Liver peroxisomes

Lee, J., Richburg, J.H., Younkin, S.C. Boekelheide, K. (1997) The Fas system is a key regulator of germ cell apoptosis in the testes. Endocrinology, 128, 2081-2088 Lewis, D.F.V Lake, B.G. (1993) Interaction of some peroxisome prolrferators with the mouse liver peroxisome proliferator-activated receptor (PPAR) a molecular modelling and quantitative stracture-activity relationship (QSAR) study. Xenobiotica, 23, 79-96 Lewis, L.M., Flechtner, T.W., Kerkay, J., Pearson, K.H. Nakamoto, S. (1978) Bis(2-ethyl-hexyl) phthalate concentrations in the serum of hemodialysis patients. Clin. Chem., 24, 741-746... 

Osumi, T. Hashimoto, T. (1978) Enhancement of fatty acyl-CoA oxidizing activity in rat liver peroxisomes by di-(2-ethylhexyl)phthalate. J. Biochem. Tokyo, 83, 1361-1365 Page, B.D. Lacroix, G.M. (1992) Studies into the transfer and migration of phthalate esters from aluminum foil-paper laminates to butter and margarine. Food Add. Contam., 9, 197-212... 

In mammals, high concentrations of fats in the diet result in increased synthesis of the enzymes of peroxisomal /3 oxidation in the liver. Liver peroxisomes do not contain the enzymes of the citric acid cycle and cannot catalyze the oxidation of acetyl-CoA to C02. Instead,... 

Webber K. O. and Hajra A. K. (1993). Purification of dihydroxyacetone phosphate acyltransferase from guinea pig liver peroxisomes. Arch. Biochem. Biophys. 300 88-97. 

Keller G. A., Pazirandeh M. and Krisans S. (1986) 3-Hydroxy-3-methylglutaryl coenzyme A reductase localization in rat liver peroxisomes and microsomes of control and cholestyramine-treated animals quantitative biochemical and immunoelectron microscopical analyses. J. Cell Biol. 103, 875-886. 

Hepatic Effects. No studies were located regarding hepatic effects in humans after oral exposure to DEHP. Limited information on hepatic effects in humans exposed to DEHP is available from studies of dialysis patients and cultured human hepatocytes. In one individual there was an increased number of liver peroxisomes after 1 year, but not after 1 month of treatment (Ganning et al. 1984, 1987). A serious limitation of this observation is that repeat biopsies were not obtained from the same patient, so that an appropriately controlled analysis is not possible. Additionally, analysis of liver biopsies from patients receiving other kinds of hypolipidemic drugs has not yielded any evidence for peroxisomal proliferation (Doull et al. 1999). Recognizing some limitations of using primary hepatocytes in vitro because of their tendency to lose some metabolic capabilities (Reid 1990), in cultured human hepatocytes there were no changes in the activities of peroxisomal palmitoyl-CoA oxidase and/or carnitine acetyltransferase when... 

Based on the animal data, the most consistent effect of exposure to DEHP is the increase in the concentration of liver peroxisomes. This effect occurs to varying degrees in all species that have been evaluated. However, evidence for an effect of DEHP exposure on human liver peroxisomes is weak. Limited data regarding biopsies from human livers, under circumstances in which DEHP was present in the hemodialysis equipment, did not lead to meaningful conclusions (Ganning et al. 1984, 1987). Therefore, a liver biopsy with subsequent histopathological examination of the cells would seldom if ever be justified as a test for the long-term effects of DEHP exposure due to the difficulties associated with this procedure. 

Effect Currently there are no simple methods of measuring the effects of DEHP exposure. An increase in liver peroxisomes and peroxisomal enzyme activities appears to be the best marker of effect in rodents. This is not of great value in human studies since there is extensive evidence that humans, as well as primates, are refractory to peroxisome proliferators. Accordingly, research to identify reliable biomarkers for DEHP effects in humans would be useful in order to evaluate the prevalence and magnitude of exposure in an at-risk population. 

Lazarow PB, deDuve C. 1976. A fatty acyl-CoA oxidizing system in rat liver peroxisomes enhancement by clofibrate, a hypolipidemic drug. Proc Natl Acad Sci 73 2043-2046. 

Lhuguenot JC, Mitchell AM, Elcombe CR. 1988. The metabolism of mono-(2-ethylhexyl)phthalatc (MEHP) and liver peroxisome proliferation in the hamster. Toxicol Ind Health 4 431-441. 

The mechanism of trichloroethylene-induced liver peroxisome proliferation and gender-related differences in response was investigated using a wild-type Sv/129 and PPARa-null mice. Trichloroethylene treatment (0.75 g kg for 2 weeks by gavage) re-... 

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... 

Peroxisomes and peroxisomal /3-oxidation are reported in a number of fish species. Liver peroxisome volume densities are in the range of 1.3-4% for most fish species43, similar to that reported for rodents. Rates of piscine hepatic total /3-oxidation are generally reported to be 10% of those found in mammals when corrected for temperature. However, the relative rates of peroxisomal vs. mitochondrial /3-oxidation vary substantially between fish species11,41,50. The pertinent question here is whether fish demonstrate a capacity to increase peroxisomal /3-oxidation in the presence of PPs as described for rodents ... 

Orbea, A., K. Beier, A. Volkl, H.D. Fahimi and M.P. Cajaraville. Ultrastructural, immunocytochemical and morphometric characterization of liver peroxisomes in gray mullet, Mugil caphalus. Cell Tissue Res. 297 493-502, 1999. 

Kase, F., Bjorkhem, I., and Pedersen, J. I., Formation of cholic acid from 3a,7a,12a-trihydroxy-5P-cholestan-26-oic acid by rat liver peroxisomes. J. lipid Res. 24,1560-1567 (1983). 

