The Peroxisomal Enzyme L-PBE Is Required to Prevent the Dietary Toxicity of Medium-Chain Fatty Acids

Abstract

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.

Reduced Dietary Omega-6 to Omega-3 Fatty Acid Ratio and 12/15-Lipoxygenase Deficiency Are Protective against Chronic High Fat Diet-Induced Steatohepatitis

“…Data were normalized against two reference housekeeping genes: beta-2 microglobulin (B2m) and hydroxymethylbilane synthase (Hmbs) which were chosen based on stable gene expression levels, based on our pilot study. Others have also found a stable invariant expression of these genes in the livers of other high fat diet-induced obesity mouse models and hepatic cells [24], [25], [26]. The PCR primers used to amplify each gene are: B2m F-5′-CCCCACTGAGACTGATACATACG-3′ R-5′-CGATCCCAGTAGACGGTCTTG-3′, Ccr7 F- 5′-GTACGAGTCGGTGTGCTTCAA-3′ R-5′-GGTAGGTATCCGTCATGGTCT-3′, Ccl19 F- 5′-GTGATGGAGGGGTCAGGA-3′ R-5′-GGGATGGGACAGCCTAAACT-5′, Ccl21 F-5′-GTGATGGAGGGGGTCAGGA-3′ R-5′-GGGATGGGACAGCCTAAACT-3′, Cxcl1 (KC) F- 5′-CTGGGATTCACCTCAAGAACATC-3′ R-5′-CAGGGTCAAGGCAAGCCTC-3′, Cxcl2/3 (Mip2) F-5′-CCACCAACCACCAGGCTAC-3′ R-5′-GCTTCAGGGTCAAGGGCAAA-3′, Hmbs F-5′-TGTGGTGGCGATGCTGAAA-3′ R-5′-TTGTCTCCCGTGGACATA-3′, Ifng F-5′-ATGAACGCTACACACTGCATC-3′ R-5′-CCATCCTTTTGCCAGTTCCTC-3′, Il10 F-5′-GCTCTTACTGACTGGCATGAG-3′ R-5′-CGCAGCTCTAGGAGCATGTG-3′, Il12a F-5′-CTGTGCCTTGGTAGCATCTATG-3′ R-5′-CGCAGAGTCTCGCCATTATGAT-3′, Il12b F-5′-CTCAGAAGCTAACCATCTCCTGG-3′ R-5′-CACAGGTGAGGTTCACTGTTTC-3′, Il18 F-5′-GACTCTTGCGTCAACTTCAAGG-3′ R-5′-CAGGCTGTCTTTTGTCAACGA-3′, Srebp1 F-5′-GCAGCCACCATCTAGCCTG-3′ R-5′-CAGCAGTGAGTCTGCCTTGAT-3′, Tnfa F-5′-CCCTCACACTCAGATCATCTTCT-3′ R-5′-GCTACGACGTGGGCTACAG-3′.…”

Hepatic dysfunction in peroxisomal disorders

“…Additional proof for the requirement of MFP1 to degrade DCA was provided by challenging MFP1 mice with an excess of medium chain fatty acids (coconut oil diet, enriched in C12 triglyceride) [125]. This caused very extensive liver pathology including inflammation and fibrosis leading to death within 3 weeks which was prevented by blocking ω-hydroxylation with 1-aminobenzotriazole.…”

“…Certainly, the assumption that the steatohepatitis in Acox1 -/-mice is mediated by DCA does not fit with the unaffected liver in Mfp1 -/-and Acaa1 -/-mice. On the other hand, the extensive liver degeneration in coconut oil treated Mfp1 knockouts which do accumulate DCA is not accompanied with steatosis [125]. It would therefore be informative to challenge mice that are supposed to have impaired DCA degradation such as L-Pex5 (or other Pex mice), Abcd3, Acox1 and Acaa1 knockouts with a coconut oil diet and compare their responses with Mfp1 -/-mice.…”

“…It would therefore be informative to challenge mice that are supposed to have impaired DCA degradation such as L-Pex5 (or other Pex mice), Abcd3, Acox1 and Acaa1 knockouts with a coconut oil diet and compare their responses with Mfp1 -/-mice. The downstream cellular events including potential mitochondrial toxicity, reactive oxygen production and lipid homeostasis should also be examined [125].…”

The Pex1-G844D mouse: A model for mild human Zellweger spectrum disorder

“…The two probe sets indicating increased expression in Pex1-G844D homozygous relative to heterozygous mice represented the Cyp4a14 and Ufd1l genes. Investigators reported the Cyp4 gene family is transcriptionally regulated in a PPARα/PPARγ-dependent manner with the Cyp4a14 gene product being involved in omega-oxidation of fatty acids [45]. The Ufd1l (aka Ufd1) gene plays a critical role in endoplasmic reticulum (ER)-associated degradation (ERAD) and cholesterol metabolism [46].…”