Rat Long Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Uptake and Partitioning to Cellular Triacylglycerol in McArdle-RH7777 Cells

Fatty acid transport protein (FATP)2, a member of the FATP family of fatty acid uptake mediators, has independently been identified as a hepatic peroxisomal very long-chain acyl-CoA synthetase (VLACS). Here we address whether FATP2 is 1) a peroxisomal enzyme, 2) a plasma membrane-associated long-chain fatty acid (LCFA) transporter, or 3) a multifunctional protein. We found that, in mouse livers, only a minor fraction of FATP2 localizes to peroxisomes, where it contributes to approximately half of the peroxisomal VLACS activity. However, total hepatic (V)LACS activity was not significantly affected by loss of FATP2, while LCFA uptake was reduced by 40%, indicating a more prominent role in hepatic LCFA uptake. This suggests FATP2 as a potential target for a therapeutic intervention of hepatosteatosis. Adeno-associated virus 8-based short hairpin RNA expression vectors were used to achieve liver-specific FATP2 knockdown, which significantly reduced hepatosteatosis in the face of continued high-fat feeding, concomitant with improvements in liver physiology, fasting glucose, and insulin levels. Based on our findings, we propose a model in which FATP2 is a multifunctional protein that shows subcellular localization-dependent activity and is a major contributor to peroxisomal (V)LACS activity and hepatic fatty acid uptake, suggesting FATP2 as a potential novel target for the treatment of nonalcoholic fatty liver disease.

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Long-Chain Acyl-CoA Synthetase is Associated with the Growth of Malassezia spp.

Journal of Fungi ◽

10.3390/jof5040088 ◽

2019 ◽

Vol 5 (4) ◽

pp. 88 ◽

Cited By ~ 1

Author(s):

Tenagy ◽

Kengo Tejima ◽

Xinyue Chen ◽

Shun Iwatani ◽

Susumu Kajiwara

Keyword(s):

Fatty Acid ◽

Fungal Pathogen ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Long Chain Fatty Acids ◽

Double Mutation ◽

Triacsin C ◽

Chain Acyl ◽

Malassezia Spp ◽

Long Chain

The lipophilic fungal pathogen Malassezia spp. must acquire long-chain fatty acids (LCFAs) from outside the cell. To clarify the mechanism of LCFA acquisition, we investigated fatty acid uptake by this fungus and identified the long-chain acyl-CoA synthetase (ACS) gene FAA1 in three Malassezia spp.: M. globosa, M. pachydermatis, and M. sympodialis. These FAA1 genes could compensate for the double mutation of FAA1 and FAA4 in Saccharomyces cerevisiae, suggesting that Malassezia Faa1 protein recognizes exogenous LCFAs. MgFaa1p and MpFaa1p utilized a medium-chain fatty acid, lauric acid (C12:0). Interestingly, the ACS inhibitor, triacsin C, affected the activity of the Malassezia Faa1 proteins but not that of S. cerevisiae. Triacsin C also reduced the growth of M. globosa, M. pachydermatis, and M. sympodialis. These results suggest that triacsin C and its derivatives are potential compounds for the development of new anti-Malassezia drugs.

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Abstract 5381: Insulin-Stimulated Glucose Oxidation is Increased in Hearts from High Fat Diet-Induced Obese Mice Lacking Malonyl CoA Decarboxylase

Circulation ◽

10.1161/circ.118.suppl_18.s_539 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

John Edward R Ussher ◽

Timothy R Koves ◽

Jagdip S Jaswal ◽

Christopher B Newgard ◽

Jason R Dyck ◽

...

Keyword(s):

Fatty Acid ◽

Glucose Oxidation ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Myocardial Fatty Acid ◽

Malonyl Coa ◽

Mitochondrial Fatty Acid ◽

Chain Acyl ◽

Wet Weight ◽

Long Chain

OBJECTIVE - Diet-induced obesity (DIO) leads to an accumulation of intra-myocardial fatty acid metabolites that have been proposed to cause myocardial insulin resistance and dysfunction. Our goal was to determine the effect of DIO on myocardial fatty acid metabolite accumulation and how this is altered when mitochondrial fatty acid uptake is inhibited. This was achieved by using mice lacking malonyl CoA decarboxylase (MCD−/−), which have higher levels of malonyl CoA, an endogenous inhibitor of mitochondrial fatty acid uptake. METHODS - Wild type (WT) and MCD−/− mice were fed a low (4% kcal from lard) or high (60% kcal from lard) fat diet for 12 weeks to determine the effect of DIO on the intra-myocardial accumulation of long chain acylcarnitines, long chain acyl CoAs, triglycerides (TGs), and ceramides. A parallel feeding study was performed to assess myocardial function and energy metabolism in isolated working hearts in the absence/presence of insulin. RESULTS - We demonstrate that MCD−/− mice do not accumulate intramyocardial long chain acylcarnitines to the same extent as WT mice following DIO (0.56 ± 0.10 vs. 0.28 ± 0.07 pmol myristoylcarnitine/mg protein, P <0.05), but do accumulate similar amounts of long chain acyl CoAs (3.88 ± 0.34 vs. 4.35 ± 1.19 nmol/g wet weight). Interestingly, DIO only lead to an accumulation of TGs in the hearts of MCD−/− mice (3.29 ± 0.62 vs. 10.92 ± 3.72 μmol/g wet weight, P <0.05). Despite this elevation in TGs, MCD−/− mice showed increased insulin-stimulated glucose oxidation (2.46 ± 0.25 vs. 1.74 ± 0.18 fold increase, P <0.05) during aerobic isolated working heart perfusions and did not elicit any dysfunction. CONCLUSIONS - Our data reveal discordance between myocardial TG accumulation and glucose metabolism, suggesting that TG buffers against toxic lipids, and that inhibition of mitochondrial fatty acid oxidation does not cause myocardial dysfunction following DIO.

