title: 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.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and nishanth.sunny@medicine.ufl.edu.
authors.forename: Nishanth E
authors.initials: NE
authors.lastname: Sunny
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and.
authors.forename: Srilaxmi
authors.initials: S
authors.lastname: Kalavalapalli
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and.
authors.forename: Fernando
authors.initials: F
authors.lastname: Bril
authors.affiliation: Department of Pathology, University of Florida, Gainesville, Florida;
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Garrett
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and.
authors.forename: Manisha
authors.initials: M
authors.lastname: Nautiyal
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Mathew
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, California.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Williams
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and Division of Endocrinology, Diabetes, and Metabolism, Malcom Randall Veterans Administration Medical Center (VAMC), Gainesville, Florida; Division of Diabetes, University of Texas Health Science Center at San Antonio, and Division of Diabetes, Audie L. Murphy VAMC, San Antonio, Texas; and.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cusi
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002952:Citric Acid Cycle / Q000187:drug effects; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology; D020239:Receptor Cross-Talk
chemical_list: D000597:Amino Acids, Branched-Chain; D007328:Insulin
keywords: branched chain amino acids; insulin resistance; mitochondrial metabolism; nonalcoholic fatty liver disease