Abstract
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.
Highlights
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
The decrease in plasma lipid levels in animals fed n-3 PUFA was accounted for mainly by a decrease in the plasma concentration of apoBcontaining lipoproteins consistent with a previous report [59]. These studies were prompted by previous work in rats where we found that dietary n-3 PUFA accelerated LDL clearance by the liver without altering hepatic LDLr expression [36]
The current studies demonstrate that dietary n-3 PUFA increases hepatic IDL/LDL uptake in LDLr-deficient mice and that this effect accounts for ف33% of the decrease in the plasma concentration of these particles
Summary
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. 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 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. Human turnover studies suggest that n-3 PUFA decreases serum triglyceride concentrations in part by inhibiting VLDL triglyceride secretion by the liver [10] Consistent with these human studies are data showing that dietary n-3 PUFA decreases VLDL triglyceride secretion from perfused rat [11] and 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. Dietary n-3 PUFA has been shown to accelerate chylomicron triglyceride clearance in rats [31] and to enhance the conversion VLDL apolipoprotein (apo)B to LDL apoB in pigs [32]
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