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Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action.
J Lipid Res. 1995 Dec; 36(12):2541-51.JL

Abstract

For the last 30 years fibrates have been widely prescribed to treat human dyslipidemia. However, the primary mechanism by which they lower plasma lipid levels is still unknown. Studies with transgenic mice have suggested that changes in apoC-III expression levels have a dramatic influence on plasma triglyceride levels. These results suggested that fibrates could reduce lipid levels by lowering apoC-III gene expression. In the current studies, we sought to determine whether the selected fibrates, bezafibrate, clofibrate, fenofibrate, and gemfibrozil, could reduce hepatic apoC-III mRNA and plasma apoC-III levels. Chow-fed rats were orally gavaged daily with a dosing vehicle alone or with 100 mg/kg of each of the fibrates for 1 week and in addition with gemfibrozil for 2 weeks. Bezafibrate and fenofibrate lowered plasma triglyceride by approximately half and dramatically reduced hepatic apoC-III mRNA and plasma apoC-III levels. In contrast, clofibrate did not reduce plasma triglyceride levels and only partially reduced apoC-III mRNA and plasma protein levels. Gemfibrozil strongly reduced plasma triglyceride levels and had an intermediate but significant effect on apoC-III mRNA and plasma apoC-III levels. Some of the fibrates, especially gemfibrozil also reduced plasma apoC-II levels, an effect that could contribute to the observed triglyceride-lowering effect. In addition, the ratio of plasma apoE to plasma apoC-II plus apoC-III was strongly and inversely correlated with plasma triglyceride levels. As plasma apoE levels were not reduced in gemfibrozil-treated animals, this could also have contributed to the triglyceride-lowering effect of this fibrate. Fibrate-mediated triglyceride lowering was not the result of a decreased apoB or VLDL production and, therefore, suggested an enhanced VLDL remnant catabolism. Our results suggest that the mechanism by which fibrates lower plasma triglycerides is by reducing the level of hepatic apoC-III expression.

Authors+Show Affiliations

Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48106, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo 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, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8847480

Citation

Haubenwallner, S, et al. "Hypolipidemic Activity of Select Fibrates Correlates to Changes in Hepatic Apolipoprotein C-III Expression: a Potential Physiologic Basis for Their Mode of Action." Journal of Lipid Research, vol. 36, no. 12, 1995, pp. 2541-51.
Haubenwallner S, Essenburg AD, Barnett BC, et al. Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action. J Lipid Res. 1995;36(12):2541-51.
Haubenwallner, S., Essenburg, A. D., Barnett, B. C., Pape, M. E., DeMattos, R. B., Krause, B. R., Minton, L. L., Auerbach, B. J., Newton, R. S., & Leff, T. (1995). Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action. Journal of Lipid Research, 36(12), 2541-51.
Haubenwallner S, et al. Hypolipidemic Activity of Select Fibrates Correlates to Changes in Hepatic Apolipoprotein C-III Expression: a Potential Physiologic Basis for Their Mode of Action. J Lipid Res. 1995;36(12):2541-51. PubMed PMID: 8847480.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action. A1 - Haubenwallner,S, AU - Essenburg,A D, AU - Barnett,B C, AU - Pape,M E, AU - DeMattos,R B, AU - Krause,B R, AU - Minton,L L, AU - Auerbach,B J, AU - Newton,R S, AU - Leff,T, PY - 1995/12/1/pubmed PY - 1995/12/1/medline PY - 1995/12/1/entrez SP - 2541 EP - 51 JF - Journal of lipid research JO - J. Lipid Res. VL - 36 IS - 12 N2 - For the last 30 years fibrates have been widely prescribed to treat human dyslipidemia. However, the primary mechanism by which they lower plasma lipid levels is still unknown. Studies with transgenic mice have suggested that changes in apoC-III expression levels have a dramatic influence on plasma triglyceride levels. These results suggested that fibrates could reduce lipid levels by lowering apoC-III gene expression. In the current studies, we sought to determine whether the selected fibrates, bezafibrate, clofibrate, fenofibrate, and gemfibrozil, could reduce hepatic apoC-III mRNA and plasma apoC-III levels. Chow-fed rats were orally gavaged daily with a dosing vehicle alone or with 100 mg/kg of each of the fibrates for 1 week and in addition with gemfibrozil for 2 weeks. Bezafibrate and fenofibrate lowered plasma triglyceride by approximately half and dramatically reduced hepatic apoC-III mRNA and plasma apoC-III levels. In contrast, clofibrate did not reduce plasma triglyceride levels and only partially reduced apoC-III mRNA and plasma protein levels. Gemfibrozil strongly reduced plasma triglyceride levels and had an intermediate but significant effect on apoC-III mRNA and plasma apoC-III levels. Some of the fibrates, especially gemfibrozil also reduced plasma apoC-II levels, an effect that could contribute to the observed triglyceride-lowering effect. In addition, the ratio of plasma apoE to plasma apoC-II plus apoC-III was strongly and inversely correlated with plasma triglyceride levels. As plasma apoE levels were not reduced in gemfibrozil-treated animals, this could also have contributed to the triglyceride-lowering effect of this fibrate. Fibrate-mediated triglyceride lowering was not the result of a decreased apoB or VLDL production and, therefore, suggested an enhanced VLDL remnant catabolism. Our results suggest that the mechanism by which fibrates lower plasma triglycerides is by reducing the level of hepatic apoC-III expression. SN - 0022-2275 UR - https://www.unboundmedicine.com/medline/citation/8847480/Hypolipidemic_activity_of_select_fibrates_correlates_to_changes_in_hepatic_apolipoprotein_C_III_expression:_a_potential_physiologic_basis_for_their_mode_of_action_ L2 - http://www.jlr.org/cgi/pmidlookup?view=long&pmid=8847480 DB - PRIME DP - Unbound Medicine ER -