title: Metabolism and proteomics of large and small dense LDL in combined hyperlipidemia: effects of rosuvastatin.
abstract: Small dense LDL (sdLDL) has been reported to be more atherogenic than large buoyant LDL (lbLDL). We examined the metabolism and protein composition of sdLDL and lbLDL in six subjects with combined hyperlipidemia on placebo and rosuvastatin 40 mg/day. ApoB-100 kinetics in triglyceride-rich lipoproteins (TRLs), lbLDL (density [d] = 1.019-1.044 g/ml), and sdLDL (d= 1.044-1.063 g/ml) were determined in the fed state by using stable isotope tracers, mass spectrometry, and compartmental modeling. Compared with placebo, rosuvastatin decreased LDL cholesterol and apoB-100 levels in TRL, lbLDL, and sdLDL by significantly increasing the fractional catabolic rate of apoB-100 (TRL, +45%; lbLDL, +131%; and sdLDL, +97%), without a change in production. On placebo, 25% of TRL apoB-100 was catabolized directly, 37% was converted to lbLDL, and 38% went directly to sdLDL; rosuvastatin did not alter these distributions. During both phases, sdLDL apoB-100 was catabolized more slowly than lbLDL apoB-100 (P< 0.01). Proteomic analysis indicated that rosuvastatin decreased apoC-III and apoM content within the density range of lbLDL (P< 0.05). In our view, sdLDL is more atherogenic than lbLDL because of its longer plasma residence time, potentially resulting in more particle oxidation, modification, and reduction in size, with increased arterial wall uptake. Rosuvastatin enhances the catabolism of apoB-100 in both lbLDL and sdLDL.
authors.affiliation: Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA.
authors.forename: Nuntakorn
authors.initials: N
authors.lastname: Thongtang
authors.affiliation: Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Diffenderfer
authors.affiliation: Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA.
authors.forename: Esther M M
authors.initials: EMM
authors.lastname: Ooi
authors.affiliation: School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: P Hugh R
authors.initials: PHR
authors.lastname: Barrett
authors.affiliation: KineMed, Inc., Emeryville, CA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Turner
authors.affiliation: Atlanta Veterans Affairs Medical Center, Decatur, GA; and; Emory University School of Medicine, Atlanta, GA.
authors.forename: Ngoc-Anh
authors.initials: NA
authors.lastname: Le
authors.affiliation: Atlanta Veterans Affairs Medical Center, Decatur, GA; and; Emory University School of Medicine, Atlanta, GA.
authors.forename: W Virgil
authors.initials: WV
authors.lastname: Brown
authors.affiliation: Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA;. Electronic address: ernst.schaefer@tufts.edu.
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Schaefer
mesh_terms: D008078:Cholesterol, LDL / Q000737:chemistry* / Q000378:metabolism*; D005260:Female; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010316:Particle Size; D040901:Proteomics; D000068718:Rosuvastatin Calcium / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D008078:Cholesterol, LDL; D000068718:Rosuvastatin Calcium
keywords: LDL subfractions; atherosclerosis; dyslipidemia; lipoproteins/kinetics; mass spectrometry; mathematical modeling; statins