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Arabidopsis LONG-CHAIN ACYL-COA SYNTHETASE 1 (LACS1), LACS2, and LACS3 facilitate fatty acid uptake in yeast

Plant Physiology and Biochemistry ◽

10.1016/j.plaphy.2011.10.003 ◽

2012 ◽

Vol 51 ◽

pp. 31-39 ◽

Cited By ~ 27

Author(s):

Ian P. Pulsifer ◽

Sabine Kluge ◽

Owen Rowland

Keyword(s):

Fatty Acid ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Chain Acyl ◽

Long Chain

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AMPK-mediated increase in myocardial long-chain fatty acid uptake critically depends on sarcolemmal CD36

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2007.01.141 ◽

2007 ◽

Vol 355 (1) ◽

pp. 204-210 ◽

Cited By ~ 88

Author(s):

Daphna D.J. Habets ◽

Will A. Coumans ◽

Peter J. Voshol ◽

Marion A.M. den Boer ◽

Maria Febbraio ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Uptake ◽

Chain Fatty Acid ◽

Acid Uptake ◽

Long Chain Fatty Acid ◽

Long Chain

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S1893 Comparison of Plasma Insulin and Leptin Concentrations with Long Chain Fatty Acid Uptake in Hepatocytes and Adipocytes from Mice with Hepatic Steatosis Clarifies the Hormonal Regulation of Fatty Acid Disposition

Gastroenterology ◽

10.1016/s0016-5085(08)63635-5 ◽

2008 ◽

Vol 134 (4) ◽

pp. A-778 ◽

Cited By ~ 1

Author(s):

Shengli Zhou ◽

Fengxia Ge ◽

Paul D. Berk

Keyword(s):

Fatty Acid ◽

Hepatic Steatosis ◽

Hormonal Regulation ◽

Plasma Insulin ◽

Fatty Acid Uptake ◽

Chain Fatty Acid ◽

Acid Uptake ◽

Long Chain Fatty Acid ◽

Long Chain

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Biocatalyst Engineering by Assembly of Fatty Acid Transport and Oxidation Activities for In Vivo Application of Cytochrome P-450BM-3 Monooxygenase

Applied and Environmental Microbiology ◽

10.1128/aem.64.10.3784-3790.1998 ◽

1998 ◽

Vol 64 (10) ◽

pp. 3784-3790 ◽

Cited By ~ 42

Author(s):

Silke Schneider ◽

Marcel G. Wubbolts ◽

Dominique Sanglard ◽

Bernard Witholt

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Coenzyme A ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Uptake System ◽

Whole Cells ◽

E Coli ◽

Cytochrome P 450 ◽

Long Chain

ABSTRACT The application of whole cells containing cytochrome P-450BM-3 monooxygenase [EC 1.14.14.1 ] for the bioconversion of long-chain saturated fatty acids to ω-1, ω-2, and ω-3 hydroxy fatty acids was investigated. We utilized pentadecanoic acid and studied its conversion to a mixture of 12-, 13-, and 14-hydroxypentadecanoic acids by this monooxygenase. For this purpose,Escherichia coli recombinants containing plasmid pCYP102 producing the fatty acid monooxygenase cytochrome P-450BM-3were used. To overcome inefficient uptake of pentadecanoic acid by intact E. coli cells, we made use of a cloned fatty acid uptake system from Pseudomonas oleovorans which, in contrast to the common FadL fatty acid uptake system of E. coli, does not require coupling by FadD (acyl-coenzyme A synthetase) of the imported fatty acid to coenzyme A. This system fromP. oleovorans is encoded by a gene carried by plasmid pGEc47, which has been shown to effect facilitated uptake of oleic acid in E. coli W3110 (M. Nieboer, Ph.D. thesis, University of Groningen, Groningen, The Netherlands, 1996). By using a double recombinant of E. coli K27, which is a fadDmutant and therefore unable to consume substrates or products via the β-oxidation cycle, a twofold increase in productivity was achieved. Applying cytochrome P-450BM-3 monooxygenase as a biocatalyst in whole cells does not require the exogenous addition of the costly cofactor NADPH. In combination with the coenzyme A-independent fatty acid uptake system from P. oleovorans, cytochrome P-450BM-3 recombinants appear to be useful alternatives to the enzymatic approach for the bioconversion of long-chain fatty acids to subterminal hydroxylated fatty acids.

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