Oral administration of D-003, a mixture of very long chain fatty acids prevents casein-induced endogenous hypercholesterolemia in rabbits.
D-003 is a mixture of very long chain saturated fatty acids (VLCSFA) purified from sugar cane wax with cholesterol-lowering effects proven in animal models and healthy volunteers. D-003 inhibits cholesterol biosynthesis through the regulation of HMG-CoA reductase activity. Rabbits fed diets enriched with casein develop endogenous hypercholesterolemia (EH), making them a very useful model for determining the mechanism of action of drugs affecting lipids. We examined whether D-003 prevented EH. Rabbits were fed a casein diet for 4 weeks, administered simultaneously with D-003 (5, 50, and 100 mg.kg-1.day-1). As expected, nontreated rabbits became hypercholesterolemic; however, as early as 15 days following administration, the treated group (50 and 100 mg.kg-1.day-1) had significantly decreased total cholesterol and low-density lipoprotein cholesterol (LDL-C). Triglycerides were not affected; however, at study completion, HDL-C levels significantly increased at all the doses assayed. D-003 inhibited de novo synthesis of cholesterol, since the incorporation of 3H2O into sterols in the liver and proximal small bowel was significantly depressed. Also, D-003 significantly raised the rate of removal of [125I]-LDL from serum and significantly elevated [125I]-LDL binding activity to liver homogenates. Taken together, these results show that the efficacy of D-003 in reducing casein-derived hypercholesterolemia could involve, at least partially, an inhibition of hepatic cholesterol biosynthesis, which may elicit a decreased cholesterol concentration in hepatocytes, preventing the loss of hepatic LDL receptors induced by casein administration. However, since casein-induced hypercholesterolemia is also a consequence of a stimulation of cholesterol absorption in the lumen and an increase of the output of cholesterol associated with LDL, the effect of D-003 on cholesterol absorption and LDL synthesis by the liver should be investigated.
Menéndez
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R
Center of Natural Products, National Center for Scientific Research, PO Box 6880, Havana, Cuba. rmenendez76@yahoo.com
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Pérez
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González
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Jiménez
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D000284:Administration, Oral; D000818:Animals; D002364:Caseins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008078:Cholesterol, LDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000008:administration & dosage*; D006937:Hypercholesterolemia / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D008055:Lipids / Q000097:blood; D008297:Male; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011817:Rabbits
D002364:Caseins; D008078:Cholesterol, LDL; C418063:D-003 sugarcane wax acid mixture; D005227:Fatty Acids; D008055:Lipids