Description
Obesity and insulin resistance are two major risk factors for developing type 2 diabetes, which is characterized by failure of insulin-producing pancreatic b-cells to keep the blood glucose levels normal. In the task of developing new treatments for this disease, it is crucial to understand how obesity and nutrient overload affects pancreatic b-cell function.
A large body of evidence documents that exposure of pancreatic b-cells to high levels of either free fatty acids or glucose, or both, leads to b-cell dysfunction (gluco/lipotoxicity).
These effects of nutrient overload are implicated in the failure of b-cells in type 2 diabetes.
The peroxisome proliferator-activated receptors (PPARs) are interesting in this context because they are lipid-activated transcription factors and activate genes involved in lipid metabolism. PPARa is expressed in pancreatic islets and β-cell lines, and primarily activates genes involved in fatty acid uptake, transport and oxidation. Interestingly, glucose downregulates the expression of PPARa in pancreatic β-cells1 and the resulting down-regulation of fatty acid oxidation may contribute to the toxic effect on b-cells of sustained high glucose levels seen in type 2 diabetic subjects. However, the mechanism involved in the repression of PPARα expression by glucose is only partly understood. We have recently shown that the repression of PPARα expression by glucose involves inactivation of the AMP-activated protein kinase (AMPK)2, but the down-stream targets as well as the involved promoter elements of PPARα have not been determined. To investigate this, different promoter studies were performed in the rat INS-1E β-cell line. By the use of 5'Rapid Amplification of cDNA Ends (RACE) the transcription start sites of several PPARα mRNAs was uncovered. In addition, two novel 5'untranslated exons giving rise to two rat PPARα transcripts not previously reported were also identified. The expression of the different rat PPARα splice forms were all found to be repressed by glucose and de-repressed by co-culture with the specific activator of AMPK, metformin.
Chromatin immunoprecipitation (ChIP) is currently being used to search for transcription factors that bind to the PPARα promoter in a glucose dependent manner. These studies indicate a possible involvement of the transcription factor Sp1.
Another PPAR subtype, PPARδ, is also expressed in pancreatic β-cells and recent data shows that PPARδ, like PPARα, stimulates fatty acid oxidation in β-cells. An investigation of the ability of PPARδ (and PPARα) to protect against the detrimental effects of fatty acid overload on pancreatic β-cells is about to be initiated. Furthermore, specific knock-down of either PPARδ or PPARα, or both, by lentiviral expression of shRNAs against the PPARs is expected to contribute greatly to understanding the role of PPARα and δ in pancreatic β-cell function and dysfunction.
Roduit R, Morin J, Masse F, Segall L, Roche E, Newgard CB, Assimacopoulus-Jeannet & Prentki M 2000 J.Biol.Chem. 275 35799-35806Ravnskjaer K, Boergesen M, Dalgaard LT & Mandrup S 2006 J. Mol. Endocrinol. 36(2) 289-299
Emneord: Metabolism, diabetes, beta-cells
| Period | 3. Sept 2006 |
|---|---|
| Event title | PhD Summer School 2006 |
| Event type | Conference |
| Organiser | Danish PhD School of Molecular Metabolism |
| Location | Gl.Avernæs, DenmarkShow on map |
Keywords
- Metabolism, diabetes, beta-cells