Acyl CoA synthetase-1 links facilitated long chain fatty acid uptake to intracellular metabolic trafficking differently in hearts of male versus female mice. (May 2016)

• Record Type: Journal Article
• Authors: Goldenberg, Joseph R.; Wang, Xuerong; Lewandowski, E. Douglas
• Is Part Of: Journal of molecular and cellular cardiology. Volume 94(2016:May)
• Page Start: 1
• Page End: 9
• Publication Date: 2016-05
• Subjects: Heart -- Cardiac metabolism -- Fatty acid uptake -- Ceramide -- Triglyceride -- Acyl CoA synthetase; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2016.03.006
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Rationale: 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. Objective: 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. Methods and results: 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. Conclusions: 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. Graphical abstract: Highlights: ACSL1 and female sex hormones accelerate fatty acid uptake rates in beating hearts. Faster female LCFA uptake rates require sex hormone-dependent ACSL1 expression. ACSL1 increases acyl derivative conversion to ceramide; no changes to TAG storage. Lipid trafficking of acyl derivatives differs between males and females.