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 [] = 1.019-1.044 g/ml), and sdLDL ( = 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 ( < 0.01). Proteomic analysis indicated that rosuvastatin decreased apoC-III and apoM content within the density range of lbLDL ( < 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.

The effects of low-carbohydrate diets on cardiovascular risk factors: A meta-analysis

“…This finding indicates that LDL-C-lowering treatment does not reduce the residual risk of cardiovascular events, indicating that even if the acceptable LDL-C target is met, there are risk factors other than LDL-C. The research data show that as the carbohydrates are limited in a low-carbohydrate diet, the increases in protein and fat intake will increase the concentration of plasma LDL-C; however, this elevation increases the LDL particle size from small to large, and atherosclerosis is caused by smaller LDL particles [34].That is, cholesterol-rich large buoyancy lowdensity lipoprotein particles (lbLDL) have been shown to have lower atherogenic atherosclerosis potential, while small density particles (sdLDLs) and moderate concentrations of low-density lipoprotein particles are more strongly correlated with cardiovascular disease outcomes [35,36], sdLDL particles (phenotype B) were more strongly associated with CVD outcomes than lbLDL particles (phenotype A). After a low-carbohydrate diet, the risk of CVD is reduced, while the opposite occurs after a high-carbohydrate diet [37].…”

Effects of carbohydrate-restricted diets on low-density lipoprotein cholesterol levels in overweight and obese adults: a systematic review and meta-analysis

“…24,25,113,114 sdLDL particles are characterised by a longer plasma residence time, which results in higher particle oxidation and glycation, further reduction in size and increased accumulation within arterial intima. 26,113 Increased concentrations of sdLDL particles produced by delipidated larger atherogenic VLDL and large LDL, and direct de novo hepatic production, correlate with increasing TG and decreasing HDL-C levels. 25 Hence, increased TG concentration and higher TG/HDL-C ratios are superior predictors of an increasingly atherogenic LDL phenotype (phenotype B) than LDL-C, as it indicates higher levels of remnant lipoprotein particle cholesterol along with higher non-HDL-C and LDL density.…”

“…Namely, cholesterolenriched large buoyant LDL particles (lbLDL) have shown to be less atherogenic, while small dense (sdLDL) and medium sized LDL particles more strongly associate with CVD outcomes. [22][23][24][25][26] Data suggest that a shift towards lbLDL occurs among participants following a CRD, resulting in a decreased CVD-risk, while the opposite occurs among those on highcarbohydrate diets. 27 However, the role of low-carbohydrate ketogenic diets in the long-term management of obesity and cardiometabolic risk markers is not well established.…”

Familial Combined Hyperlipidemia: Current Knowledge, Perspectives, and Controversies

“…FCHL confers an increased risk of premature cardiovascular disease partly due to a rise in the accumulation of atherogenic particles, which may require the use of moderate-to high-intensity statin. Rosuvastatin increases the catabolism of sdLDL apoB-100 levels without changes in the conversion of TRL apoB-100 to sdLDL, though at a lower rate than large buoyant LDL-C 63 . Additional cardiovascular risk has been associated to increased postprandial lipemia in FCHL patients; despite its efficacy in sdLDL and LDL-C reduction, statin therapy has not shown modifications on postprandial lipemia for most FCHL patients, except for MTP-493G/T carriers, in whom a greater reduction of postprandial lipemia has been associated with the use of atorvastatin in comparison to noncarriers 36 .…”