PPARd IS A LIPID SENSOR AND A REGULATOR OF FATTY ACID OXIDATION IN PANCREATIC β-CELLS

Kim Ravnskjær; Tina Nielsen; Michael Børgesen; Susanne Mandrup

PPARd IS A LIPID SENSOR AND A REGULATOR OF FATTY ACID OXIDATION IN PANCREATIC β-CELLS

Kim Ravnskjær, Tina Nielsen, Michael Børgesen, Susanne Mandrup

Research output: Contribution to conference without publisher/journal › Poster › Research

Abstract

PPARa has long been known as a key regulator of mammalian fatty acid oxidation during fasting. However, high PPARa expression is restricted to a limited number of tissues, mainly liver, kidney, brown adipose tissue and the myocardium. Recently also the ubiquitously expressed PPARd was reported to stimulate fatty acid oxidation when activated by agonists in myocytes, cardiomycytes and adipo-cytes. A role for PPARd as regulator of basal fatty acid catabolism and energy expenditure was therefore suggested.

Here we show that PPARd is the most abundantly expressed PPAR subtype in both primary pancreatic islets and in the insulinoma cell line INS-1E. This is reflected at the functional level in activity assays using a PPRE-driven luciferase reporter construct. The fatty acids oleic, arachidonic and linolenic acid are able to acivate this construct synergistically with the synthetic RXR agonist LG100268. Selective activation of PPARd in INS-1E cells with the PPARd agonist L165041 in the presence or absence of the RXRa agonist LG100268 induces luciferase activity 3- and 7-fold respectively and mimics the effect of the fatty acids. The same subset genes involved in fatty acid uptake and oxidation are synergistically activated by fatty acids and the selective PPARd and RXRa agonists. This effect is blunted by specific knockdown of PPARd. In addition, we show that ectopically expressed PPARd and RXRa are able synergistically to recruit RNA polymerase II, TBP and TRAP220 to the promoters of known PPAR target genes in vivo.

In parallel with increased expression of genes involved in fatty oxidation, b-oxidation of 14C-oleate is increased 7-fold upon incubation of INS-1E cells with L165041 and LG100268. In keeping with this, adenoviral co-expression of PPARd and RXRa leads to a 5-fold increase in 14C-oleate oxidation.

The current observations suggest that PPARd is an important lipid sensor and regulator of lipid oxidation in pancreatic b-cells.

Original language	English
Publication date	2005
Publication status	Published - 2005
Event	Keystone Synposia - Bioactive Lipids, Lipidomics and their Targets - Whistler, Canada Duration: 12. Apr 2005 → 17. Apr 2005 Conference number: Z1

Conference

Conference	Keystone Synposia - Bioactive Lipids, Lipidomics and their Targets
Number	Z1
Country/Territory	Canada
City	Whistler
Period	12/04/2005 → 17/04/2005

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@conference{121282a0484111ddb1a1000ea68e967b,

title = "PPARd IS A LIPID SENSOR AND A REGULATOR OF FATTY ACID OXIDATION IN PANCREATIC β-CELLS",

abstract = " PPARa has long been known as a key regulator of mammalian fatty acid oxidation during fasting. However, high PPARa expression is restricted to a limited number of tissues, mainly liver, kidney, brown adipose tissue and the myocardium. Recently also the ubiquitously expressed PPARd was reported to stimulate fatty acid oxidation when activated by agonists in myocytes, cardiomycytes and adipo-cytes. A role for PPARd as regulator of basal fatty acid catabolism and energy expenditure was therefore suggested.Here we show that PPARd is the most abundantly expressed PPAR subtype in both primary pancreatic islets and in the insulinoma cell line INS-1E. This is reflected at the functional level in activity assays using a PPRE-driven luciferase reporter construct. The fatty acids oleic, arachidonic and linolenic acid are able to acivate this construct synergistically with the synthetic RXR agonist LG100268. Selective activation of PPARd in INS-1E cells with the PPARd agonist L165041 in the presence or absence of the RXRa agonist LG100268 induces luciferase activity 3- and 7-fold respectively and mimics the effect of the fatty acids. The same subset genes involved in fatty acid uptake and oxidation are synergistically activated by fatty acids and the selective PPARd and RXRa agonists. This effect is blunted by specific knockdown of PPARd. In addition, we show that ectopically expressed PPARd and RXRa are able synergistically to recruit RNA polymerase II, TBP and TRAP220 to the promoters of known PPAR target genes in vivo.In parallel with increased expression of genes involved in fatty oxidation, b-oxidation of 14C-oleate is increased 7-fold upon incubation of INS-1E cells with L165041 and LG100268. In keeping with this, adenoviral co-expression of PPARd and RXRa leads to a 5-fold increase in 14C-oleate oxidation.The current observations suggest that PPARd is an important lipid sensor and regulator of lipid oxidation in pancreatic b-cells. ",

