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Journal of Lipid Research, Vol. 43, 772-784, May 2002
Copyright © 2002 by Lipid Research, Inc.
* Departments of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8887
Molecular Genetics, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8887
1 To whom correspondence should be addressed at 1600 West College, Suite 680, Grapevine, TX 76051. e-mail: jay.horton{at}utsouthwestern.edu
We determined the effects of dietary n-6 and n-3 polyunsaturated fatty acids (PUFA) on parameters of plasma lipoprotein and hepatic lipid metabolism in LDL receptor (LDLr) knockout mice. Dietary n-3 PUFA decreased the rate of appearance and increased the hepatic clearance of IDL/LDL resulting in a marked decrease in the plasma concentration of these particles. Dietary n-3 PUFA increased the hepatic clearance of IDL/LDL through a mechanism that appears to involve apolipoprotein (apo)E but is independent of the LDLr, the LDLr related protein (LRP), the scavenger receptor B1, and the VLDLr. The decreased rate of appearance of IDL/VLDL in the plasma of animals fed n-3 PUFA could be attributed to a marked decrease in the plasma concentration of precursor VLDL. Decreased plasma VLDL concentrations were due in part to decreased hepatic secretion of VLDL triglyceride and cholesteryl esters, which in turn was associated with decreased concentrations of these lipids in liver. Decreased hepatic triglyceride concentrations in animals fed n-3 PUFA were due in part to suppression of fatty acid synthesis as a result of a decrease in sterol regulatory element binding protein-1 (SREBP-1) expression and processing. In conclusion, these studies indicate that n-3 PUFA can markedly decrease the plasma concentration of apoB-containing lipoproteins and enhance hepatic LDL clearance through a mechanism that does not involve the LDLr pathway or LRP.—Vasandani, C., A. I. Kafrouni, A. Caronna, Y. Bashmakov, M. Gotthardt, J. D. Horton, and D. K. Spady. Upregulation of hepatic LDL Transport by n-3 fatty acids in LDL receptor knockout mice. J. Lipid Res. 2002. 43: 772–784.
Abbreviations: ACC, acetyl CoA carboxylase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FAS, fatty acid synthase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LPL, lipoprotein lipase; LRP, receptor related protein; MTP, microsomal triglyceride transport protein; PPAR, peroxisome proliferator-activated receptor; SREBP, sterol regulatory element-binding protein; SR-BI, scavenger receptor BI
Supplementary key words polyunsaturated fatty acids • fish oil • liver • lipoproteins • cholesterol • triglyceride • VLDL
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