PEROXISOMALβ-OXIDATION ANDPEROXISOMEPROLIFERATOR–ACTIVATEDRECEPTORα: An Adaptive Metabolic System

Abstract

beta-Oxidation occurs in both mitochondria and peroxisomes. Mitochondria catalyze the beta-oxidation of the bulk of short-, medium-, and long-chain fatty acids derived from diet, and this pathway constitutes the major process by which fatty acids are oxidized to generate energy. Peroxisomes are involved in the beta-oxidation chain shortening of long-chain and very-long-chain fatty acyl-coenzyme (CoAs), long-chain dicarboxylyl-CoAs, the CoA esters of eicosanoids, 2-methyl-branched fatty acyl-CoAs, and the CoA esters of the bile acid intermediates di- and trihydroxycoprostanoic acids, and in the process they generate H2O2. Long-chain and very-long-chain fatty acids (VLCFAs) are also metabolized by the cytochrome P450 CYP4A omega-oxidation system to dicarboxylic acids that serve as substrates for peroxisomal beta-oxidation. The peroxisomal beta-oxidation system consists of (a) a classical peroxisome proliferator-inducible pathway capable of catalyzing straight-chain acyl-CoAs by fatty acyl-CoA oxidase, L-bifunctional protein, and thiolase, and (b) a second noninducible pathway catalyzing the oxidation of 2-methyl-branched fatty acyl-CoAs by branched-chain acyl-CoA oxidase (pristanoyl-CoA oxidase/trihydroxycoprostanoyl-CoA oxidase), D-bifunctional protein, and sterol carrier protein (SCP)x. The genes encoding the classical beta-oxidation pathway in liver are transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPAR alpha). Evidence derived from mice deficient in PPAR alpha, peroxisomal fatty acyl-CoA oxidase, and some of the other enzymes of the two peroxisomal beta-oxidation pathways points to the critical importance of PPAR alpha and of the classical peroxisomal fatty acyl-CoA oxidase in energy metabolism, and in the development of hepatic steatosis, steatohepatitis, and liver cancer.

Daidzein supplementation prevents non-alcoholic fatty liver disease through alternation of hepatic gene expression profiles and adipocyte metabolism

“…The activation of adiponectin resulted in the upregulation of its downstream genes, PPARa and AMPK (Figure 4), 51 which encode for many of the enzymes involved in fatty acid b-oxidation, such as ACAS, ACAD and carnitine palmitoyltransferase I. 42,45,46 In our current study, ACAS and ACAD levels were increased by dadizein supplementation (Figure 4b). Daidzein supplementation also increased the expression of b-catenin, an antiadipogenic transcription factor 56 (Figure 4c).…”

“…40,41 Interestingly, daidzein supplementation normalized the depression of glutathione S-transferase-a3 and superoxide dismutase 2 by the HF diet, and further downregulated the expression of c-Jun N-terminal kinase and IkB kinase that is augmented by the HF diet (Table 1), which might be associated with the higher antioxidative capacity of daidzein metabolite, equol, rather than other isoflavones. 15 Besides these results, our hepatic transcript profiles showed that daidzein supplementation reduced hepatic lipid levels through the activation of ACAS and ACAD, which are involved in fatty acid b-oxidation, [42][43][44][45][46][47] and this activation was due to the upregulation of PPARa, their upstream gene. 48 Daidzein supplementation also functions as hepatic antisteatotic materials by the regulation of adipocyte metabolism.…”

PPAR-α effects on the heart and other vascular tissues

“…Binding to PPAR-␣ by fatty acid, eicosanoid, and fibrate drug ligands leads to activation of numerous genes involved in ␤-oxidative catabolism of fatty acids (26,42,44). In addition to inducing all the genes encoding enzymes of the classical fatty acid ␤-oxidation pathway [e.g., acyl-CoA oxidase, very-long-chain and medium-chain acyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase (66)], PPAR-␣ also activates the genes necessary for cellular uptake of fatty acids (fatty acid transport protein) and their initial derivatization for entry into the ␤-oxidation cycle (acyl-CoA synthetase) (for a review, see Ref. 76).…”

Metabolism of methiocarb and carbaryl by rat and human livers and plasma, and effect on their PXR, CAR and PPARα activities

“…Some compounds have both PXR and CAR activities whereas others are either PXR agonists or CAR agonists. PPARα functions as the receptor for the induction of CYP4A gene, which is involved in fatty acid metabolism (Reddy and Hashimoto, 2001). PPARα agonists have been reported to induce the gene expression of 17β-hydroxysteroid dehydrogenase type IV, which catalyzes the conversion of estradiol to its inactive metabolite estrone (Fan et al, 1998).…”