Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance

Abstract

Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD-NO) compared to those with obesity (NAFLD-Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD-NO and 15 NAFLD-Ob) and 20 CTs without obesity, by gas chromatography-mass spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep-IR; Hep-IR 5 endogenous glucose production 3 insulin), and the new glutamate-serine-glycine (GSG) index (glutamate/[serine 1 glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD-Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD-NO subjects compared to CTs. Glutamate, tyrosine, and the GSG-index were correlated with Hep-IR. The GSG-index correlated with liver enzymes, in particular, gamma-glutamyltransferase (R 5 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG-index, while only the new GSG-index was able to discriminate fibrosis F3-4 from F0-2 in this cohort. Conclusion: Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG-index is a possible marker of severity of liver disease independent of body mass index. (HEPATOLOGY 2018;67:145-158).

The role of the microbiome in NAFLD and NASH

“…This molecule's blood levels have higher predictive power of the disease than conventional diagnostics. In NAFLD and NASH patients in addition to phenylalanine, phenylacetate precursor, abundances of other amino acids, notably branched chain amino acids (BCAAs), are altered and associate with disease severity, suggesting that there may be other metabolites produced by microbiome that play role in the disease (Gaggini et al, 2018). Interestingly, mice chronically treated with phenylacetate feature elevated expression of genes related to fat metabolism (Lpl, Fasn), increased levels of hepatic triglycerides, and eventually developed liver steatosis (Hoyles et al, 2018).…”

“…Interestingly, mice chronically treated with phenylacetate feature elevated expression of genes related to fat metabolism (Lpl, Fasn), increased levels of hepatic triglycerides, and eventually developed liver steatosis (Hoyles et al, 2018). In NAFLD and NASH patients in addition to phenylalanine, phenylacetate precursor, abundances of other amino acids, notably branched chain amino acids (BCAAs), are altered and associate with disease severity, suggesting that there may be other metabolites produced by microbiome that play role in the disease (Gaggini et al, 2018).…”

Gut Microbial Metabolism and Nonalcoholic Fatty Liver Disease

“…Perturbations in microbial metabolism of AAAs and BCAAs and ensuing alterations in the serum metabolite profile have more recently been identified in NAFLD . Hoyles et al performed an integrated analysis of the gut metagenome, hepatic transcriptome, and serum and urine metabolomes in a cohort of women with obesity but without diabetes.…”

“…(79) Perturbations in microbial metabolism of AAAs and BCAAs and ensuing alterations in the serum metabolite profile have more recently been identified in NAFLD. (70,132) Hoyles et al (70) performed an integrated analysis of the gut metagenome, hepatic transcriptome, and serum and urine metabolomes in a cohort of women with obesity but without diabetes. Compared to those without NAFL, women with NAFL had significant alterations in the gut metagenome, including differences in BCAA and AAA pathways, as well as in the serum metabolome.…”

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

“…We read with interest the article of Gaggini et al reporting plasma concentrations of amino acids (AAs) in nonalcoholic fatty liver disease (NAFLD). (1) The researchers observed that patients with NAFLD had high levels of isoleucine and valine (branched-chain amino acids; BCAA), tyrosine, alanine, lysine, and glutamate. More specifically, the researchers found that BCAA correlated with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels; therefore, they concluded that plasma levels of amino-transferases reflect increased transamination reactions, and that amino acids are markers of hepatic inflammation and fibrosis.…”