scholarly journals Very-Long-Chain and Branched-Chain Fatty Acyl-CoAs Are High Affinity Ligands for the Peroxisome Proliferator-Activated Receptor α (PPARα)†

Biochemistry ◽  
2006 ◽  
Vol 45 (24) ◽  
pp. 7669-7681 ◽  
Author(s):  
Heather A. Hostetler ◽  
Ann B. Kier ◽  
Friedhelm Schroeder
Keyword(s):  
Fatty Acyl ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Affinity Ligands ◽  
High Affinity ◽  
Branched Chain ◽  
Long Chain

Distinct transcriptional regulation of long-chain acyl-CoA synthetase isoforms and cytosolic thioesterase 1 in the rodent heart by fatty acids and insulin

2006 ◽  
Vol 290 (6) ◽  
pp. H2480-H2497 ◽  
Author(s):  
David J. Durgan ◽  
Justin K. Smith ◽  
Margaret A. Hotze ◽  
Oluwaseun Egbejimi ◽  
Karalyn D. Cuthbert ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acyl ◽  
Null Mouse ◽  
Peroxisome Proliferator ◽  
Futile Cycle ◽  
Peroxisome Proliferator Activated Receptor ◽  
Rat Cardiomyocytes ◽  
Adult Rat ◽  
Chain Acyl ◽  
Long Chain

The molecular mechanism(s) responsible for channeling long-chain fatty acids (LCFAs) into oxidative versus nonoxidative pathways is (are) poorly understood in the heart. Intracellular LCFAs are converted to long-chain fatty acyl-CoAs (LCFA-CoAs) by a family of long-chain acyl-CoA synthetases (ACSLs). Cytosolic thioesterase 1 (CTE1) hydrolyzes cytosolic LCFA-CoAs to LCFAs, generating a potential futile cycle at the expense of ATP utilization. We hypothesized that ACSL isoforms and CTE1 are differentially regulated in the heart during physiological and pathophysiological conditions. Using quantitative RT-PCR, we report that the five known acsl isoforms ( acsl1, acsl3, acsl4, acsl5, and acsl6) and cte1 are expressed in whole rat and mouse hearts, as well as adult rat cardiomyocytes (ARCs). Streptozotocin-induced insulin-dependent diabetes (4 wk) and fasting (≤24 h) both dramatically induced cte1 and repressed acsl6 mRNA, with no significant effects on the other acsl isoforms. In contrast, high-fat feeding (4 wk) induced cte1 without affecting expression of the acsl isoforms in the heart. Investigation into the mechanism(s) responsible for these transcriptional changes uncovered roles for peroxisome proliferator-activated receptor-α (PPARα) and insulin as regulators of specific acsl isoforms and cte1 in the heart. Culturing ARCs with oleate (0.1–0.4 mM) or the PPARα agonists WY-14643 (1 μM) and fenofibrate (10 μM) consistently induced acsl1 and cte1. Conversely, PPARα null mouse hearts exhibited decreased acsl1 and cte1 expression. Culturing ARCs with insulin (10 nM) induced acsl6, whereas specific loss of insulin signaling within the heart (cardiac-specific insulin receptor knockout mice) caused decreased acsl6 expression. Our data expose differential regulation of acsl isoforms and cte1 in the heart, where acsl1 and cte1 are PPARα-regulated genes, whereas acsl6 is an insulin-regulated gene.

scholarly journals Thioesterase superfamily member 2 (Them2)/acyl-CoA thioesterase 13 (Acot13): a homotetrameric hotdog fold thioesterase with selectivity for long-chain fatty acyl-CoAs

2009 ◽  
Vol 421 (2) ◽  
pp. 311-322 ◽  
Author(s):  
Jie Wei ◽  
Hye Won Kang ◽  
David E. Cohen
Keyword(s):  
Acyl Chain ◽  
Substrate Inhibition ◽  
Fatty Acyl ◽  
Mouse Heart ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Chain Acyl ◽  
Hotdog Fold ◽  
Long Chain ◽  
Myristoyl Coa

Them2 (thioesterase superfamily member 2) is a 140-amino-acid protein of unknown biological function that comprises a single hotdog fold thioesterase domain. On the basis of its putative association with mitochondria, accentuated expression in oxidative tissues and interaction with StarD2 (also known as phosphatidylcholine-transfer protein, PC-TP), a regulator of fatty acid metabolism, we explored whether Them2 functions as a physiologically relevant fatty acyl-CoA thioesterase. In solution, Them2 formed a stable homotetramer, which denatured in a single transition at 59.3 °C. Them2 exhibited thioesterase activity for medium- and long-chain acyl-CoAs, with Km values that decreased exponentially as a function of increasing acyl chain length. Steady-state kinetic parameters for Them2 were characteristic of long-chain mammalian acyl-CoA thioesterases, with minimal values of Km and maximal values of kcat/Km observed for myristoyl-CoA and palmitoyl-CoA. For these acyl-CoAs, substrate inhibition was observed when concentrations approached their critical micellar concentrations. The acyl-CoA thioesterase activity of Them2 was optimized at physiological temperature, ionic strength and pH. For both myristoyl-CoA and palmitoyl-CoA, the addition of StarD2 increased the kcat of Them2. Enzymatic activity was decreased by the addition of phosphatidic acid/phosphatidylcholine small unilamellar vesicles. Them2 expression, which was most pronounced in mouse heart, was associated with mitochondria and was induced by activation of PPARα (peroxisome-proliferator-activated receptor α). We conclude that, under biological conditions, Them2 probably functions as a homotetrameric long-chain acyl-CoA thioesterase. Accordingly, Them2 has been designated as the 13th member of the mammalian acyl-CoA thioesterase family, Acot13.

