Absolute Synthetic Rate Research Articles

Elevated high density lipoprotein cholesterol levels correlate with decreased apolipoprotein A-I and A-II fractional catabolic rate in women.

High levels of HDL-cholesterol (HDL-C) protect against coronary heart disease susceptibility, but the metabolic mechanisms underlying elevated HDL-C levels are poorly understood. We now report the turnover of isologous radioiodinated HDL apolipoproteins, apo A-I and apo A-II, in 15 female subjects on a metabolic diet with HDL-C levels ranging from 51 to 122 mg/dl. The metabolic parameters, fractional catabolic rate (FCR) and absolute synthetic rate (SR), were determined for apo A-I and apo A-II in all subjects. There was an inverse correlation between plasma HDL-C and the FCR of apo A-I and apo A-II (r = -0.75, P less than 0.001, and r = -0.54, P = 0.036, respectively), but no correlation with the SR of either apo A-I or apo A-II (r = 0.09, and r = -0.16, respectively, both P = NS). Apo A-I levels correlated inversely with apo A-I FCR (r = -0.64, P = 0.01) but not with apo A-I SR (r = 0.30, P = NS). In contrast, plasma levels of apo A-II did not correlate with apo A-II FCR (r = -0.38, P = 0.16), but did correlate with apo A-II SR (r = 0.65, P = 0.009). Further analysis showed that apo A-I and apo A-II FCR were inversely correlated with the HDL-C/apo A-I + A-II ratio (r = -0.69 and -0.61, P = 0.005 and 0.015, respectively). These data suggest that: (a) low HDL apolipoprotein FCR is the predominant metabolic mechanism of elevated HDL-C levels; (b) apo A-I FCR is the primary factor in controlling plasma apo A-I levels, but apo A-II SR is the primary factor controlling plasma apo A-II levels; (c) low HDL apolipoprotein FCR is associated with a lipid-rich HDL fraction. These findings elucidate aspects of HDL metabolism which contribute to high HDL-C levels and which may constitute mechanisms for protection against coronary heart disease.

The effect of combined fenofibrate and cholestyramine therapy on low-density lipoprotein kinetics in familial hypercholesterolemia patients

The effects of combined drug treatment (fenofibrate and cholestyramine) have been investigated in vivo by simultaneously determining total and receptor-independent LDL catabolism with 125I-labelled LDL and 131I-labelled LDL coupled with cyclohexanedione. Receptor-mediated catabolism of LDL determined as the difference between the turnover of 125I and 131I, was found to be reduced in heterozygotes with familial hypercholesterolemia. Treatment with combined fenofibrate and cholestyramine markedly stimulated both receptor-mediated (by more than 2-fold) and receptor-independent catabolism. LDL-Apo B and LDL-cholesterol levels were reduced by 38% and 36%, respectively. The combined treatment also reduced the absolute synthetic rate of LDL-Apo B (by 9%). The mechanisms responsible for these kinetic effects are discussed.

Albumin Synthesis in Premature Infants: Determination of Turnover with [15N]Glycine

Albumin turnover was studied in seven small premature infants who received a constant infusion of [15N]glycine for 60-72 h. Gas chromatography-mass spectrometry was used to measure the rate of appearance of [15N]glycine in albumin isolated from the blood. By comparing the linear increment of [15N]glycine in blood albumin with plateau labelling of urinary [15N]hippurate, which was assumed to reflect intrahepatic isotopic abundance in [15N]glycine, the fractional synthetic rate for albumin was found to be 0.09-0.177 day-1 (mean +/- SD = 0.122 +/- 0.041 day-1). The absolute synthesis rate for albumin was 0.3 +/- 0.099 g/dl plasma X day-1 and the total plasma synthetic rate was 117.6 +/- 37.0 mg/kg X day-1. The glycine flux was 326.0-927.7 mumol/kg X h-1 (mean +/- SD 516.7 +/- 218.4 mumol/kg hr-1). The percentage of the glycine flux incorporated into albumin in the total vasculature was 0.425 +/- 0.344. The fractional synthetic rate and the absolute synthetic rate for albumin in these small premature infants are much higher than values obtained in healthy young adults studied with a similar methodology. The relatively low serum albumin concentrations typical of premature infants appear to be referable to more rapid turnover of a small plasma pool rather than a diminution in the rate of albumin synthesis.

Protein Turnover in Insulin-Treated, Alloxan-Diabetic Lean and Obese Zucker Rats

Obese and lean Zucker rats were made diabetic by intracardiac injections of alloxan (65–72 mg/kg body weight) and then given daily injections of protamine zinc insulin [1.25 U/(100 g/d)] for 6, 9 and 12 d. Body weight, food intake, plasma glucose and immunoreactive insulin concentrations were not different for lean and obese diabetic rats of similar ages. Rates of increase in carcass protein, mixed muscle protein and myofibrillar protein were less in obese than in lean rats. However, rates of increase for the sarcoplasmic fraction were not different. Fractional rates of synthesis of total muscle protein and myofibrillar protein, as determined by continuous intravenous infusion of [14C]tyrosine, were comparable in the two genotypes. Fractional rate of myofibrillar protein degradation, as determined by urinary 3-methylhistidine excretion, was higher in obese than in lean rats. Differences in calculated absolute rates between genotypes did not parallel differences in the fractional rates, due mainly to a smaller protein mass in obese rats. As a consequence, absolute synthetic rates were lower in obese rats, while absolute degradation rates were similar in the two genotypes. In contrast, rates of liver protein synthesis were similar in obese and lean rats, whether expressed as fractional or absolute rates. These results indicate that decreased protein deposition in the obese animal is a consequence of both an absolute decrease in protein synthesis in muscle as well as a disproportionately elevated protein degradation in muscle. Hyperinsulinemia normally seen in obese rats may be an adaptive response to minimize the impaired balance between protein synthesis and degradation.