Pacot, C., Petit, M., Rollin, M., Behechti, N., Moisant, M., Deslex, P., Althoff, J., Lhuguenot, J. C., and Latruffe, N. (1996). Difference between guinea pig and rat in the liver peroxisomal response to equivalent plasmatic level of ciprofibrate. Arch Biochem Biophys 327, 181-188. 

Uchida Y, Kondo N, Orii T, Hashimoto T. Purification and properties of rat liver peroxisomal very-long-chain acyl-CoA synthetase. J Biochem 1996 119 565-71. 

The import of catalase and other proteins into rat liver peroxisomes can be assayed in a cell-free system similar to that used for monitoring mitochondrial protein Import (see Figure 16-25). By testing various mutant catalase proteins in this system, researchers discovered that the sequence Ser-Lys-Leu (SKL in one-letter code) or a related sequence at the C-terminus was necessary for peroxisomal targeting. Further, addition of the SKL sequence to the C-termlnus of a normally cytosolic protein leads to uptake of the altered protein by peroxisomes in cultured cells. All but a few of the many different peroxisomal matrix proteins bear a sequence of this type, known as peroxisomal-targeting sequence 1, or simply PTSl. 

Peroxisomes are present in greater number in the liver than in other tissues. Liver peroxisomes contain the enzymes for the oxidation of very-long-chain fatty acids such as C24 0 and phytanic acid, for the cleavage of the cholesterol side chain necessary for the synthesis of bile salts, for a step in the biosynthesis of ether lipids, and for several steps in arachidonic acid metabohsm. Peroxisomes also contain catalase and are capable of detoxifying hydrogen peroxide. 

Singh, H., Beckman, K. Poulos, A. (1996)7 Lipid Res., 37, 2616-2626. Evidence of two catalytically active carnitine medium/long chain acyltiansferases in rat liver peroxisomes. 

Fujiki, Y, Fowler, S., Shio, H., Hubbard, A.L. Lazarow, P. (1982)7. CellBioL, 93, 103-110. Polypeptide and phospholipid composition of the membrane of the rat liver peroxisomes comparison with endoplasmic reticulum and mitochondrial membranes. 

Markwell, M.A.K., Tolbert, N.E. Bieber, L.L. (1976)TrcA Biochem. Biophys., 176, 479-488. Comparison of the carnitine acyltransferase activities from rat liver peroxisomes and microsomes. 

Western Blot Analysis of the COT Proteins in Rat Liver Peroxisomes... 

Figure 4. Immuuolocali/ation of peroxisomal COT. The peptide ANEDEYKKTEEI corresponding to the N-terminus of COT protein (sequence 43 54,) wa.s used to obtain the antibodies as described elsewhere. Rat liver peroxisomes were isolated in a Nycodenz cushion as described elsewhere." 10mg of rat liver peroxisomal extracts were separated by SDS/PACiE and. subjected (0 immuno-blotting using specific A43 antibodies (A) for carnitine octanoyllransferase or preimmune sera (U). Two bands corresponding to Mr of approximately 69 and 79 k Da are observed. The markers (M) were used 10 determine the approximate molecular weights of the species indicated in the figure.

Two other oxidase activities have been described in rat liver peroxisomes, one acting on glutaryl-CoA, the other on valproyl-CoA. The glutaryl-CoA oxidase activity, however, co-purifies with the inducible pahnitoyl-CoA oxidase. The valproyl-CoA oxidase was claimed to differ from the above described acyl-CoA oxidases, but in our hands this activity was recovered mainly in the cytosol (Casteels, M. Van Veldhoven P. P., unpublished data). 

Investigation of the 3-hydroxyacyl-CoA dehydrogenase activities in purified rat liver peroxisomes, using the 3-hydroxyacyl-CoAs of straight chain fatty acids, of 2-methyl-branched chain fatty acids and of trihydroxycoprostanic acid as substrates, revealed initially 5 different enzymes (named I to V)." Enzyme IV was a monomeric 78 kD protein, possessed crotonase activity, was induced by clofibrate, and was identified as the inducible multifunctional protein. Interestingly, enzyme III, a monomeric 80 kD protein, also hydrated crotonyl-CoA. In contrast to enzyme IV, enzyme III was not induced by clofibrate." This was the first indication, pubhshed in 1994, that peroxisomes contained a second multifunctional protein. It was named multifunctional protein 2 (MFP-2) (the inducible, firstly isolated protein is referred to as MFP-1). Based on its substrate spectrum, the newly identified multifunctional protein was postulated to be involved in bile acid formation. ... 

Krisans, S.K., Mortensen, R.M. Lazarow, P.B. (1980) J. Biol. Chem. 255, 9599-9607. Acyl-CoA synthetase in rat liver peroxisomes. Computer-assisted analysis of cell fractionation experiments. Mannaerts, G.P, Van Veldhoven, P., Van Broekhoven, A., Vandebroek, G. Debeer, L.J. (1982) Biochem. J. 204, 17-23. Evidence that peroxisomal acyl-CoA synthetase is located at the cytoplasmic side of the peroxisomal membrane. 

Watkins, P.A., Howard, A.E., Gould, SJ, Avigan, J. Mihalik, SJ. (1996) J. Lipid Res. 37, 2288-2295. Phytanic acid activation in rat liver peroxisomes is catalyzed by long chain acyl-CoA synthetase. 

Singh, H. Poidos, A. (1988) Biochem. Biophys. 266, 486-495. Distinct long chain and very long chain fatty acyl CoA synthetases in rat liver peroxisomes and miaosomes. 

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