Change In Fractional Catabolic Rate Research Articles

Interleukin-6 blockade raises LDL via reduced catabolism rather than via increased synthesis: a cytokine-specific mechanism for cholesterol changes in rheumatoid arthritis

ObjectivesPatients with rheumatoid arthritis (RA) have reduced serum low-density lipoprotein cholesterol (LDL-c), which increases following therapeutic IL-6 blockade. We aimed to define the metabolic pathways underlying these lipid changes.MethodsIn the...

Nicotinic Acid Decreases Apolipoprotein B100-Containing Lipoprotein Levels by Reducing Hepatic Very Low Density Lipoprotein Secretion through a Possible Diacylglycerol Acyltransferase 2 Inhibition in Obese Dogs

Apolipoprotein B100 (apoB100) is an essential component of very low density lipoprotein (VLDL) and low-density lipoprotein (LDL), both independent markers of cardiovascular risk. Nicotinic acid (NA) is an efficacious drug for decreasing VLDL and LDL, but the underlying mechanisms are unclear. For this purpose, six obese insulin-resistant dogs were given 350 mg/day of NA for 1 week and then 500 mg/day for 3 weeks. Turnover of apoB100-containing lipoproteins was investigated using stable isotope-labeled tracers. Multicompartmental modeling was used to derive kinetic parameters before and at the end of NA treatment. Hepatic diacylglycerol acyltransferase 2 (DGAT2), microsomal triglyceride transfer protein (MTP), hepatic lipase (HL), and adipose lipoprotein lipase (LPL) mRNA expression was also determined. NA treatment decreased plasma triglyceride (TG) (p < 0.001), VLDL-TG (p < 0.05), total cholesterol (p < 0.0001), and LDL cholesterol (p < 0.05), whereas plasma nonesterified fatty acids were unchanged. The decrease in VLDL-apoB100 concentration (p < 0.001) was the result of a lower absolute production rate (APR) (p < 0.001), despite a moderate decrease (p < 0.05) in fractional catabolic rate (FCR). LDL-apoB100 concentration was reduced (p < 0.05), an effect related to a decrease in LDL APR (p < 0.05) and no change in FCR. NA treatment reduced DGAT2 expression (p < 0.05), whereas MTP, HL, and LPL expression was unchanged. Our results suggest that NA treatment reduced VLDL and LDL concentration as a consequence of a decrease in VLDL production.

Extended-Release Niacin Alters the Metabolism of Plasma Apolipoprotein (Apo) A-I and ApoB-Containing Lipoproteins

Extended-release niacin effectively lowers plasma TG levels and raises plasma high-density lipoprotein (HDL) cholesterol levels, but the mechanisms responsible for these effects are unclear. We examined the effects of extended-release niacin (2 g/d) and extended-release niacin (2 g/d) plus lovastatin (40 mg/d), relative to placebo, on the kinetics of apolipoprotein (apo) A-I and apoA-II in HDL, apoB-100 in TG-rich lipoproteins (TRL), intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), and apoB-48 in TRL in 5 men with combined hyperlipidemia. Niacin significantly increased HDL cholesterol and apoA-I concentrations, associated with a significant increase in apoA-I production rate (PR) and no change in fractional catabolic rate (FCR). Plasma TRL apoB-100 levels were significantly lowered by niacin, accompanied by a trend toward an increase in FCR and no change in PR. Niacin treatment significantly increased TRL apoB-48 FCR but had no effect on apoB-48 PR. No effects of niacin on concentrations or kinetic parameters of IDL and LDL apoB-100 and HDL apoA-II were noted. The addition of lovastatin to niacin promoted a lowering in LDL apoB-100 attributable to increased LDL apoB-100 FCR. Niacin treatment was associated with significant increases in HDL apoA-I concentrations and production, as well as enhanced clearance of TRL apoB-100 and apoB-48.

Effect of atorvastatin on chylomicron remnant metabolism in visceral obesity: a study employing a new stable isotope breath test

Elevated plasma concentration of chylomicron remnants may be causally related to atherosclerosis in obesity. We examined the effect of atorvastatin on chylomicron remnant metabolism in 25 obese men with dyslipidaemia. A remnant-like emulsion labeled with cholesteryl [13C]oleate was injected intravenously into patients; the fractional catabolic rate (FCR) of the remnant-like emulsion was determined by measurement of 13CO2 in the breath and analyzed using compartmental modelling. Compared with placebo, atorvastatin significantly decreased the plasma concentrations of total cholesterol, triglycerides, LDL cholesterol, apolipoprotein B (apoB), and lathosterol (P < 0.001). ApoB-48 and remnant-like particle-cholesterol (RLP-C) both decreased significantly by 23% (P = 0.002) and 33% (P = 0.045), respectively. The FCR of the remnant-like emulsion increased significantly from 0.054 ± 0.008 to 0.090 ± 0.010 pools/h (P = 0.002). The decrease in RLP-C was associated with the decrease in plasma triglycerides (r = 0.750, P = 0.003). Furthermore, the change in FCR of remnant-like emulsions was inversely associated with the change in LDL-C (r = −0.575, P = 0.040), suggesting removal of LDL and chylomicron remnants by similar hepatic receptor pathways. We conclude that in obese subjects, inhibition of cholesterol synthesis with atorvastatin decreases the plasma concentrations of both LDL-C and triglyceride-rich remnants and that this may be partially due to an enhancement in hepatic clearance of these lipoproteins.—Chan, D. C., G. F. Watts, P. H. R. Barrett, I. J. Martins, A. P. James, J. C. L. Mamo, T. A. Mori, and T. G. Redgrave. Effect of atorvastatin on chylomicron remnant metabolism in visceral obesity: a study employing a new stable isotope breath test. J. Lipid Res. 2002. 43: 706–712.

