title: Peroxisome proliferator-activated receptor alpha-retinoid X receptor agonists induce beta-cell protection against palmitate toxicity.
abstract: Fatty acids can stimulate the secretory activity of insulin-producing beta-cells. At elevated concentrations, they can also be toxic to isolated beta-cells. This toxicity varies inversely with the cellular ability to accumulate neutral lipids in the cytoplasm. To further examine whether cytoprotection can be achieved by decreasing cytoplasmic levels of free acyl moieties, we investigated whether palmitate toxicity is also lowered by stimulating its beta-oxidation. Lower rates of palmitate-induced beta-cell death were measured in the presence of L-carnitine as well as after addition of peroxisome proliferator-activated receptor alpha (PPARalpha) agonists, conditions leading to increased palmitate oxidation. In contrast, inhibition of mitochondrial beta-oxidation by etomoxir increased palmitate toxicity. A combination of PPARalpha and retinoid X receptor (RXR) agonists acted synergistically and led to complete protection; this was associated with enhanced expression levels of genes involved in mitochondrial and peroxisomal beta-oxidation, lipid metabolism, and peroxisome proliferation. PPARalpha-RXR protection was abolished by the carnitine palmitoyl transferase 1 inhibitor etomoxir. These observations indicate that PPARalpha and RXR regulate beta-cell susceptibility to long-chain fatty acid toxicity by increasing the rates of beta-oxidation and by involving peroxisomes in fatty acid metabolism.
authors.affiliation: Diabetes Research Center (DRC), Brussels Free University-VUB, Belgium. karine.hellemans@vub.ac.be
authors.forename: Karine
authors.initials: K
authors.lastname: Hellemans
authors.forename: Karen
authors.initials: K
authors.lastname: Kerckhofs
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Hannaert
authors.forename: Geert
authors.initials: G
authors.lastname: Martens
authors.forename: Paul
authors.initials: P
authors.lastname: Van Veldhoven
authors.forename: Daniel
authors.initials: D
authors.lastname: Pipeleers
mesh_terms: D000077556:Alitretinoin; D000818:Animals; D002250:Carbon Radioisotopes / Q000378:metabolism; D002331:Carnitine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002994:Clofibrate / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists*; D010168:Palmitates / Q000037:antagonists & inhibitors / Q000633:toxicity*; D020011:Protective Agents / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D047488:Retinoid X Receptors / Q000819:agonists*; D014212:Tretinoin / Q000378:metabolism
chemical_list: D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D047493:PPAR alpha; D010168:Palmitates; D020011:Protective Agents; D012333:RNA, Messenger; D047488:Retinoid X Receptors; D000077556:Alitretinoin; D014212:Tretinoin; D002994:Clofibrate; D005947:Glucose; C054207:etomoxir; D002331:Carnitine