The peroxisomal enzyme L-PBE is required to prevent the dietary toxicity of medium-chain fatty acids.
Specific metabolic pathways are activated by different nutrients to adapt the organism to available resources. Although essential, these mechanisms are incompletely defined. Here, we report that medium-chain fatty acids contained in coconut oil, a major source of dietary fat, induce the liver ω-oxidation genes Cyp4a10 and Cyp4a14 to increase the production of dicarboxylic fatty acids. Furthermore, these activate all ω- and β-oxidation pathways through peroxisome proliferator activated receptor (PPAR) α and PPARγ, an activation loop normally kept under control by dicarboxylic fatty acid degradation by the peroxisomal enzyme L-PBE. Indeed, L-pbe(-/-) mice fed coconut oil overaccumulate dicarboxylic fatty acids, which activate all fatty acid oxidation pathways and lead to liver inflammation, fibrosis, and death. Thus, the correct homeostasis of dicarboxylic fatty acids is a means to regulate the efficient utilization of ingested medium-chain fatty acids, and its deregulation exemplifies the intricate relationship between impaired metabolism and inflammation.
Center for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland.
Jun
J
Ding
Ursula
U
Loizides-Mangold
Gianpaolo
G
Rando
Vincent
V
Zoete
Olivier
O
Michielin
Janardan K
JK
Reddy
Walter
W
Wahli
Howard
H
Riezman
Bernard
B
Thorens
D000818:Animals; D000074263:Coconut Oil; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D004041:Dietary Fats / Q000008:administration & dosage / Q000493:pharmacokinetics; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D017114:Liver Failure, Acute / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D020675:Peroxisomes / Q000378:metabolism*; D010938:Plant Oils / Q000008:administration & dosage / Q000493:pharmacokinetics; D015398:Signal Transduction
C512110:Cyp4a10 protein, mouse; C436963:Cyp4a14 protein, mouse; D004041:Dietary Fats; D005227:Fatty Acids; D047493:PPAR alpha; D047495:PPAR gamma; D010938:Plant Oils; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; D000074263:Coconut Oil