Effects of ciprofibrate and 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA) on the distribution of carnitine and CoA and their acyl-esters and on enzyme activities in rats. Relation between hepatic carnitine concentration and carnitine acetyltransferase activity

Bhuiyan, A.K.M.J.; Bartlett, K.; Sherratt, H. S. A.; Agius, Loranne

doi:10.1042/bj2530337

Cited by 36 publications

(19 citation statements)

References 37 publications

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“…7c). These results are consistent with in vitro kinetic assays showing that CrAT activity is principally regulated by substrate availability (21,22). Similar to the acylcarnitine profile of ZDF rats (Fig.…”

Section: Carnitine Homeostasis Is Compromised By Chronicsupporting

confidence: 79%

Carnitine Insufficiency Caused by Aging and Overnutrition Compromises Mitochondrial Performance and Metabolic Control

Noland¹,

Koves²,

Seiler³

et al. 2009

Journal of Biological Chemistry

288

339

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In addition to its essential role in permitting mitochondrial import and oxidation of long chain fatty acids, carnitine also functions as an acyl group acceptor that facilitates mitochondrial export of excess carbons in the form of acylcarnitines. Recent evidence suggests carnitine requirements increase under conditions of sustained metabolic stress. Accordingly, we hypothesized that carnitine insufficiency might contribute to mitochondrial dysfunction and obesity-related impairments in glucose tolerance. Consistent with this prediction whole body carnitine dimunition was identified as a common feature of insulin-resistant states such as advanced age, genetic diabetes, and diet-induced obesity. In rodents fed a lifelong (12 month) high fat diet, compromised carnitine status corresponded with increased skeletal muscle accumulation of acylcarnitine esters and diminished hepatic expression of carnitine biosynthetic genes. Diminished carnitine reserves in muscle of obese rats was accompanied by marked perturbations in mitochondrial fuel metabolism, including low rates of complete fatty acid oxidation, elevated incomplete ␤-oxidation, and impaired substrate switching from fatty acid to pyruvate. These mitochondrial abnormalities were reversed by 8 weeks of oral carnitine supplementation, in concert with increased tissue efflux and urinary excretion of acetylcarnitine and improvement of whole body glucose tolerance. Acetylcarnitine is produced by the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT). A role for this enzyme in combating glucose intolerance was further supported by the finding that CrAT overexpression in primary human skeletal myocytes increased glucose uptake and attenuated lipid-induced suppression of glucose oxidation. These results implicate carnitine insufficiency and reduced CrAT activity as reversible components of the metabolic syndrome.Disturbances in mitochondrial genesis, morphology, and function are increasingly recognized as components of insulin resistance and the metabolic syndrome (1-3). Still unclear is whether poor mitochondrial performance is a predisposing factor or a consequence of the disease process. The latter view is supported by recent animal studies linking diet-induced insulin resistance to a dysregulated mitochondrial phenotype in skeletal muscle, marked by excessive ␤-oxidation, impaired substrate switching during the fasted to fed transition, and coincident reduction of organic acid intermediates of the tricarboxylic acid cycle (4, 5). In these studies, both diet-induced and genetic forms of insulin resistance were specifically linked to high rates of incomplete fat oxidation and intramuscular accumulation of fatty acylcarnitines, byproducts of lipid catabolism that are produced under conditions of metabolic stress (5, 6). Most compelling, we showed that genetically engineered inhibition of fat oxidation lowered intramuscular acylcarnitine levels and preserved glucose tolerance in mice fed a high fat diet (5, 7). In aggregate, the findings established a stron...

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Section: Carnitine Homeostasis Is Compromised By Chronicsupporting

confidence: 79%

Carnitine Insufficiency Caused by Aging and Overnutrition Compromises Mitochondrial Performance and Metabolic Control

Noland¹,

Koves²,

Seiler³

et al. 2009

Journal of Biological Chemistry

288

339

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“…Tissues modulate their CoA levels in response to diet and disease, and these changes are tied to fluctuations in the level of total PanK activity. The metabolic state of the animal (fasting or feeding) (15)(16)(17)(18)(19), pathological conditions (diabetes) (23,24), and hypolipidemic drugs (fibrates) (14,19,20) all significantly alter the cellular levels of CoA. These alterations are reflected in concomitant changes in tissue PanK activity (21,22), indicating an important role for PanK expression in controlling the cellular CoA levels.…”

