZI; CARLOS J. PIROLA

San Francisco

Congreso; 69th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2019; 2018

The American Association for the Study of Liver Diseases

The progression of NAFLD into severehistological forms is associated with complex molecularprocesses that include epigenetic and metabolic reprogrammingand mitochondrial (mt) dysfunction. Whether or not thesechanges specifically occur in the liver tissue is not entirelyknown. Liver Mitochondria are highly abundant organellesthat play a critical role in energy balance through oxidativephosphorylation-(OXPHOS). Of particular interest are mtgenesthat are associated with phenotypes of the MetabolicSyndrome (MetS), including diabetes, and obesity and cardiomyopathy. These mt-genes include the mitochondriallyencoded cytochrome B (MT-CYB), which is a component ofthe OXPHOS-ubiquinol-cytochrome c reductase complex III.Methods: We hypothesized that NAFLD-severity might beassociated with liver MT-CYB genetic diversity; hence, weincluded 185 liver specimens linked to clinical, histological,and biochemical information. To compare frequencies ofvariants and mutations, we sequenced the entire MT-CYBgene in the liver of patients with simple steatosis-NAFL (n=92)and NASH (n=93). By HPLC?mass spectrometry, in a subsample,we explored the circulating level of metabolites ofthe Krebs cycle to contrast the hypothesis that an increasednumber of MT-CYB mutations might induce significantmetabolic changes. Results: The comparison of liver MTCYBgenetic diversity among patients with NAFL and NASHshowed that the disease severity is associated with a highrate of mutation/variation (P = 5.5E-10). Specifically, the liverof patients with NASH showed higher number of polymorphicsites when compared with the liver of patients with NAFL (ratesper 1000: 15.6 vs. 12.1, respectively). The cumulative numberof variants was associated with the histological degree ofsteatosis (p=0.0003), lobular inflammation (p=0.008), NASscore(p=0.03), and transaminase levels (p=0.02). In addition,the number of variants was associated with features of theMet-S, including higher diastolic blood pressure (p=0.01) andlower BMI (p=1E-10). The burden of liver MT-CYB-diversitywas associated with circulating levels of alpha-ketoglutarate(p=0.01), branched-chain amino acids (p=0.014), glutamate(p=0.032), and hydroxyglutaric acid (p=0.019). Conclusion:The liver of patients with NASH exhibits a high level of MTCYBvariance, the consequences of which seems to be notonly a state of OXPHOS-deficiency but a systemic metabolicderangement.