Peroxisomes, fatty acids

Fatty acid oxidation. Seeds, administered orally to rats at a dose of 200 g/kg, increased hepatic mitochondrial and the peroxisomal fatty acid oxidation rate " . Glucosidase inhibition. Ethyl acetate and water soluble fractions of the seed were inactive on the intestine " ... 

Mannaerts G.P. et al., (1979). Mitochondrial and peroxisomal fatty acid oxidation in hver homogenates and isolated hepatocytes from control and clofibrate-treated rats. Journal of Biological Chemistry 254 4585-4595. 

Chronic administration of peroxisome proliferators to rodents results in sustained oxidative stress due to overproduction of peroxisomal hydrogen peroxide. The induction of peroxisomal fatty acid P-oxidation by cinnamyl anthranilate in vivo under bioassay conditions (Lake et al, 1997) supports this h othesis. Other data on the induction of oxidative stress are not available for cinnamyl anthranilate. 

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. 

Patients with a peroxisome biogenesis defect (Zellweger syndrome) are especially low in DHA for two reasons (1) they have no peroxisomal fatty acid /1-oxidation and... 

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... 

Induction of peroxisome proliferation following treatment with DEHP is not due to the parent compound, but to DEHP metabolites. Studies with MEHP in vitro have demonstrated that the proximate peroxisome proliferators are mono(2-ethyl-5-oxohexyl) phthalate (metabolite VI) and mono(2-ethyl-5-hydroxyhexyl) phthalate, (metabolite IX) and that for 2-ethylhexanol, the proximate proliferator is 2-ethylhexanoic acid (Elcombe and Mitchell 1986 Mitchell et al. 1985a). Similar findings were observed by Maloney and Waxman (1999), who showed that MEHP (but not DEHP) activated mouse and human PPARa and PPARy, while 2-ethylhexanoic acid activated mouse and human PPARa only, and at much higher concentrations. Based on its potency to induce enzyme activities, such as the peroxisomal fatty acid (3-oxidation cycle and carnitine acetyltransferase, DEHP might be considered a relatively weak proliferator. 

Sharma R, Lake BG, Gibson GG. 1988. Co-induction of microsomal cytochrome P-452 and the peroxisomal fatty acid -oxidation pathway in therat by clofibrate and di-(2-ethylhexyl)phthalate. 

Sohlenius, A. K., Eriksson, A. M., Hogstrom, C., Kimland, M., Depierre, J. W. Perfluorooctane sulfonic acid is a potent inducer of peroxisomal fatty-acid beta-oxidation and other activities known to be affected by peroxisome proliferators in mouse liver. Pharmacol Toxicol, 72 90-93... 

Figure 22.18. Initiation of Peroxisomal Fatty Acid Degradation. The first dehydration in the degradation of fatty acids in peroxisomes requires a flavoprotein dehydrogenase that transfers electrons to O2 to yield H2O2.

In summary, substantial progress has been made over the past few years in understanding the cytoplasmic organelle peroxisome and factors that alter its normal functions. Peroxisome proliferator-in-duced increase in the liver peroxisomes is associated with an approximately two-fold increase in catalase activity and several-fold increases in the activity of the peroxisomal fatty acid jS-oxidation system. It is also evident from the available literature that hepatic peroxisomal proliferation appears to be a carcinogenic event in rodents, and this may depend on the potency of the inducer. However, there is no single mechanism that is attributed to the peroxisome proliferation or carcinogenesis induced by... 

OXIDATION IN PEROXISOMES /FOxidation of fatty acids also occurs within peroxisomes. In animals peroxisomal /Foxidation appears to shorten very long-chain fatty acids. The resulting medium-chain fatty acids are further degraded within mitochondria. In many plant cells, /Foxidation occurs predominantly in peroxisomes. (Fatty acids are not an important source of energy in most plant tissues. Although some plant mitochondria contain /Foxidation enzymes, this pathway is not... 

