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The magnitude of decrease in hepatic very low density lipoprotein apolipoprotein B secretion is determined by the extent of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition in miniature pigs.
Endocrinology 1999; 140(11):5293-302E

Abstract

It has been postulated that the rate of hepatic very low density lipoprotein (VLDL) apolipoprotein (apo) B secretion is dependent upon the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. To test this hypothesis in vivo, apoB kinetic studies were carried out in miniature pigs before and after 21 days treatment with high-dose (10 mg/kg/day), atorvastatin (A) or simvastatin (S) (n = 5). Pigs were fed a diet containing fat (34% of calories) and cholesterol (400 mg/day; 0.1%). Statin treatment decreased plasma total cholesterol [31 (A) vs. 20% (S)] and low density lipoprotein (LDL) cholesterol concentrations [42 (A) vs. 24% (S)]. Significant reductions in plasma total triglyceride (46%) and VLDL triglyceride (50%) concentrations were only observed with (A). Autologous [131I]VLDL, [125I]LDL, and [3H]leucine were injected simultaneously, and apoB kinetic parameters were determined by triple-isotope multicompartmental analysis using SAAM II. Statin treatment decreased the VLDL apoB pool size [49 (A) vs. 24% (S)] and the hepatic VLDL apoB secretion rate [50 (A) vs. 33% (S)], with no change in the fractional catabolic rate (FCR). LDL apoB pool size decreased [39 (A) vs. 26% (S)], due to reductions in both the total LDL apoB production rate [30 (A) vs. 21% (S)] and LDL direct synthesis [32 (A) vs. 23% (S)]. A significant increase in the LDL apoB FCR (15%) was only seen with (A). Neither plasma VLDL nor LDL lipoprotein compositions were significantly altered. Hepatic HMG-CoA reductase was inhibited to a greater extent with (A), when compared with (S), as evidenced by 1) a greater induction in hepatic mRNA abundances for HMG-CoA reductase (105%) and the LDL receptor (40%) (both P < 0.05); and 2) a greater decrease in hepatic free (9%) and esterified cholesterol (25%) (both P < 0.05). We conclude that both (A) and (S) decrease hepatic VLDL apoB secretion, in vivo, but that the magnitude is determined by the extent of HMG-CoA reductase inhibition.

Authors+Show Affiliations

Department of Medicine, The John P. Robarts Research Institute, University of Western Ontario, London, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10537160

Citation

Burnett, J R., et al. "The Magnitude of Decrease in Hepatic Very Low Density Lipoprotein Apolipoprotein B Secretion Is Determined By the Extent of 3-hydroxy-3-methylglutaryl Coenzyme a Reductase Inhibition in Miniature Pigs." Endocrinology, vol. 140, no. 11, 1999, pp. 5293-302.
Burnett JR, Wilcox LJ, Telford DE, et al. The magnitude of decrease in hepatic very low density lipoprotein apolipoprotein B secretion is determined by the extent of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition in miniature pigs. Endocrinology. 1999;140(11):5293-302.
Burnett, J. R., Wilcox, L. J., Telford, D. E., Kleinstiver, S. J., Barrett, P. H., Newton, R. S., & Huff, M. W. (1999). The magnitude of decrease in hepatic very low density lipoprotein apolipoprotein B secretion is determined by the extent of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition in miniature pigs. Endocrinology, 140(11), pp. 5293-302.
Burnett JR, et al. The Magnitude of Decrease in Hepatic Very Low Density Lipoprotein Apolipoprotein B Secretion Is Determined By the Extent of 3-hydroxy-3-methylglutaryl Coenzyme a Reductase Inhibition in Miniature Pigs. Endocrinology. 1999;140(11):5293-302. PubMed PMID: 10537160.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The magnitude of decrease in hepatic very low density lipoprotein apolipoprotein B secretion is determined by the extent of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition in miniature pigs. AU - Burnett,J R, AU - Wilcox,L J, AU - Telford,D E, AU - Kleinstiver,S J, AU - Barrett,P H, AU - Newton,R S, AU - Huff,M W, PY - 1999/10/28/pubmed PY - 1999/10/28/medline PY - 1999/10/28/entrez SP - 5293 EP - 302 JF - Endocrinology JO - Endocrinology VL - 140 IS - 11 N2 - It has been postulated that the rate of hepatic very low density lipoprotein (VLDL) apolipoprotein (apo) B secretion is dependent upon the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. To test this hypothesis in vivo, apoB kinetic studies were carried out in miniature pigs before and after 21 days treatment with high-dose (10 mg/kg/day), atorvastatin (A) or simvastatin (S) (n = 5). Pigs were fed a diet containing fat (34% of calories) and cholesterol (400 mg/day; 0.1%). Statin treatment decreased plasma total cholesterol [31 (A) vs. 20% (S)] and low density lipoprotein (LDL) cholesterol concentrations [42 (A) vs. 24% (S)]. Significant reductions in plasma total triglyceride (46%) and VLDL triglyceride (50%) concentrations were only observed with (A). Autologous [131I]VLDL, [125I]LDL, and [3H]leucine were injected simultaneously, and apoB kinetic parameters were determined by triple-isotope multicompartmental analysis using SAAM II. Statin treatment decreased the VLDL apoB pool size [49 (A) vs. 24% (S)] and the hepatic VLDL apoB secretion rate [50 (A) vs. 33% (S)], with no change in the fractional catabolic rate (FCR). LDL apoB pool size decreased [39 (A) vs. 26% (S)], due to reductions in both the total LDL apoB production rate [30 (A) vs. 21% (S)] and LDL direct synthesis [32 (A) vs. 23% (S)]. A significant increase in the LDL apoB FCR (15%) was only seen with (A). Neither plasma VLDL nor LDL lipoprotein compositions were significantly altered. Hepatic HMG-CoA reductase was inhibited to a greater extent with (A), when compared with (S), as evidenced by 1) a greater induction in hepatic mRNA abundances for HMG-CoA reductase (105%) and the LDL receptor (40%) (both P < 0.05); and 2) a greater decrease in hepatic free (9%) and esterified cholesterol (25%) (both P < 0.05). We conclude that both (A) and (S) decrease hepatic VLDL apoB secretion, in vivo, but that the magnitude is determined by the extent of HMG-CoA reductase inhibition. SN - 0013-7227 UR - https://www.unboundmedicine.com/medline/citation/10537160/The_magnitude_of_decrease_in_hepatic_very_low_density_lipoprotein_apolipoprotein_B_secretion_is_determined_by_the_extent_of_3_hydroxy_3_methylglutaryl_coenzyme_A_reductase_inhibition_in_miniature_pigs_ L2 - https://academic.oup.com/endo/article-lookup/doi/10.1210/endo.140.11.7150 DB - PRIME DP - Unbound Medicine ER -