TETRADECYLTHIOACETIC ACID INCORPORATED INTO VERY-LOW-DENSITY LIPOPROTEIN - CHANGES IN THE FATTY-ACID COMPOSITION AND REDUCED PLASMA-LIPIDS IN CHOLESTEROL-FED HAMSTERS

The mechanism behind the hypolipidemic effect of tetradecylthioacetic acid (CMTTD, a non-beta-oxidizable 3-thia fatty acid) was studied in h amsters fed a high cholesterol diet (2%), which resulted in hyperlipid emia. Treating hyperlipidemic hamsters with CMTTD resulted in a progre ssive hypocholesterolemic and hypotriacylglycerolemic effect. Decrease d plasma cholesterol was followed by a 39% and 30% reduction in VLDL-c holesterol and LDL-cholesterol, respectively. In contrast, the HDL-cho lesterol content was not affected, thus decreasing the VLDL-cholestero l/HDL-cholesterol and LDL-cholesterol/HDL-cholesterol radios. 3-Hydrox y-3-methylglutaryl- (HMG) CoA reductase activity and its mRNA level we re unchanged after CMTTD administration. Also, the LDL receptor and LD L receptor-related protein (LRP-4) mRNAs were unchanged. The decrease in plasma triacylglycerol was accompanied by a 45% and 56% reduction i n VLDL-triacylglycerol and LDL-triacylglycerol, respectively. The hypo lipidemic effect of CMTTD was followed by a 1.4-fold increase in mitoc hondrial fatty acid oxidation and a 2.3-fold increase in peroxisomal f atty acid oxidation. CMTTD treatment led to an accumulation of dihomo- gamma-linolenic acid (20:3n-6) in liver, plasma, very low density lipo protein, and hart. Noteworthy, CMTTD accumulated more in the heart, pl asma, and VLDL particles compared to the liver, and in the VLDL partic le alpha-linolenic acid (18:3n-3) decreased whereas eicosatetraenoic a cid (20:4n-3) increased. In addition, linoleic acid (18:2n-6) and the total amount of polyunsaturated fatty acids decreased, the latter main ly due to a decrease in n-6 fatty acids. the present data show that CM TTD was detected in plasma and incorporated into VLDL, liver, and hear t. The relative incorporation (mol %) of CMTTD was heart > VLDL > live r. In conclusion, CMTTD causes both a hypocholesterolemic and hypotria cylglycerolemic effect in hyperlipidemic hamsters.