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Peroxisome proliferator‐activated receptor α–retinoid X receptor agonists induce beta‐cell protection against palmitate toxicity
Author(s) -
Hellemans Karine,
Kerckhofs Karen,
Hannaert JeanClaude,
Martens Geert,
Van Veldhoven Paul,
Pipeleers Daniel
Publication year - 2007
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2007.06131.x
Subject(s) - peroxisome , retinoid x receptor , peroxisome proliferator activated receptor , lipotoxicity , carnitine , toxicity , beta oxidation , biology , fatty acid , mitochondrial toxicity , biochemistry , receptor , peroxisome proliferator activated receptor alpha , fatty acid metabolism , retinoid x receptor alpha , chemistry , endocrinology , medicine , mitochondrion , retinoid , nuclear receptor , retinoic acid , insulin , insulin resistance , transcription factor , organic chemistry , gene
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 β‐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 α (PPARα) agonists, conditions leading to increased palmitate oxidation. In contrast, inhibition of mitochondrial β‐oxidation by etomoxir increased palmitate toxicity. A combination of PPARα 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 β‐oxidation, lipid metabolism, and peroxisome proliferation. PPARα–RXR protection was abolished by the carnitine palmitoyl transferase 1 inhibitor etomoxir. These observations indicate that PPARα and RXR regulate beta‐cell susceptibility to long‐chain fatty acid toxicity by increasing the rates of β‐oxidation and by involving peroxisomes in fatty acid metabolism.