Cross-talk between branched-chain amino acids and hepatic mitochondria is compromised in nonalcoholic fatty liver disease

Abstract

Elevated plasma branched-chain amino acids (BCAA) in the setting of insulin resistance have been relevant in predicting type 2 diabetes mellitus (T2DM) onset, but their role in the etiology of hepatic insulin resistance remains uncertain. We determined the link between BCAA and dysfunctional hepatic tricarboxylic acid (TCA) cycle, which is a central feature of hepatic insulin resistance and nonalcoholic fatty liver disease (NAFLD). Plasma metabolites under basal fasting and euglycemic hyperinsulinemic clamps (insulin stimulation) were measured in 94 human subjects with varying degrees of insulin sensitivity to identify their relationships with insulin resistance. Furthermore, the impact of elevated BCAA on hepatic TCA cycle was determined in a diet-induced mouse model of NAFLD, utilizing targeted metabolomics and nuclear magnetic resonance (NMR)-based metabolic flux analysis. Insulin stimulation revealed robust relationships between human plasma BCAA and indices of insulin resistance, indicating chronic metabolic overload from BCAA. Human plasma BCAA and long-chain acylcarnitines also showed a positive correlation, suggesting modulation of mitochondrial metabolism by BCAA. Concurrently, mice with NAFLD failed to optimally induce hepatic mTORC1, plasma ketones, and hepatic long-chain acylcarnitines, following acute elevation of plasma BCAA. Furthermore, elevated BCAA failed to induce multiple fluxes through hepatic TCA cycle in mice with NAFLD. Our data suggest that BCAA are essential to mediate efficient channeling of carbon substrates for oxidation through mitochondrial TCA cycle. Impairment of BCAA-mediated upregulation of the TCA cycle could be a significant contributor to mitochondrial dysfunction in NAFLD.

Metabolic profiling of fatty liver in young and middle‐aged adults: Cross‐sectional and prospective analyses of the Young Finns Study

“…Notwithstanding the importance of lipid measures in the metabolic syndrome and their potential role in the pathogenesis of fatty liver, many biomarkers in other metabolic pathways were also strongly linked with the risk for fatty liver. Circulating levels of branched‐chain and aromatic amino acids were strongly directly associated with the presence of fatty liver as well as its future risk, confirming previous small cross‐sectional studies . Deviating levels of these amino acids have been considered to be attributable to dysfunctional mitochondrial energy metabolism, adiposity, and insulin resistance and have been associated with the risk for the development of type 2 diabetes in multiple studies .…”

“…Circulating levels of branched-chain and aromatic amino acids were strongly directly associated with the presence of fatty liver as well as its future risk, confirming previous small crosssectional studies. (32)(33)(34) Deviating levels of these amino acids have been considered to be attributable to dysfunctional mitochondrial energy metabolism, adiposity, and insulin resistance and have been associated with the risk for the development of type 2 diabetes in multiple studies. (22,23,33,(35)(36)(37) Prospective studies have suggested that aberrations in the dispositions of branched-chain and aromatic amino acids precede insulin resistance, (35) and here we extend these findings by revealing the predictive associations with the 10year risk for fatty liver.…”

“…(32)(33)(34) Deviating levels of these amino acids have been considered to be attributable to dysfunctional mitochondrial energy metabolism, adiposity, and insulin resistance and have been associated with the risk for the development of type 2 diabetes in multiple studies. (22,23,33,(35)(36)(37) Prospective studies have suggested that aberrations in the dispositions of branched-chain and aromatic amino acids precede insulin resistance, (35) and here we extend these findings by revealing the predictive associations with the 10year risk for fatty liver. In addition, the levels of glutamine have been inversely associated with insulin resistance and diabetes risk, (35,38) and here the glutamine concentration in serum was also inversely associated with the presence of fatty liver.…”

Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction

“…Detailed metabolic analyses in NAFLD does indicate certain similarities with our model, including the effects on the TCA cycle [49,50]. The effect of fenofibrate in increasing the longchain acylcarnitines in our model is intriguing.…”

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

“…(11) For example, it has been hypothesized that BCAAs might increase Hep-IR through mammalian target of rapamycin signaling. (8,10,15) However, because during fasting most circulating AAs derive from muscle catabolism, (16) which is increased in IR states, it is likely that an alteration in AA concentrations reflects IR rather than the presence of NAFLD. Most previous studies involved mainly subjects with obesity and IR, where AA catabolism is up-regulated, and thus it is not easy to establish if increased fasting concentrations of AAs are related to NAFLD or to peripheral IR.…”