title: Acyl CoA synthetase-1 links facilitated long chain fatty acid uptake to intracellular metabolic trafficking differently in hearts of male versus female mice.
abstract: Acyl CoA synthetase-1 (ACSL1) is localized at intracellular membranes, notably the mitochondrial membrane. ACSL1 and female sex are suggested to indirectly facilitate lipid availability to the heart and other organs. However, such mechanisms in intact, functioning myocardium remain unexplored, and roles of ACSL1 and sex in the uptake and trafficking of fats are poorly understood.
  
  
  
  To determine the potential for ACSL1 and sex-dependent differences in metabolic trapping and trafficking effects of long-chain fatty acids (LCFA) within cardiomyocytes of intact hearts.
  
  
  
  (13)C NMR of intact, beating mouse hearts, supplied (13)C palmitate, revealed 44% faster trans-sarcolemmal uptake of LCFA in male hearts overexpressing ACSL1 (MHC-ACSL1) than in non-transgenic (NTG) males (p<0.05). Acyl CoA content was elevated by ACSL1 overexpression, 404% in males and 164% in female, relative to NTG. Despite similar ACSL1 content, NTG females displayed faster LCFA uptake kinetics compared to NTG males, which was reversed by ovariectomy. NTG female LCFA uptake rates were similar to those in ACSL1 males and ACSL1 females. ACSL1 and female sex hormones both accelerated LCFA uptake without affecting triglyceride content or turnover. ACSL1 hearts contained elevated ceramide, particularly C22 ceramide in both sexes and specifically, C24 in males. ACSL1 also induced lower content of fatty acid transporter-6 (FATP6) indicating cooperative regulation with ACSL1. Surprisingly, ACSL1 overexpression did not increase mitochondrial oxidation of exogenous palmitate, which actually dropped in female ACSL1 hearts.
  
  
  
  ACSL1-mediated metabolic trapping of exogenous LCFA accelerates LCFA uptake rates, albeit to a lesser extent in females, which distinctly affects LCFA trafficking to acyl intermediates but not triglyceride storage or mitochondrial oxidation and is affected by female sex hormones.
authors.affiliation: Center for Cardiovascular Research, University of Illinois College of Medicine at Chicago, 909 South Wolcott Avenue, Chicago, IL 60612, USA; Department of Physiology and Biophysics, University of Illinois College of Medicine at Chicago, 835 South Wolcott Avenue, Chicago, IL 60612, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Goldenberg
authors.affiliation: Center for Cardiovascular Research, University of Illinois College of Medicine at Chicago, 909 South Wolcott Avenue, Chicago, IL 60612, USA.
authors.forename: Xuerong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Center for Cardiovascular Research, University of Illinois College of Medicine at Chicago, 909 South Wolcott Avenue, Chicago, IL 60612, USA; Department of Physiology and Biophysics, University of Illinois College of Medicine at Chicago, 835 South Wolcott Avenue, Chicago, IL 60612, USA; Sanford Burnham Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA. Electronic address: dougl@sbpdiscovery.org.
authors.forename: E Douglas
authors.initials: ED
authors.lastname: Lewandowski
mesh_terms: D000818:Animals; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006334:Heart Function Tests; D006439:Hemodynamics; D050356:Lipid Metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D012518:Sarcomeres / Q000378:metabolism; D012737:Sex Factors
chemical_list: D005227:Fatty Acids; D012739:Gonadal Steroid Hormones; C544400:ACSL1 protein, mouse; D003066:Coenzyme A Ligases
keywords: Acyl CoA synthetase; Cardiac metabolism; Ceramide; Fatty acid uptake; Heart; Triglyceride