Section: Discussionmentioning

confidence: 99%

Feedback Regulation of Murine Pantothenate Kinase 3 by Coenzyme A and Coenzyme A Thioesters

Zhang

Rock

Jackowski

2005

Journal of Biological Chemistry

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Pantothenate kinase catalyzes a key regulatory step in coenzyme A biosynthesis, and there are four mammalian genes that encode isoforms of this enzyme. Pantothenate kinase isoform PanK3 is highly related to the previously characterized PanK1␤ isoform (79% identical, 91% similar), and these two almost identical proteins are expressed most highly in the same tissues. PanK1␤ and PanK3 had very similar molecular sizes, oligomeric form, cytoplasmic cellular location, and kinetic constants for ATP and pantothenate. However, these two PanK isoforms possessed distinct regulatory properties. PanK3 was significantly more sensitive to feedback regulation by acetyl-CoA (IC 50 ‫؍‬ 1 M) than PanK1␤ (IC 50 ‫؍‬ 10 M), and PanK3 was stringently regulated by long-chain acyl-CoA (IC 50 ‫؍‬ 2 M), whereas PanK1␤ was not. Domain swapping experiments localized the difference in the two proteins to a 48-amino-acid domain, where they are the most divergent. Consistent with these more stringent regulatory properties, metabolic labeling experiments showed that coenzyme A (CoA) levels in cells overexpressing PanK3 were lower than in cells overexpressing an equivalent amount of PanK1␤. Thus, the distinct regulatory properties exhibited by the family of the pantothenate kinases allowed the rate of CoA biosynthesis to be controlled by regulatory signals from CoA thioesters involved in different branches of intermediary metabolism.Pantothenate is the essential precursor for CoA, 2 which is a cofactor for a multitude of metabolic reactions including the oxidation of fatty acids, carbohydrates, pyruvate, lactate, ketone bodies, and amino acids, as well as many synthetic reactions. PanK catalyzes the first committed step and is the rate-controlling enzyme in CoA biosynthesis in bacteria (1) and mammals (2). PanK expression levels define the upper threshold of the cellular CoA content (3, 4), and PanK biochemical activity is feedback-regulated by CoA and/or CoA thioesters (3, 5-8), providing a mechanism to coordinate the rate of CoA synthesis with metabolic demand. Loss of feedback regulation by mutation at a single residue results in runaway CoA production (9). A notable exception to this rule is the PanK from Staphylococcus aureus, which lacks CoA feedback regulation (10), consistent with a role for CoA as the primary thiol in the disulfide redox system in this organism, as well as being the major acylgroup carrier (11-13). In mammals, PanK activity and/or CoA content are altered in response to metabolic state (14 -18), insulin (2), glucagon or glucocorticoids (15), fibrates (14, 19 -22), or diabetes (23, 24). CoA is found in all cellular compartments, but the highest concentrations of CoA exist in mitochondria and peroxisomes (25,26). Mitochondrial CoA is used as a cofactor in the tricarboxylic acid cycle and fatty acid ␤-oxidation, and the concentrations of CoA and its thioesters regulate the rates of these processes (27). Peroxisomes play a major role in very long chain fatty acid ␤-oxidation and also have high concentrations of CoA (28, 29),...

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“…The metabolic state (starvation or feeding) (15)(16)(17)(18)(19), pathological conditions (diabetes) (20,21), and hypolipidemic drugs (fibrates) (17,22,23) all significantly alter the cellular levels of CoA, and these fluctuations are reflected by concomitant changes in tissue PanK activity (13,14). CoA participates in most of the reactions catalyzed by PPAR␣ target genes (i.e., fatty acid ␤-oxidation), and CoA and its thioesters are also regulators of key enzymes in intermediary metabolism, such as pyruvate dehydrogenase, citrate lyase, and carnitine palmitoyl transferase.…”

