Outlook: membrane junctions enable the metabolic trapping of fatty acids by intracellular acyl-CoA synthetases

Füllekrug, Joachim; Ehehalt, Robert; Poppelreuther, Margarete

doi:10.3389/fphys.2012.00401

Cited by 22 publications

(22 citation statements)

References 32 publications

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“…After excluding the possibilities of impaired Mtp activity and exaggerated FA uptake, we found that enterocytes overexpressing Lxra show increased acsl3a transcript abundance, and that the encoded protein's forced expression is suffi cient to recapitulate, in part, the phenotype of Tg ( fabp2:EGFP-nr1h3 ) transgenic animals. Of course, other Lxr effectors acting in the intestine may contribute to the global control of lipid traffi cking; however, our work demonstrates that, among the myriad regulatory events governing lipid droplet biogenesis, site-specifi c activation of fatty acyl-CoA represents a mechanism for funneling these metabolites to storage ( 28,29,55,57 ).…”

Section: Discussionmentioning

confidence: 91%

“…Acsl3 targeting to cytoplasmic lipid droplets is achieved by an N-terminal cytoplasmic lipid droplet anchor motif that is not present in other Acsl family members ( 28 ) This enzyme acts throughout lipid droplet biogenesis to activate CoA thioesters for subsequent incorporation into the growing storage depot ( 29 ). The induction of the encoding acls3a transcript raised the possibility that this enzyme might serve to activate FAs for incorporation into glycerolipids and cholesteryl esters at the surface of lipid droplets, "channeling" them away from incorporation into chylomicrons ( 56,57 ).…”

Section: Intestinal Overexpression Of Lxra Delays Lipid Absorptionmentioning

confidence: 99%

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Lxr-driven enterocyte lipid droplet formation delays transport of ingested lipids

Cruz-García

Schlegel

2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org of atherosclerosis ( 2 ). The most widely used treatment for atherosclerosis is statin drugs, which potently inhibit 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis ( 3 ). Nevertheless, statins do not fully mitigate cardiovascular risk. Recent epidemiological investigations reveal that postprandial (nonfasting) plasma lipid levels are a major determinant of cardiovascular risk because they refl ect the persistence of highly atherogenic remnant lipoprotein particles in the circulation ( 4 ). Statin drugs do not modulate the abundance or atherogenicity of remnant lipoprotein particles ( 5 ).Elucidation of the regulatory events controlling the pace of entry of ingested lipids into the blood stream in chylomicrons might afford the opportunity to blunt postprandial hyperlipidemia. Human jejunal biopsies ( 6 ), prolonged, label-free lipid droplet imaging of live loops of mouse intestine ( 7 ), and fl uorescent lipid probe-based visualization of intestinal lipid droplets in zebrafi sh larvae ( 8 ) have revealed that a substantial fraction of absorbed lipids remain in the enterocyte for many hours following a meal. These fi ndings suggest that there is an intrinsic mechanism for delaying, in part, transit of absorbed lipids. The molecular mechanism accounting for this hours-long retention of absorbed lipids in the intestine is not known.Liver X receptors (Lxrs) are nuclear receptor transcription factors that regulate energy metabolism through engaging specifi c metabolite substrates such as oxysterols and then altering the expression of diverse, but functionally integrated genes ( 9, 10 ). Lxrs are central inducers of cholesterol catabolism ( 9, 10 ). Known direct target genes of Lxr transactivation include factors involved in reverse cholesterol transport; lipoprotein modifi cation; cholesterol Atherosclerotic cardiovascular disease is the leading cause of death worldwide ( 1 ). Elevated serum cholesterol is a major causal risk factor for development and progression

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Section: Discussionmentioning

confidence: 91%

Section: Intestinal Overexpression Of Lxra Delays Lipid Absorptionmentioning

confidence: 99%

Lxr-driven enterocyte lipid droplet formation delays transport of ingested lipids

Cruz-García

Schlegel

2014

Journal of Lipid Research

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“…It has been variously speculated that FA entry might occur via junctions between the plasma membrane and the endoplasmic reticulum (ER). Alternatively, entry may be mediated by fatty acid binding protein (FABP) isoforms (47), or facilitated by the FA transport proteins (FATP/ACSVL) (52) that are themselves acyl-CoA synthetases. Several groups, however, have shown that the directionality of FA entry or “vectorial transport” is driven by the intracellular metabolism of the FAs (4, 47, 122).…”

Section: Fatty Acid Use By Acyl-coa Synthetasesmentioning

confidence: 99%

“…Alternatively, studies of FA uptake may be an exception to the idea that location dictates function, because changing the expression level of intracellular ACSLs or FATPs alters cellular FA retention (47, 133, 207). In 3T3-L1 cells, for example, overexpressing FATP1 or FATP4 on the ER or overexpressing ACSL1 on the mitochondria increases FA uptake and retention by 40% (207).…”

Section: Acyl-coa Synthetases and Fatty Acid Transport Proteinsmentioning

confidence: 99%

Acyl-CoA Metabolism and Partitioning

Grevengoed¹,

Klett

Coleman³

2014

Annu. Rev. Nutr.

351

330

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Long-chain fatty acyl-CoAs are critical regulatory molecules and metabolic intermediates. The initial step in their synthesis is the activation of fatty acids by one of 13 long-chain acyl-CoA synthetase isoforms. These isoforms are regulated independently and have different tissue expression patterns and subcellular locations. Their acyl-CoA products regulate metabolic enzymes and signaling pathways, become oxidized to provide cellular energy, and are incorporated into acylated proteins and complex lipids like triacylglycerol, phospholipids, and cholesterol esters. Their differing metabolic fates are determined by a network of proteins that channel the acyl-CoAs towards or away from specific metabolic pathways and serve as the basis for partitioning. This review evaluates the evidence for acyl-CoA partitioning by reviewing experimental data on proteins that are believed to contribute to acyl-CoA channeling, the metabolic consequences of loss of these proteins, and the potential role of maladaptive acyl-CoA partitioning in the pathogenesis of metabolic disease and carcinogenesis.

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“…Acyl CoA synthetase-1 (ACSL1), a protein reported to be localized at mitochondrial and endoplasmic reticular membranes, has been hypothesized to remotely affect LCFA uptake in mouse hearts, hepatocytes, adipocytes, epithelial cells, and E. coli through vectorial acylation as part of the mechanism “metabolic trapping” [7-15]. Despite the importance of ACSL1 in initiating intracellular lipid usage, the impact of ACSL1 on active fatty acid uptake rates and the consequences of altered uptake on cellular lipid utilization in the heart are not understood.…”

Section: Introductionmentioning

confidence: 99%

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

Goldenberg

Wang

Lewandowski

2016

Journal of Molecular and Cellular Cardiology

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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 13C NMR of intact, beating mouse hearts, supplied 13C 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.

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Outlook: membrane junctions enable the metabolic trapping of fatty acids by intracellular acyl-CoA synthetases

Cited by 22 publications

References 32 publications

Lxr-driven enterocyte lipid droplet formation delays transport of ingested lipids

Lxr-driven enterocyte lipid droplet formation delays transport of ingested lipids

Acyl-CoA Metabolism and Partitioning

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

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