Hypolipidemic 3thia Fatty Acids

Fatty Acid Oxidation and Ketogenesis in Rat Liver under Proliferation of Mitochondria and Peroxisomes

Rolf K. Berge, Lise Madsen, and Hege Vaagenes

Department of Clinical Biochemistry University of Bergen Haukeland Hospital N-5021 Bergen, Norway

High serum levels of triglyceride (TG)-rich lipoproteins, i.e. very low density lipoproteins (VLDL) and its remnants are important risk factors for coronary artery disease.1 Serum TGs can be lowered either by dietary treatment with fish oils or by pharmacological treatment with drugs of the fibrate class. Classically, the decrease in plasma TG concentrations upon fibrate treatment (Table 1) are thought to be the result of a decreased hepatic secretion of VLDL accompanied by an enhanced plasma TG clearance, possibly due to the induction of lipoprotein lipase (LPL) activity in peripheral tissues.2

Several lines of evidence have implicated apolipoprotein (apo) C-III in plasma TG metabolism. Reports have indicated that apo C-III inhibits TG hydrolysis by LPL and hepatic lipase in vitro and impairs the uptake of TG-rich lipoproteins by the liver. Moreover, transgenic animal studies, in which the plasma TG levels are proportional to plasma apo C-III concentrations and liver apo C-III gene expression, provided more direct evidence for the causal involvement of apo C-III in hypertriglyceridemia. Recently, it has been shown that fibrate downregulates apo C-III expression (Table 1) and this may contribute for the hypotriglyceridemic action of these drugs.2

In addition to lowering plasma TG, n-3 fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) are reported to have a number of additional beneficial effects on the cardiovascular system which include antihypertensive and antithrombotic actions.3-5 EPA and DHA are major fatty acid constituents of fish oil and it has been assumed that both EPA and DHA are responsible for its hypotriglyceridemic activity. However, growing evidence indicates that EPA and DHA may possess different hypolipidemic properties. We have reported that EPA is the fatty acid primarily responsible for the TG-lowering effect of fish oil (Table 1), but the mechanism underlying this hypotriglyceridemic effect has not yet been fully elucidated. Interestingly, however, we

Table 1. Effect of EPA, DHA, fibrate and TTA on plasma TGs and liver ApoC-III mRNA levels in rats.

Group

Plasma TG

Plasma VLDL-TG

ApoC-III mRNA

Fenofibrate

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