Low-density lipoprotein-apolipoprotein B metabolism following apheresis: simulation studies of mass changes and tracer kinetics.

Low-density lipoprotein (LDL) apheresis is an effective method to treat severe hyperlipoproteinemia such as heterozygous familial hypercholesterolemia (FH). It is unknown whether apheresis induces changes in metabolic parameters of LDL-apolipoprotein B (apoB) such as the fractional catabolic rate (FCR) or production rate. We performed simulation studies to determine the effect of potential changes in the LDL FCR on LDL-apoB mass and on exogenous and endogenous tracer studies. For these studies, we assumed a two-compartment LDL model and the following metabolic parameters: plasma LDL-apoB, 180 mg.dL(-1); LDL-apoB production rate, 36 mg.dL(-1).d(-1) (approximately 14.4 mg.kg(-1).d(-1)); and LDL-apo FCR, 0.2 d(-1). It was also assumed that apheresis instantaneously decreased the LDL-apoB concentration to 60 mg.dL(-1) and that LDL-apoB production was not perturbed. The simulations examined three possible outcomes: (1) no change in FCR, (2) a temporary doubling in FCR, and (3) a temporary tripling in FCR. Monoexponential models were fit to the rebound of LDL-apoB mass data generated using the different FCRs. In no instance did the FCR determined from the fit match the FCR used to generate the data; FCRs were either higher or lower than the original FCR used to generate the data. Simulations of the kinetics of exogenously labeled LDL showed that if apheresis was performed on day 7 of a turnover study, it would be possible to detect large changes in LDL-apoB FCR. In contrast, during an endogenous labeling study, potential increases in FCR induced by apheresis may not be detected. However, our simulations do show that endogenous labeling studies performed before and after apheresis should yield data that will permit detection of changes in the FCR. Thus, these studies indicate that large differences in the LDL-apoB FCR induced by apheresis can be detected by either an exogenous tracer experiment perturbed by apheresis or by endogenous labeling experiments performed before and after apheresis. Small changes in the FCR that may be induced by apheresis will probably be indistinguishable from experimental noise.

Effects of fish oil on VLDL triglyceride kinetics in humans

Dietary n-3 fatty acids (FAs) found in fish oils markedly lower plasma triglyceride (TG) and very low density lipoprotein (VLDL) levels in both normal and hypertriglyceridemic subjects. The present study examined the mechanism of this effect. Ten subjects with widely different plasma triglyceride levels (82 to 1002 mg/dl) were fed metabolically controlled diets containing 20% fat. The control diet contained a blend of cocoa butter and peanut oil (P/S = 0.8). The test diet contained fish oil (P/S = 1.1) and provided 10-17 g of n-3 FAs per day (depending on calorie intake). After 3 to 5 weeks of each diet, the kinetics of VLDL-TG were determined over a 48-h period after the injection of [3H]glycerol. The fish oil diet reduced the VLDL-TG synthetic rate from 23 +/- 14.3 (mean +/- SD) to 12.6 +/- 7.5 mg/h per kg ideal weight (P less than 0.005) and increased the fractional catabolic rate (FCR) for VLDL-TG from 0.23 +/- 0.12 to 0.38 +/- 0.16 h -1 (P less than 0.005). At the same time, there was a 66% reduction of plasma triglyceride levels, resulting largely from a 78% decrease in VLDL-TG levels (398 +/- 317 to 87 +/- 77 mg/dl; P less than 0.005). There was a strong correlation (r = 0.83; P less than 0.01) between the change in synthetic rates and pool sizes, but there was no correlation (r = 0.24; NS) between changes in FCRs and pool sizes. The VLDL cholesterol: triglyceride ratio increased during the n-3 diet suggesting that smaller VLDL particles were present. These particles would be expected to leave the VLDL fraction more rapidly than larger particles producing a higher FCR. We conclude that the hypotriglyceridemic effect of fish oil appears to be caused primarily by an inhibition of very low density lipoprotein-triglyceride synthesis, but an additional, independent effect upon VLDL catabolism cannot be ruled out.

Influence of mevinolin on metabolism of low density lipoproteins in primary moderate hypercholesterolemia.

Mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was used for treatment of 12 patients with moderate hypercholesterolemia, but not classical familial hypercholesterolemia. For most patients, measurements of turnover of low density lipoprotein-apolipoprotein B (LDL-apoB) were made on placebo and during treatment with two doses of mevinolin. LDL turnover was determined after injection of autologous 125I-labeled radioiodinated LDL. Compared to placebo, a low dose of mevinolin (10 mg, twice daily (BID] caused reductions of plasma total cholesterol and LDL-cholesterol averaging 15% and 20%, respectively; corresponding reductions on high doses of mevinolin (20 mg BID) were 22% and 31%, respectively. Triglyceride levels were unchanged by the drug. High density lipoprotein cholesterol levels rose significantly on the high dose, but not on the low dose. Neither dose produced a stastistically significant change in fractional catabolic rate (FCR) for LDL-apoB for the whole group, although several patients had increases in FCR on both doses. In contrast, both doses of mevinolin caused decreases in production rates of LDL-apoB. Thus, the fall in LDL levels in patients with moderate hypercholesterolemia can be explained more by a reduction in the input rate of LDL-apoB than by enhanced fractional removal of LDL from the circulation.