PPARα-activation results in enhanced carnitine biosynthesis and OCTN2-mediated hepatic carnitine accumulation

Vlies, Naomi van; Ferdinandusse, Sacha; Turkenburg, Marjolein; Wanders, Ronald J. A.; Vaz, Frédéric M.

doi:10.1016/j.bbabio.2007.07.001

Cited by 87 publications

(93 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These compounds activate PPAR␣, a lipid-sensing nuclear receptor that functions as a master regulator of fatty acid metabolism. Recent studies in PPAR␣ null mice confirmed an essential role for this nuclear receptor in regulating carnitine homeostasis, because these animals have a profound systemic carnitine deficiency associated with reduced hepatic expression of OCTN2 and ␥-butyrobetaine hydroxylase-1 (35,36). Consistent with these reports, short term high fat feeding (4 days), which activates the PPAR network, increases systemic carnitine levels (34,37).…”

Section: Discussionsupporting

confidence: 73%

“…Other clinical factors that disrupt carnitine status include renal dysfunction and use of drugs that form carnitine conjugates (32,33). Conversely, compounds belonging to the fibrate class of hypolipidemic drugs raise systemic carnitine levels, in parallel with increased hepatic expression of the carnitine biosynthetic machinery (34,35). These compounds activate PPAR␣, a lipid-sensing nuclear receptor that functions as a master regulator of fatty acid metabolism.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…Hepatic and intestinal carnitine levels are increased after PPAR␣ agonist (clofibrate and Wy14643) treatment of rodents and pigs (van Vlies et al, 2007;Ringseis et al, 2008). Increased carnitine levels are due to enhanced carnitine biosynthesis and uptake (Ringseis et al, 2008).…”

Section: Peroxisome Proliferator-activated Receptormentioning

confidence: 99%

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

2010

View full text Add to dashboard Cite

“…2007) and mice (Hirai et al, 2007;Koch et al, 2008;van Vlies et al, 2007). In humans, treatment with insulin is associated with an increase in carnitine transport into and expression of OCTN2 in skeletal muscle (Stephens et al, 2006).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The plasma carnitine concentration regulates renal OCTN2 expression and carnitine transport in rats

Schürch

Todesco

Nováková

et al. 2010

European Journal of Pharmacology

View full text Add to dashboard Cite

Previous findings in rats and in human vegetarians suggest that the plasma carnitine concentration and/or carnitine ingestion may influence the renal reabsorption of carnitine. We tested this hypothesis in rats with secondary carnitine deficiency following treatment with N-trimethyl-hydrazine-3-propionate (THP) for 2 weeks and rats treated with excess L-carnitine for 2 weeks. Compared to untreated control rats, treatment with THP was associated with an approximately 70% decrease in plasma carnitine and with a 74% decrease in the skeletal muscle carnitine content. In contrast, treatment with Lcarnitine increased plasma carnitine levels by 80% and the skeletal muscle carnitine content by 50%. Treatment with L-carnitine affected neither the activity of carnitine transport into isolated renal brush border membrane vesicles, nor renal mRNA expression of the carnitine transporter OCTN2. In contrast, in carnitine deficient rats, carnitine transport into isolated brush border membrane vesicles was increased 1.9-fold compared to untreated control rats. Similarly, renal mRNA expression of OCTN2 increased by a factor of 1.7 in carnitine deficient rats, whereas OCTN2 mRNA expression remained unchanged in gut, liver or skeletal muscle. Our study supports the hypothesis that a decrease in the carnitine plasma and/or glomerular filtrate concentration increases renal expression and activity of OCTN2.

show abstract

PPARα-activation results in enhanced carnitine biosynthesis and OCTN2-mediated hepatic carnitine accumulation

Cited by 87 publications

References 27 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

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

The plasma carnitine concentration regulates renal OCTN2 expression and carnitine transport in rats

Contact Info

Product

Resources

About