Peroxisomes, fatty acid metabolism

Cinnamyl anthranilate has the characteristic effects of a peroxisome proliferator on mouse liver, increasing the activity of peroxisomal fatty acid-metabolizing enzymes and microsomal CYP4A and increasing hepatocellular proliferation. These effects are mediated by the intact ester, and were not seen after administration of the hydrolysis products, cinnamyl alcohol and anthranilic acid. The corresponding effects on rat liver were very much weaker. No relevant data from humans were available. 

Levels of Significant Exposure to DEHP - Inhalation 3-2. Levels of Significant Exposure to DEHP - Ora 3-3. Peroxisomal Fatty Acid Metabolism 3-4. DEHP Metabolites... 

To date there are no true inborn errors associated with essential fatty acid metabolism. However, we do know that the final step of DHA formation is the peroxisomal beta-oxidation of a homologous C24 fatty acid [7]. Consequently, patients with a generalised defect of peroxisomal function, such as Zellweger syndrome, are prone to develop deficiencies of essential fatty acids including DHA [9]. 

With the clofibrate type of inducer, other changes are also apparent. Thus, there is a proliferation in the number of peroxisomes (an intracellular organelle) as well as induction of a particular form of cytochrome P-450 involved in fatty acid metabolism. A number of other enzymes associated with the role of this organelle in fatty acid metabolism are also increased, such as carnitine acyltransferase and catalase. This phenomenon is discussed in more detail in chapter 6. 

Ikeda, T., Aiba, K., Fukuda, K., Tanaka, M. The induction of peroxisome proliferation in rat liver by perfluorinated fatty acids, metabolically inhert derivatives of fatty acids. J. Biochem., 98 475 82 (1985). 

Yoshikawa T, Ide T, Shimano H, Yahagi N, Amemiya-Kudo M, Matsuzaka T, Yatoh S, Kitamine T, Okazaki H, Tamura Y, et al. Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-Ic promoter through inhibition of LXR signaling. Mol. Endocrinol. 2003 17 1240-1254. 

The stigma of the emcic acid (C22 ln - 9) in rapeseed oil has lingered despite firm evidence that this fatty acid was more of a threat to rats than to humans. It is sufficient to say that the discovery of chain shortening of emcic acid to oleic acid by peroxisomes was one of the most fundamental breakthroughs in understanding fatty acid metabolism in the last few decades. Once in the oleic acid form, the emcic acid residue is as readily catabolized by mitochondria, as are palmitic and other fatty acids (4). The reduction of emcic acid in rapeseed oil resulted in a marked increase in octadecanoic acids, and their contribution in canola oil is around 95% of all fatty acids present (Table 2). 

Genetic Diseases that Disrupt Peroxisomal Steps of Fatty Acid Metabolism... 

Latruffe, N., M. Cherkaoui-Malki, V. Nicolas-Frances, B. Jannin, M.-C. Clemencet, F. Hansmannel, P. Passilly-Degrace and J.-P. Berlot. Peroxisome-proliferator-activated receptors as physiological sensors of fatty acid metabolism molecular regulation in peroxisomes. Biochem. Soc. Trans. 29 305-309, 2001. 

With the clofibrate type of inducer other changes are also apparent. Thus, there is a proliferation in the number of peroxisomes (an intracellular organelle), as well as induction of a particular form of cytochrome P-450 involved in fatty acid metabolism. A number of other enzymes associated with the role of this organelle in fatty acid metabolism are also increased, such as carnitine acyltransferase and catalase. This phenomenon is discussed in more detail in Chapter 6. The onset of the inductive response is in the order of a few hours (3-6 h after polycyclic hydrocarbons, 8-12 h after barbiturates), is maximal after 3-5 days with barbiturates (24-48 h with polycyclic hydrocarbons) and lasts for at least 5 days (somewhat longer with polycyclic hydrocarbon induction). The magnitude of the inductive effect may depend on the size and duration of dosing with the inducer, and will also be influenced by the sex, species, strain of animal and the tissue exposed. 

Aoyama, T., Peters, J. M., Iritani, N., Nakajima, T., Furihata, K., Hashimoto, T., and Gonzalez, F. J. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem 273 (1998) 5678-5684. 

The aim of this study was to determine the organelle and the specific enzymes involved in the two-carbon shortening process of 24 6n-3 to 22 6n-3. We hypothesized that peroxisomes are not only indispensable, but also the exclusive site for the retroconversion step of 22 6n-3 from 24 6n-3 by measuring the rate of synthesis of radiolabeled 22 6n-3 and its intermediates from [l- C]18 3n-3 in human skin fibroblasts from normal controls and patients with disorders of peroxisomal or mitochondrial fatty acid metabolism. An overview of the patient cell lines studied and their biochemical defect related to fatty acid metabolism is given in Table 1. 

Fibroblast cell lines from patients with aldehyde oxidase 1 (AOxl) and D-bifunctional protein (DBF) deficiency accumulated metabolic intermediates between 18 3n-3 and 24 6n-3 similar to control cells when incubated with [l- C] 18 3n-3 (Table 2). However, the rate of 22 6n-3 synthesis was <10% of control in these cell lines, indicating that these 2 peroxisomal fatty acid P-oxidation enzymes are involved in the retrocon-version of 24 6n-3 to 22 6n-3. The involvement of AOxl in the synthesis of 22 6n-3 was also demonstrated in vivo by Infante et al. (21) who detected less radiolabeled 22 6n-3 synthesis in AOxl knockout mouse livers compared with control litter-mates after the intraperitoneal injection of [U- C]18 3n-3. 

Wanders, R.J.A., Denis, S., Wouters, F., Wirtz, K.W. Seedorf U (1997) Biochem. Biophys. Res. Commun. 236, 565-569. Sterol carrier protein X (SCPx) is a peroxisomal branched-chain 3-ketothiolase specifically reacting with 3-oxo-pristanoyl-CoA a new, unique role for SCPx in branched-chain fatty acid metabolism in peroxisomes. 

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