The nonalcoholic steatohepatitis metabotype: Imbalance of circulating amino acids and transamination reactions reflect impaired mitochondrial function

SOOKOIAN, SILVIA; PIROLA, CARLOS J.

HEPATOLOGY (BALTIMORE, MD.)

JOHN WILEY & SONS INC

Lugar: Hoboken, NJ; Año: 2017

0270-9139

We read with interest the article of Gaggini et al. reporting plasma concentrations of amino acids (AA) in nonalcoholic fatty liver disease (NAFLD) . The authors observed that patients with NAFLD had high levels of isoleucine and valine (branched-chain amino acids, BCAA), tyrosine, alanine, lysine, and glutamate. They proposed that the observed metabolic profile is the consequence of increased insulin resistance and protein catabolism. More specifically, the authors found that BCAA correlated with ALT and AST levels; therefore, they concluded that these observations reflect increased transamination reactions. While these results are confirmatory findings of knowledge that is already known and of which, the associated molecular mechanisms have been extensively studied (2), some points deserve to be highlighted. For example, we observed that in patients with NAFLD, circulating levels of essential AA, such as including L-glutamic acid, and other metabolites (2-hydroxyglutarate), were significantly associated not only with serum levels of AST but liver transcriptional activity and protein level of aminotransferases (2). We also found that 2 hydroxyglutaric acid, L-glutamic acid, and alanine/pyruvate ratio were significantly associated with NAFLD disease severity. Notably, L-alanine/pyruvate ratio significantly correlated with BMI even after adjusting for HOMA-IR. Furthermore, cross-sectional and longitudinal-data from the Framingham Heart Study showed implicated dysregulated glutamate cycling and AA metabolism in metabolic risk. For instance, glutamic acid and 2-ketoglutaric acid were both significantly associated with ALT and AST in discovery (n=650) and replication (n=554) analysis. Most importantly, among 119-plasma metabolites assessed, the top AA biomarker was glutamic acid, which was directly associated with obesity, dyslipidemia, and dysglycemia in discovery and replication datasets. The ratio serine/glutamic acid, a reflection of serine-pyruvate and alanine transaminase activity, was also significantly associated with metabolic syndrome-components.Interestingly, not only all metabolic reactions above-mentioned occur in the mitochondrial matrix but each of the resulting metabolite is a by-product of the Krebs cycle (Figure). Remarkably, transaminations of AA, including BCAA, are in part mediated by AST and ALT (Figure). Likewise, NAFLD severity is associated with impaired mitochondrial-(mt) function (4-5), altered mt-morphology, and increased mt-genome variability. Together, it is plausible to speculate that the circulating ?NASH-metabotype? resembles a "mitochondrial disease"