scholarly journals Involvement of the peroxisome proliferator-activated receptor α in regulating long-chain acyl-CoA thioesterases

2000 ◽  
Vol 41 (5) ◽  
pp. 814-823 ◽  
Author(s):  
Mary C. Hunt ◽  
Per J.G. Lindquist ◽  
Jeffrey M. Peters ◽  
Frank J. Gonzalez ◽  
Ulf Diczfalusy ◽  
...  
Keyword(s):  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Chain Acyl ◽  
Long Chain

scholarly journals III. Peroxisomal β-oxidation, PPARα, and steatohepatitis

2001 ◽  
Vol 281 (6) ◽  
pp. G1333-G1339 ◽  
Author(s):  
Janardan K. Reddy
Keyword(s):  
Fatty Acids ◽  
Dicarboxylic Acids ◽  
Fatty Acyl ◽  
Branched Chain Fatty Acids ◽  
Oxidation Chain ◽  
Branched Chain ◽  
Cytochrome P 450 ◽  
Oxidation System ◽  
Long Chain ◽  
Chain Fatty Acids

Peroxisomes are involved in the β-oxidation chain shortening of long-chain and very-long-chain fatty acyl-CoAs, long-chain dicarboxylyl-CoAs, the CoA esters of eicosanoids, 2-methyl-branched fatty acyl-CoAs, and the CoA esters of the bile acid intermediates, and in the process, they generate H2O2. There are two complete sets of β-oxidation enzymes present in peroxisomes, with each set consisting of three distinct enzymes. The classic PPARα-regulated and inducible set participates in the β-oxidation of straight-chain fatty acids, whereas the second noninducible set acts on branched-chain fatty acids. Long-chain and very-long-chain fatty acids are also metabolized by the cytochrome P-450 CYP4A ω-oxidation system to dicarboxylic acids that serve as substrates for peroxisomal β-oxidation. Evidence derived from mouse models of PPARα and peroxisomal β-oxidation deficiency highlights the critical importance of the defects in PPARα-inducible β-oxidation in energy metabolism and in the development of steatohepatitis.

scholarly journals The CYP4A Isoforms Hydroxylate Epoxyeicosatrienoic Acids to Form High Affinity Peroxisome Proliferator-activated Receptor Ligands

2002 ◽  
Vol 277 (38) ◽  
pp. 35105-35112 ◽  
Author(s):  
L. Ashley Cowart ◽  
Shouzuo Wei ◽  
Mei-Hui Hsu ◽  
Eric F. Johnson ◽  
Murali U. Krishna ◽  
...  
Keyword(s):  
Epoxyeicosatrienoic Acids ◽  
Peroxisome Proliferator ◽  
Receptor Ligands ◽  
Peroxisome Proliferator Activated Receptor ◽  
High Affinity

scholarly journals Branched-Chain Fatty Acids as Mediators of the Activation of Hepatic Peroxisome Proliferator-Activated Receptor Alpha by a Fungal Lipid Extract

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1259 ◽  
Author(s):  
Garima Maheshwari ◽  
Robert Ringseis ◽  
Gaiping Wen ◽  
Denise K. Gessner ◽  
Johanna Rost ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Reporter Gene ◽  
Target Genes ◽  
Reporter Gene Assay ◽  
Lipid Extract ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Branched Chain Fatty Acids ◽  
Gene Assay ◽  
Branched Chain

The study aimed to test the hypothesis that monomethyl branched-chain fatty acids (BCFAs) and a lipid extract of Conidiobolus heterosporus (CHLE), rich in monomethyl BCFAs, are able to activate the nuclear transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha). Rat Fao cells were incubated with the monomethyl BCFAs 12-methyltridecanoic acid (MTriA), 12-methyltetradecanoic acid (MTA), isopalmitic acid (IPA) and 14-methylhexadecanoic acid (MHD), and the direct activation of PPARalpha was evaluated by reporter gene assay using a PPARalpha responsive reporter gene. Furthermore, Fao cells were incubated with different concentrations of the CHLE and PPARalpha activation was also evaluated by using the reporter gene assay, and by determining the mRNA concentrations of selected PPARalpha target genes by real-time RT-PCR. The reporter gene assay revealed that IPA and the CHLE, but not MTriA, MHD and MTA, activate the PPARalpha responsive reporter gene. CHLE dose-dependently increased mRNA concentrations of the PPARalpha target genes acyl-CoA oxidase (ACOX1), cytochrome P450 4A1 (CYP4A1), carnitine palmitoyltransferase 1A (CPT1A) and solute carrier family 22 (organic cation/carnitine transporter), member 5 (SLC22A5). In conclusion, the monomethyl BCFA IPA is a potent PPARalpha activator. CHLE activates PPARalpha-dependent gene expression in Fao cells, an effect that is possibly mediated by IPA.

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