Peroxisomes, fatty acid / -oxidation

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. 

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. 

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. 

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... 

Table 1. EITects of TTA on activities of key enzymes in mitochondrial and peroxisomal fatty acid oxidation in human glioma cells (D-54 Mg).

Willumsen, N., Hexeberg, S, Skorve, J., Lundquist, M. Berge, R.K. (1993). J. Lipid Res. 34 13-22. Docosahexaenoic acid shows no triglyceride-lowering effects but increases the peroxisomal fatty acid oxidation in liver of rats. 

Table 2. Effect of EPA-derivatives on peroxisomal fatty acid oxidation, activity and expression of fatty acyl CoA oxidase, and expression of peroxisomal multifunctional protein.

The 3-thia, non-P-oxidable thia fatty acids (as exemplified by TTA (tetradecylth-ioacetic acid, HOOC-CH2-S-CH2(13)-CH3) decrease plasma triglycerides and cholesterol levels when administered to rats. At the same time TTA increased the hepatic fatty acid oxidation capacities. Recently we have demonstrated that stimulation of mitochondrial P-oxidation, but not peroxisomal fatty acid oxidation, decreases hepatic triglyceride formation. This has also been shown with co-3 fatty acids and fibrates in different animal models (rats, rabbits and dogs). Altogether the mitochondrion seems to be the principal target for the plasma triglycerid lowering effect. 

In rats fed a single dose of EPA the plasma TG concentration was decreased within hours, accompanied by an increased hepatic fatty acid oxidation.Table 2 shows after 10 days of repeated administrations of EPA, the plasma concentration of TG was decreased almost 40% and both the mitochondrial and peroxisomal oxidation was increased. On the other hand, administration of DHA increased the peroxisomal fatty acid oxidation, but both the plasma TG levels and mitochondrial fatty acid oxidation were unchanged (Table 2). These results among others suggest that the hypotriglyceri-daemic effect of n-3 fatty acids is independent of the peroxisomal fatty acid oxidation. 

Direct measurement of peroxisomal fatty acid oxidation has shown that particularly hydrogenated fish oil and hydrogenated rapeseed oil increased the activity of the peroxisomal P-oxidation enzyme system [7]. 

Fig. 4. Induction of peroxisomal fatty acid oxidation by fatty acids in hepatoma cells in vitro. Morris hepatoma cells 7800 Ci [19] were grown in Ham s F 10 medium with 10% horse serum and 3% calf serum in the absence or presence of 1 mM fatty acid for 3 days (two parallels)...

The most important substrates handled by the peroxisomal fatty acid oxidation system from the perspective of peroxisomal disorders are (1) very-long-chain fatty acids (VLCFA), notably hexacosanoic acid (C26 0), (2) pris-tanic acid (2,6,10,14-tetramethylpentadecanoic acid), as derived from dietary sources either directly or indirectly from phytanic acid and (3) di- and trihydroxycholestanoic acid (DHCA and THCA). The latter two compounds are intermediates in the formation of the primary bile acids cholate and chenodeoxycholate from cholesterol in the liver. 

Ferdinandusse S, Denis S, van Berkel E, Dacremont G, Wanders RJA. Peroxisomal fatty acid oxidation disorders and 58 kDa sterol carrier protein X (SCPx). Activity measurements in liver and fibroblasts using a newly developed method. J Lipid Res 2000 41(3) 336-342. 

Sesamin has been associated with the reduction of serum and liver lipids (Hirose etal., 1991,1996 Ide etal., 2001 Yasumoto etal., 2001). Hirose etal. (1991) reported that sesamin decreased lymphatic absorption of cholesterol. Sesamin was found to be a promoter of hepatic fatty acid oxidation in rats (Ashakumary et al., 1999). Addition of a 1 1 mixture of sesamin and episesamin to the diet of rats (0.1-0.5% of total diet) promoted mitochondrial and peroxisomal palmitoyl coenzyme A (CoA) oxidation rates in a dose-dependent manner. Rats fed diets containing 0.5% sesamin had 2 fold higher mitochondrial activity and 10 fold higher peroxisomal activity than rats fed non-sesamin diets. Yasumoto et al. (2001) reported similar findings when a 20% sesame seed diet was fed to rats. These authors compared two experimental sesame seed lines (0730 and 0732) with the commercial cultivar Masekin. Both experimental seed lines enhanced mitochondrial and peroxisomal fatty acid oxidation rates, and were more effective than the commercial cultivar at reducing plasma triacylglycerol levels (Yasumoto et al., 2001). A study of the effects of dietary sesamin on the hepatic metabolism of arachidonic and eicosapentaenoic acids in rats showed similar increases in hepatic mitochondrial and peroxisomal fatty acid oxidation (Sawada et al., 2001). 

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