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PPARα agonists up-regulate organic cation transporters in rat liver cells
Sebastian Luci, Stefanie Geissler, Bettina König, Alexander Koch, Gabriele I. Stangl, Frank Hirche, Klaus Eder http://www.sciencedirect.com/science/article/pii/S0006291X06021541#cor1
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[/SUP]
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Received 15 September 2006; Available online 27 September 2006.
[h=3]Abstract[/h]It has been shown that clofibrate treatment increases the carnitine concentration in the liver of rats. However, the molecular mechanism is still unknown. In this study, we observed for the first time that treatment of rats with the peroxisome proliferator activated receptor (PPAR)-α agonist clofibrate increases hepatic mRNA concentrations of organic cation transporters (OCTNs)-1 and -2 which act as transporters of carnitine into the cell. In rat hepatoma (Fao) cells, treatment with WY-14,643 also increased the mRNA concentration of OCTN-2. mRNA concentrations of enzymes involved in carnitine biosynthesis were not altered by treatment with the PPARα agonists in livers of rats and in Fao cells. We conclude that PPARα agonists increase carnitine concentrations in livers of rats and cells by an increased uptake of carnitine into the cell but not by an increased carnitine biosynthesis.
Keywords: Carnitine; Peroxisome proliferator activated receptor α; Rat; Organic cation transporter
PPARα Agonists Reduce 11β-Hydroxysteroid Dehydrogenase Type 1 in the Liver
Anne Hermanowski-Vosatka[SUP]a[/SUP][SUP], [/SUP][SUP]1[/SUP], David Gerhold[SUP]b[/SUP], Steven S. Mundt[SUP]a[/SUP], Vilert A. Loving[SUP]a[/SUP], Meiqing Lu[SUP]b[/SUP], Yuli Chen[SUP]c[/SUP], Alex Elbrecht[SUP]c[/SUP], Margaret Wu[SUP]c[/SUP], Thomas Doebber[SUP]c[/SUP], Linda Kelly[SUP]c[/SUP], Denise Milot[SUP]a[/SUP], Qiu Guo[SUP]a[/SUP], Pei-Ran Wang[SUP]a[/SUP], Marc Ippolito[SUP]a[/SUP], Yu-Sheng Chao[SUP]a[/SUP], Samuel D. Wright[SUP]a[/SUP], Rolf Thieringer[SUP]a[/SUP]
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Received 8 November 2000; Available online 27 March 2002.
[h=3]Abstract[/h]11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) is an enzyme that converts cortisone to the active glucocorticoid, cortisol. Cortisol–cortisone interconversion plays a key role in the regulation of glucose metabolism, since mice deficient in 11βHSD1 are resistant to diet-induced hyperglycemia. Peroxisome proliferator activator receptors (PPAR) are key regulators of glucose and lipid homeostasis. We observed a striking downregulation of murine hepatic 11βHSD1 expression and activity after chronic treatment of wild-type mice with PPARα agonists, while 11βHSD1 in the livers of PPARα knockout mice, or in mice treated for only 7 h with PPARα agonists, was unaltered. Our results are the first to show PPARα agonists can affect glucocorticoid metabolism in the liver by altering 11βHSD1 expression after chronic treatment. Regulation of active glucocorticoid levels in the liver by PPARα agonists may in turn affect glucose metabolism, consistent with reports of their antidiabetic effects.
Sebastian Luci, Stefanie Geissler, Bettina König, Alexander Koch, Gabriele I. Stangl, Frank Hirche, Klaus Eder http://www.sciencedirect.com/science/article/pii/S0006291X06021541#cor1
[SUP], [/SUP][SUP][/SUP]Purchase
| Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, Emil-Abderhalden-Strasse 26, D-06108 Halle (Saale), Germany |
Received 15 September 2006; Available online 27 September 2006.
[h=3]Abstract[/h]It has been shown that clofibrate treatment increases the carnitine concentration in the liver of rats. However, the molecular mechanism is still unknown. In this study, we observed for the first time that treatment of rats with the peroxisome proliferator activated receptor (PPAR)-α agonist clofibrate increases hepatic mRNA concentrations of organic cation transporters (OCTNs)-1 and -2 which act as transporters of carnitine into the cell. In rat hepatoma (Fao) cells, treatment with WY-14,643 also increased the mRNA concentration of OCTN-2. mRNA concentrations of enzymes involved in carnitine biosynthesis were not altered by treatment with the PPARα agonists in livers of rats and in Fao cells. We conclude that PPARα agonists increase carnitine concentrations in livers of rats and cells by an increased uptake of carnitine into the cell but not by an increased carnitine biosynthesis.
Keywords: Carnitine; Peroxisome proliferator activated receptor α; Rat; Organic cation transporter
PPARα Agonists Reduce 11β-Hydroxysteroid Dehydrogenase Type 1 in the Liver
Anne Hermanowski-Vosatka[SUP]a[/SUP][SUP], [/SUP][SUP]1[/SUP], David Gerhold[SUP]b[/SUP], Steven S. Mundt[SUP]a[/SUP], Vilert A. Loving[SUP]a[/SUP], Meiqing Lu[SUP]b[/SUP], Yuli Chen[SUP]c[/SUP], Alex Elbrecht[SUP]c[/SUP], Margaret Wu[SUP]c[/SUP], Thomas Doebber[SUP]c[/SUP], Linda Kelly[SUP]c[/SUP], Denise Milot[SUP]a[/SUP], Qiu Guo[SUP]a[/SUP], Pei-Ran Wang[SUP]a[/SUP], Marc Ippolito[SUP]a[/SUP], Yu-Sheng Chao[SUP]a[/SUP], Samuel D. Wright[SUP]a[/SUP], Rolf Thieringer[SUP]a[/SUP]
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| [SUP]a[/SUP] | Department of Atherosclerosis and Endocrinology, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, New Jersey |
| [SUP]c[/SUP] | Department of Molecular Endocrinology, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, New Jersey |
| [SUP]b[/SUP] | Department of Genomic Pharmacology, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, New Jersey |
Received 8 November 2000; Available online 27 March 2002.
[h=3]Abstract[/h]11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) is an enzyme that converts cortisone to the active glucocorticoid, cortisol. Cortisol–cortisone interconversion plays a key role in the regulation of glucose metabolism, since mice deficient in 11βHSD1 are resistant to diet-induced hyperglycemia. Peroxisome proliferator activator receptors (PPAR) are key regulators of glucose and lipid homeostasis. We observed a striking downregulation of murine hepatic 11βHSD1 expression and activity after chronic treatment of wild-type mice with PPARα agonists, while 11βHSD1 in the livers of PPARα knockout mice, or in mice treated for only 7 h with PPARα agonists, was unaltered. Our results are the first to show PPARα agonists can affect glucocorticoid metabolism in the liver by altering 11βHSD1 expression after chronic treatment. Regulation of active glucocorticoid levels in the liver by PPARα agonists may in turn affect glucose metabolism, consistent with reports of their antidiabetic effects.
