Regulation of the production and catabolism of plasma low density lipoproteins in hypertriglyceridemic subjects. Effect of weight loss

Abstract

In subjects with hypertriglyceridemia, plasma concentrations of low density lipoprotein (LDL) cholesterol are often normal or reduced. Perturbations that alter plasma very low density lipoprotein (VLDL) concentrations are associated with opposite changes in plasma LDL levels. To determine the mechanisms regulating plasma LDL levels, we used 131I-VLDL and 125I-LDL to measure the fractional catabolic rates (FCR), production rates (PR), and rates of interconversion of apoprotein B (apo B) in VLDL, intermediate density lipoprotein, and LDL in 6 hypertriglyceridemic subjects pre- and post-weight reduction. [2-3H]glycerol was used to quantitate VLDL triglyceride PR. All data are presented as mean±SD. Percent ideal body weight fell from 132±17.9 to 119±15.9% in the group, P < 0.05. After weight loss, plasma VLDL triglyceride (486.0±364.1 vs. 191.3±65.4 mg/dl, P < 0.05) and VLDL apo B (32.2±12.0 vs. 14.8±6.8 mg/dl, P < 0.05) concentrations were reduced. VLDL triglyceride PR also fell after weight reduction (56.6±39.0 vs. 28.6±23.1 mg/kg per h, P < 0.05), as did VLDL apo B PR (47.9±41.4 vs. 19.0±14.1 mg/kg per d, P < 0.05). Pre-weight loss, plasma LDL cholesterol and apo B levels were low-normal or reduced (64.0±12.6 and 58.4±11.9 mg/dl, respectively) despite normal or elevated LDL apo B PR (17.4±7.2 mg/kg per d). The reduced cholesterol and apo B levels were associated with increased FCRs (0.68±0.29 d-1) and reduced cholesterol/protein ratios (1.01±0.18) in LDL. The plasma levels of LDL cholesterol and apo B rose after weight reduction (84.8±24.9, P < 0.05; and 69.5±14.3 mg/dl, P < 0.05, respectively, vs. base line). These increased concentrations resulted from a combination of events. First, the FCR for LDL apo B fell in 5 of 6 subjects with a significant reduction for the group as a whole (0.48±0.11 d-1, P < 0.05 vs. base line). Second, the cholesterol/protein ratio increased in all 6 subjects with a significantly greater mean after weight loss (1.25±0.27, P < 0.05 vs. base line). In contrast, the LDL apo B PR fell or was essentially unchanged in the 6 subjects after weight loss (mean, 14.4±2.8 mg/kg per d; NS vs. pre-weight loss). The changes in LDL catabolism and composition were associated with changes in the source of LDL apo B. Pre-weight loss, 73.3% of LDL was derived from VLDL, while 26.7% was directly secreted into plasma. Post-weight reduction, VLDL-derived LDL fell to 46.8% of total, while direct secretion accounted for 53.2% of LDL production. These changes were significant; P < 0.05. Thus, all subjects had direct secretion of LDL apo B and the magnitude of this source of LDL seemed to be inversely related to the rate of VLDL triglyceride secretion. These results indicate that the regulation of plasma LDL levels in hypertriglyceridemic subjects is quite complex and that the rise in LDL levels after weight loss results from reductions in the fractional catabolism of this lipoprotein. The fall in the FCR is associated with changes in the source of LDL and in its composition.