title: Cardiac energy dependence on glucose increases metabolites related to glutathione and activates metabolic genes controlled by mechanistic target of rapamycin.
abstract: BACKGROUND
  Long chain acyl-CoA synthetases (ACSL) catalyze long-chain fatty acids (FA) conversion to acyl-CoAs. Temporal ACSL1 inactivation in mouse hearts (Acsl1(H-/-)) impaired FA oxidation and dramatically increased glucose uptake, glucose oxidation, and mTOR activation, resulting in cardiac hypertrophy. We used unbiased metabolomics and gene expression analyses to elucidate the cardiac cellular response to increased glucose use in a genetic model of inactivated FA oxidation.
  
  
  RESULTS
  Metabolomics analysis identified 60 metabolites altered in Acsl1(H-/-) hearts, including 6 related to glucose metabolism and 11 to cysteine and glutathione pathways. Concurrently, global cardiac transcriptional analysis revealed differential expression of 568 genes in Acsl1(H-/-) hearts, a subset of which we hypothesized were targets of mTOR; subsequently, we measured the transcriptional response of several genes after chronic mTOR inhibition via rapamycin treatment during the period in which cardiac hypertrophy develops. Hearts from Acsl1(H-/-) mice increased expression of several Hif1α-responsive glycolytic genes regulated by mTOR; additionally, expression of Scl7a5, Gsta1/2, Gdf15, and amino acid-responsive genes, Fgf21, Asns, Trib3, Mthfd2, were strikingly increased by mTOR activation.
  
  
  CONCLUSIONS
  The switch from FA to glucose use causes mTOR-dependent alterations in cardiac metabolism. We identified cardiac mTOR-regulated genes not previously identified in other cellular models, suggesting heart-specific mTOR signaling. Increased glucose use also changed glutathione-related pathways and compensation by mTOR. The hypertrophy, oxidative stress, and metabolic changes that occur within the heart when glucose supplants FA as a major energy source suggest that substrate switching to glucose is not entirely benign.
authors.affiliation: Division of Cardiology, Department of Medicine, University of North Carolina, Chapel Hill, NC (J.C.S., C.P.).
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Schisler
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, NC (T.J.G., F.P., D.E.C., J.M.E., D.S.P., R.A.C.).
authors.forename: Trisha J
authors.initials: TJ
authors.lastname: Grevengoed
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, NC (T.J.G., F.P., D.E.C., J.M.E., D.S.P., R.A.C.).
authors.forename: Florencia
authors.initials: F
authors.lastname: Pascual
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, NC (T.J.G., F.P., D.E.C., J.M.E., D.S.P., R.A.C.).
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Cooper
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, NC (T.J.G., F.P., D.E.C., J.M.E., D.S.P., R.A.C.).
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Ellis
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, NC (T.J.G., F.P., D.E.C., J.M.E., D.S.P., R.A.C.).
authors.forename: David S
authors.initials: DS
authors.lastname: Paul
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC (M.S.W.).
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
authors.affiliation: Division of Cardiology, Department of Medicine, University of North Carolina, Chapel Hill, NC (J.C.S., C.P.).
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.affiliation: Nutrition Research Institute, Kannapolis, NC (W.J.).
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, NC (T.J.G., F.P., D.E.C., J.M.E., D.S.P., R.A.C.).
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Coleman
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism / Q000187:drug effects / Q000235:genetics*; D003066:Coenzyme A Ligases / Q000172:deficiency* / Q000235:genetics; D003545:Cysteine / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D005227:Fatty Acids; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C544400:ACSL1 protein, mouse; D003066:Coenzyme A Ligases; D005978:Glutathione; D005947:Glucose; D003545:Cysteine; D020123:Sirolimus
keywords: acyl‐CoA synthetase; fuel switching; glutathione; mTOR; oxidative stress