Low plasma lipid levels and increased cholesterol synthesis after partial ileal bypass plus lovastatin in hypercholesterolemic rabbits.
Partial ileal bypass (PIB) lowers the plasma total cholesterol (C) level, thereby increasing hepatic C synthesis to replenish bile acid and C stores. Lovastatin, a C synthesis inhibitor, may act as a potential adjuvant to PIB for lipid lowering. In this study, the effects of PIB and lovastatin, alone and in combination, were examined in plasma and tissue. For 14 weeks, 32 New Zealand White rabbits received a C-free, alfalfa-free, natural-ingredients diet previously shown to induce hypercholesterolemia. The rabbits were divided into control, lovastatin, PIB, and PIB plus lovastatin groups. Lovastatin was administered at a dose of 0.35 mg/kg twice daily. Compared with the control group, PIB alone decreased the plasma total C level by 75% (p less than 0.005), the low-density lipoprotein (LDL)-C level by 79% (p less than 0.025), and hepatic C content by 50% (p less than 0.05), while increasing hepatic C synthesis by 176% (p less than 0.05). Compared with the control group, lovastatin alone decreased the plasma total C value by 36% (p = NS), the LDL-C level by 35% (p = NS), hepatic C content by 29% (p = NS), and hepatic C synthesis by 52% (p = NS). Compared with the control group, the combination of PIB and lovastatin decreased the plasma total C level by 78% (p less than 0.005), the LDL-C level by 74% (p less than 0.025), and hepatic C content by 58% (p less than 0.05); however, the hepatic C synthesis increased by 490% (p less than 0.005) compared with the control group and by 110% (p less than 0.05) compared with PIB alone. This is the first demonstration of a metabolic reversal of the cholesterol synthesis inhibition engendered by lovastatin. We conclude that both PIB and lovastatin lower plasma total C and lipoprotein C fractions. Their combination has an additive C-lowering effect in plasma and decreases tissue C content by increasing cellular C demand. This latter effect overcomes the inhibitory effect of lovastatin on hepatic C synthesis, resulting in an augmented compensatory increase in hepatic C synthesis.
Tijerina
O
O
Department of Surgery, University of Minnesota Health Sciences Center, Minneapolis 55455.
Dombrovskis
S
S
Esper
E
E
Matts
J P
JP
Campos
C T
CT
Buchwald
H
H
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D003131:Combined Modality Therapy; D004032:Diet; D006937:Hypercholesterolemia / Q000097:blood / Q000628:therapy*; D007082:Ileum / Q000601:surgery*; D007413:Intestinal Mucosa / Q000378:metabolism; D008055:Lipids / Q000097:blood*; D008148:Lovastatin / Q000627:therapeutic use*; D008297:Male; D011817:Rabbits
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D008055:Lipids; D002784:Cholesterol; D008148:Lovastatin