Eicosapentaenoic and docosahexaenoic acid affect mitochondrial and peroxisomal fatty acid oxidation in relation to substrate preference

Abstract

Decreased triacylglycerol synthesis within hepatocytes due to decreased diacylglycerol acyltransferase (DGAT) activity has been suggested to be an important mechanism by which diets rich in fish oil lower plasma triacylglycerol levels. New findings suggest that eicosapentaenoic acid (EPA), and not docosahexaenoic acid (DHA), lowers plasma triacylglycerol by increased mitochondrial fatty acid oxidation and decreased availability of fatty acids for triacylglycerol synthesis. To contribute to the understanding of the triacylglycerol-lowering mechanism of fish oil, the different metabolic properties of EPA and DHA were studied in rat liver parenchymal cells and isolated rat liver organelles. EPA-CoA was a poorer substrate than DHA-CoA for DGAT in isolated rat liver microsomes, and in the presence of EPA, a markedly lower value for the triacyl[3H]glycerol/diacyl[3H]glycerol ratio was observed. The distribution of [1-14C]palmitic acid was shifted from incorporation into secreted glycerolipids toward oxidation in the presence of EPA (but not DHA) in rat liver parenchymal cells. [1-14C]EPA was oxidized to a much greater extent than [1-14C]DHA in rat liver parenchymal cells, isolated peroxisomes, and especially in purified mitochondria. As the oxidation of EPA was more effective and sensitive to the CPT-I inhibitor, etomoxir, when measured in a combination of both mitochondria and peroxisomes, we hypothesized that both are involved in EPA oxidation, whereas DHA mainly is oxidized in peroxisomes. In rats, EPA treatment lowered plasma triacylglycerol and increased hepatic mitochondrial fatty acid oxidation and carnitine palmitoyltransferase (CPT)-I activity in both the presence and absence of malonyl-CoA. Whereas only EPA treatment increased the mRNA levels of CPT-I, DHA treatment increased the mRNA levels of peroxisomal fatty acyl-CoA oxidase and fatty acid binding protein more effectively than EPA treatment. In conclusion, EPA and DHA affect cellular organelles in relation to their substrate preference. The present study strongly supports the hypothesis that EPA, and not DHA, lowers plasma triacylglycerol by increased mitochondrial fatty acid oxidation.

Metabolism and Functions of Lipids and Fatty Acids in Teleost Fish

“…However, β-oxidation of PUFA is variable between different PUFA molecules and can be more complicated. In mammals, 20:5n-3 is readily β-oxidised by mitochondria and, indeed, induces formation of mitochondria in rats (Madsen et al, 1999).…”

“…However, 22:6n-3 is a poor substrate for mitochondrial β-oxidation in rats where its catabolism requires peroxisomal β-oxidation (Madsen et al, 1999). This is because, as insertion of the Δ4 ethylenic bond in 22:6n-3 requires a special mechanism (described above), so does its removal.…”

“…In Antarctic fish tissues, monoeneoic fatty acids were preferentially oxidised for energy compared to long-chain saturated fatty acids (Sidell et al, 1995). As alluded to above, 20:5n-3 can be readily β-oxidised, but 22:6n-3 catabolism requires peroxisomal and mitochondrial β-oxidation, at least in rats (Madsen et al, 1999). There is no reason to believe that the mechanism for oxidising 22:6n-3 is different in fish and rats, and as peroxisomes are present in fish tissues including liver (Cancio and Cajaraville, 2000), it is likely that 22:6n-3 can serve as a source of energy in fish if necessary.…”

Polyunsaturated fatty acids: From diet to binding to ppars and other nuclear receptors

“…A delay in assimilation of 20 and 22-carbon PUFAs into neutral lipids is due to the fact that CoA thioesters of 20 and 22-carbon PUFAs are poor substrates for many reactions; as examples, eicosapentaenoic acid (C20:5 n-3, EPA) but not arachidonic (C20:4 n-6, AA) or docosapentaenoic acid (C22:5n-3), is a poor substrate for diacylglycerol acyltransferase, the terminal step in TAG biosynthesis (Madsen et al, 1999;Berge et al, 1999), and CoA thioesters of 20 and 22-carbon PUFAs are poor substrates for acylcholesterol acyltransferase I (Seo et al, 2001). Furthermore, PUFAs ≥22 carbons require prior peroxisomal β-oxidation to shorten the FA before entry into the mitochondrial β-oxidation spiral, this causing a delay in their oxidation (Sprecher, 2000).…”

The Biochemistry of n-3 Polyunsaturated Fatty Acids

“…These effects extend beyond differential ␤-oxidation to include PUFA assimilation into neutral lipids. CoA thioesters of 20:5n-3 are poor substrates for diacylglycerol acyltransferase, the last step in triglyceride synthesis (22)(23)(24). Neither 20-nor 22-carbon n-3 PUFAs are good substrates for cholesterol ester synthesis.…”