In humans, several genetic disorders of fatty acid catabolism, such as the most common MCAD-deficiency, have been reported but their description falls beyond the scope of this review. Several recent reviews have described many of these diseases and their symptoms in more detail (Longo et al., 2006 Rinaldo et ah, 2002 Wanders and Waterham, 2006 Yang et ah, 2005). For mitochondrial fatty acid oxidation disorders the symptoms often develop at infancy during an episode of increased energy demand such as fasting, exercise or illness. Peroxisomal fatty acid oxidation enzyme deficiencies often involve neuropathy and retinopathy. 

Wanders, R.J.A., Vreken, P., Ferdinandusse, S., Jansen, G.A., Waterham, H.R., van Roermund, C.W.T., van Grunsven, E.G. 2001. Peroxisomal fatty acid a- and P-oxidation in humans enzymology, peroxisomal metabolite transporters and peroxisomal diseases. Biochem. Soc. Trans. 29 250-267. 

Kaikaus, R.M., W.K. Chan, N. Lysenko, R. Ray, P.R. Ortiz de Montellano, and N.M. Bass (1993). Induction of peroxisomal fatty acid 3-oxidation and liver fatty acid-binding protein by peroxisome proliferators Mediation via the cytochrome P450IVA1 ft)-hydroxylase pathway.,/ Biol. Chem. 268, 9593-9603. 

It has long been recognized that fatty acids may be partially degraded with the subsequent esterification of chain-shortened products. For example, in 1964, Verdino et al. (20) reported that when 4,7,10,13,16,19-22 5 was fed to rats raised on a diet devoid of fat, there was a large increase in esterified arachi-donic acid. In 1970 Stoffel, et al. (21) showed that this partial degradative reaction was associated with a mitochondrial fraction however, these smdies were carried out before the importance of peroxisomal fatty acid 3-oxidation was recognized. In 1993, Christensen et al. (22) reported that when labeled [3-14C] 7,10,13,16-22 4 and 7,10,13,16,19-22 5 were incu-... 

Fig. 1. The revised pathway of 22 6n-3 biosynthesis from 18 3n-3. 18 3n-3 is converted to 24 6n-3 in microsomes then 24 6n-3 enters peroxisomes for one cycle of fatty acid (3-oxidation, via straight-chain acyl-CoA oxidase, D-bifunctional protein, and 3-oxo-acyl-CoA thiolase or sterol carrier protein X to produce 22 6n-3. The peroxisomal fatty acid (3-oxidation enzymes, branched-chain acyl-CoA oxidase, and L-bifunctional protein are not thought to participate in 22 6n-3 synthesis.

Biosynthesis of22 6n-3 in Peroxisomal Fatty Acid fi-Oxidation Enzyme Deficiency... 

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. 

Synthesis of 22 6n-3 was not impaired in cell lines with X-ALD (Table 2), suggesting that the adrenoleukodystrophy protein (ALDP), a peroxisomal membrane protein that has been hypothesized to transport very-long-chain saturated fatty acids, does not participate in the retroconversion step of 24 6n-3 to 22 6n-3. The biosynthesis of 22 6n-3 was also normal in fibroblasts from patients with Refsum disease, who have a defect in peroxisomal fatty acid a-oxidation, indicating that a-oxidation does not contribute to 22 6n-3 synthesis. 

TTA is a fatty acid analogue in which a sulfur atom replaces the P-mehylene groups in the alkyl-chain (a 3-thia fatty acid). TTA, therefore, cannot be P-oxidized. Paradoxically, TTA is both mitochondrial and peroxisomal proliferator and the hepatic mitochondrial and peroxisomal fatty acid oxidation capacities are increased (Table 2). In addition to its biochemical and morphological effects, TTA decrease serum TG (Table 1) very low density lipoprotein (VLDL)-TG, cholesterol and free fatty acid (NEFA) levels in rats. Thus, the observed reduction in plasma TG levels during TTA administration could be accomplished by retarded synthesis, reduced hepatic output, enhanced clearance or a combination of these factors. 3-Thia fatty acid resulted in a slight inhibition in the activities of ATP-citrate lyase and fatty acid synthase. However, the impact of... 

---