Section: Discussionmentioning

confidence: 99%

“…Before the discovery of multiple PanK isoforms, it was noted that the levels of liver PanK activity (13,14) decreased in conjunction with CoA levels following starvation and increased following feeding (15)(16)(17)(18)(19), increased in diabetes (20,21), and increased after treatment with hypolipidemic agents (17,22,23), suggesting that changes in PanK expression may be involved in altering the physiological status of the tissues. The peroxisome proliferator activator receptor-␣ (PPAR ␣ ) is a transcription factor that is highly expressed in liver, regulates the expression of fatty acid oxidation genes (24), and is activated by hypolipidemic agents such as the fibrates and WY146,43 (25).…”

mentioning

confidence: 99%

PPARα controls the intracellular coenzyme A concentration via regulation of PANK1α gene expression

Ramaswamy

Karim

Murti

et al. 2004

Journal of Lipid Research

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Pantothenate kinase (PanK) is thought to catalyze the first rate-limiting step in CoA biosynthesis. The fulllength cDNA encoding the human PanK1 ␣ protein was isolated, and the complete human PANK1 gene structure was determined. Bezafibrate (BF), a hypolipidemic drug and a peroxisome proliferator activator receptor-␣ (PPAR ␣ ) agonist, specifically increased hPANK1 ␣ mRNA expression in human hepatoblastoma (HepG2) cells as a function of time and dose of the drug, compared with hPANK1 ␤ , hPANK2 , and hPANK3 , which did not significantly increase. Four putative PPAR ␣ response elements were identified in the PANKI ␣ promoter, and BF stimulated hPANK1 ␣ promoter activity but did not alter the mRNA half-life. Pantothenate (Pan) is a B complex vitamin (B 5 ) and is a nutritional requirement in mammals. Pan is the precursor for the biosynthesis of CoA, the predominant acyl group carrier in cells. Acyl moieties are attached to the terminal sulfhydryl of CoA, and these compounds participate in over 100 different reactions in intermediary metabolism (1-4). Short-chain CoA thioesters, such as acetyl-CoA or succinyl-CoA, are the most abundant components of the CoA pool (5) and are important intermediates in the tricarboxylic acid cycle, which coordinates carbon utilization and oxidative energy production. CoA is also an essential cofactor in long-chain fatty acid metabolism. CoA transfers fatty acids to and from the mitochondrial carnitine transferases and carries all of the intermediates of fatty acid ␤ -oxidation in peroxisomes and mitochondria. CoA acyl-thioesters are also the substrates for the acyltransferases and desaturases involved in membrane phospholipid formation, triglyceride synthesis, and protein acylation. Thus, CoA participates in the major anabolic and catabolic pathways critical to cell growth and function.Pan is phosphorylated by pantothenate kinase (PanK) to yield 4 Ј -phosphopantothenate (P-Pan) in the first enzymatic reaction leading to CoA. PanK activity controls the cellular level of CoA in bacteria (6) and mammals (7,8), and there are multiple Pank genes that are differentially expressed and regulated in mammalian tissues (4, 9-11). The first mammalian gene identified was the mouse Pank1 gene, which encodes two proteins that differ at the N terminus due to alternative splicing of distinct initiating exons (9). PanK1 ␣ enzyme activity is feedback inhibited by both unacylated CoA and acetyl-CoA (9), whereas the PanK1 ␤ isoform is less sensitive to feedback regulation by acetyl-CoA and is stimulated by unacylated CoA (8). The human PANK2 gene also encodes two protein isoforms, Abbreviations: BF, bezafibrate; HSS, Hallervorden-Spatz syndrome; P-Pan, 4 Ј -phosphopantothenate; P-PanSH, 4 Ј -phosphopantetheine; Pan, pantothenate; PanK, pantothenate kinase; PKAN, pantothenate kinase-associated neurodegeneration; PPAR ␣ , peroxisome proliferator activator receptor-␣ ; RACE, rapid amplification of cDNA ends.

show abstract

Effects of ciprofibrate and 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA) on the distribution of carnitine and CoA and their acyl-esters and on enzyme activities in rats. Relation between hepatic carnitine concentration and carnitine acetyltransferase activity

Cited by 36 publications

References 37 publications

Carnitine Insufficiency Caused by Aging and Overnutrition Compromises Mitochondrial Performance and Metabolic Control

Carnitine Insufficiency Caused by Aging and Overnutrition Compromises Mitochondrial Performance and Metabolic Control

Feedback Regulation of Murine Pantothenate Kinase 3 by Coenzyme A and Coenzyme A Thioesters

PPARα controls the intracellular coenzyme A concentration via regulation of PANK1α gene expression

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