author = "Kim Ravnskj{\ae}r and Tina Nielsen and Michael B{\o}rgesen and Susanne Mandrup",

year = "2005",

language = "English",

note = "null ; Conference date: 12-04-2005 Through 17-04-2005",

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TY - CONF

T1 - PPARd IS A LIPID SENSOR AND A REGULATOR OF FATTY ACID OXIDATION IN PANCREATIC β-CELLS

AU - Ravnskjær, Kim

AU - Nielsen, Tina

AU - Børgesen, Michael

AU - Mandrup, Susanne

N1 - Conference code: Z1

PY - 2005

Y1 - 2005

N2 - PPARa has long been known as a key regulator of mammalian fatty acid oxidation during fasting. However, high PPARa expression is restricted to a limited number of tissues, mainly liver, kidney, brown adipose tissue and the myocardium. Recently also the ubiquitously expressed PPARd was reported to stimulate fatty acid oxidation when activated by agonists in myocytes, cardiomycytes and adipo-cytes. A role for PPARd as regulator of basal fatty acid catabolism and energy expenditure was therefore suggested.Here we show that PPARd is the most abundantly expressed PPAR subtype in both primary pancreatic islets and in the insulinoma cell line INS-1E. This is reflected at the functional level in activity assays using a PPRE-driven luciferase reporter construct. The fatty acids oleic, arachidonic and linolenic acid are able to acivate this construct synergistically with the synthetic RXR agonist LG100268. Selective activation of PPARd in INS-1E cells with the PPARd agonist L165041 in the presence or absence of the RXRa agonist LG100268 induces luciferase activity 3- and 7-fold respectively and mimics the effect of the fatty acids. The same subset genes involved in fatty acid uptake and oxidation are synergistically activated by fatty acids and the selective PPARd and RXRa agonists. This effect is blunted by specific knockdown of PPARd. In addition, we show that ectopically expressed PPARd and RXRa are able synergistically to recruit RNA polymerase II, TBP and TRAP220 to the promoters of known PPAR target genes in vivo.In parallel with increased expression of genes involved in fatty oxidation, b-oxidation of 14C-oleate is increased 7-fold upon incubation of INS-1E cells with L165041 and LG100268. In keeping with this, adenoviral co-expression of PPARd and RXRa leads to a 5-fold increase in 14C-oleate oxidation.The current observations suggest that PPARd is an important lipid sensor and regulator of lipid oxidation in pancreatic b-cells.

AB - PPARa has long been known as a key regulator of mammalian fatty acid oxidation during fasting. However, high PPARa expression is restricted to a limited number of tissues, mainly liver, kidney, brown adipose tissue and the myocardium. Recently also the ubiquitously expressed PPARd was reported to stimulate fatty acid oxidation when activated by agonists in myocytes, cardiomycytes and adipo-cytes. A role for PPARd as regulator of basal fatty acid catabolism and energy expenditure was therefore suggested.Here we show that PPARd is the most abundantly expressed PPAR subtype in both primary pancreatic islets and in the insulinoma cell line INS-1E. This is reflected at the functional level in activity assays using a PPRE-driven luciferase reporter construct. The fatty acids oleic, arachidonic and linolenic acid are able to acivate this construct synergistically with the synthetic RXR agonist LG100268. Selective activation of PPARd in INS-1E cells with the PPARd agonist L165041 in the presence or absence of the RXRa agonist LG100268 induces luciferase activity 3- and 7-fold respectively and mimics the effect of the fatty acids. The same subset genes involved in fatty acid uptake and oxidation are synergistically activated by fatty acids and the selective PPARd and RXRa agonists. This effect is blunted by specific knockdown of PPARd. In addition, we show that ectopically expressed PPARd and RXRa are able synergistically to recruit RNA polymerase II, TBP and TRAP220 to the promoters of known PPAR target genes in vivo.In parallel with increased expression of genes involved in fatty oxidation, b-oxidation of 14C-oleate is increased 7-fold upon incubation of INS-1E cells with L165041 and LG100268. In keeping with this, adenoviral co-expression of PPARd and RXRa leads to a 5-fold increase in 14C-oleate oxidation.The current observations suggest that PPARd is an important lipid sensor and regulator of lipid oxidation in pancreatic b-cells.

M3 - Poster

Y2 - 12 April 2005 through 17 April 2005

ER -

PPARd IS A LIPID SENSOR AND A REGULATOR OF FATTY ACID OXIDATION IN PANCREATIC β-CELLS

Abstract

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