Effect of cholesterol feeding on the distribution of plasma lipoproteins and on the metabolism of apolipoprotein E in the rabbit

Changes in lipoprotein distribution and in apolipoprotein E metabolism were studied in rabbits fed a diet containing 1% cholesterol. Lipoprotein distribution was monitored by rate zonal ultracentrifugation, gel filtration chromatography, and electrophoretic techniques. Normolipidemic rabbit plasma contained VLDL, IDL, LDL, and HDL. Within 1 week on the 1% cholesterol diet, the d less than 1.006 g/ml material was greatly elevated, and the lipoproteins of higher density (LDL and HDL) decreased below levels of detection. Cholesteremic d less than 1.006 g/ml material was cholesteryl ester-rich, triglyceride-poor, and contained particles of Sf 20 to greater than 400. Upon diet normalization, the LDL and HDL reappeared within 2-4 weeks accompanied by a decrease in the d less than 1.006 g/ml material. The metabolism of apoE was studied by injecting purified and 125I-labeled apoE into rabbits and following the clearance of the tracer. ApoE in the normolipemic rabbit demonstrated a fractional catabolic rate (FCR) of 0.132 hr-1 and a half-life (t1/2) of 10.3 hr. ApoE in the hypercholesterolemic rabbit demonstrated an FCR of 0.055 hr-1 and a t1/2 of 49.5 hr. ApoE concentrations in the plasma as estimated by electroimmunoassay were 19.5 mg/dl in the control rabbit and 199 mg/dl in the hypercholesterolemic rabbit. From these data, absolute synthetic rates of 20.3 mg/kg per day and 86.1 mg/kg per day were calculated for the control and the hypercholesterolemic rabbit, respectively. We conclude that the cholesterol-supplemented diet caused pronounced elevation of apoE in the plasma due to overproduction of the protein.

Neutropenia fails to prevent the acute phase stimulation of fibrinogen synthesis

This study evaluates the role of neutrophil granulocytes in mediating acute phase stimulation of fibrinogen synthesis. Turpentine was administered to neutropenic and non-neutropenic rats and fibrinogen synthetic rates measured in an isolated liver perfusion system. Using the ( 14C) carbonate technique for the measurement of the absolute synthetic rates of liver produced plasma proteins it was observed that the rates of fibrinogen synthesis of the neutropenic and non-neutropenic rats were significantly greater (p < 0.01) than those of normal control animals, but were not significantly different from each other. These results suggest that the neutrophil granulocyte may not be of major importance in mediating acute phase stimulation of fibrinogen synthesis.

Metabolism of the viatmin A transporting protein complex. I. Turnover studies in normal persons and in patients with chronic renal failure.

Abstract. Biological turnover studies of the human vitamin A transporting protein complex and its individual components, prealbumin and retinol binding protein (RBP) have been performed in normal persons and in patients with severely impaired kidney function. The metabolic behaviour of prealbumin was very similar in the two groups of subjects studied, and it was concluded that prealbumin eatabolism can be dependent to only a minor extent on normally functioning kidney glomeruli.–RBP is present in several molecular forms in plasma. In normal conditions virtually all PRB is bound to prealbumin, but small amounts of RBP also occur in free form. The concentration of the free RBP is greatly increased in patients with grossly impaired glomerular filtration. The biological half‐life for free RBP was short in normal persons (about 4 hours) whereas in the patients this parameter was increased 10 to 15 fold. These findings suggest that most if not all free RBP in plasma is catabolized by the kidney. RBP complexed with prealbumin has a considerably longer half‐life than its free counterpart in normal persons but the absolute synthetic rate of the two components of RBP is similar. Thus it is proposed that most RBP is catabolized from the pool of the uneomplexed species.–From the data it can be calculated that as much as one third of the plasma vitamin A may be deposited in the kidney tubuli on degradation of RBP, since the mechanism for the renal eatabolism of this small protein seems to involve glomerular filtration followed by tubular reabsorption.

Synthesis and turnover of membrane proteins in rat liver: an examination of the membrane flow hypothesis.

The kinetics of synthesis and degradation of the protein constituents of nuclear membranes, endoplasmic reticulum membranes (rough-surfaced microsomes), Golgi apparatus membranes and plasma membranes were determined following a single administration of L- [guanido-14C] arginine by intraperitoneal injection. Membrane protein was determined as the fraction which resists sonication and sequential extrations with 1.5 M KCl, 0.1% deoxycholate and water to remove intravesicular, intracisternal (secretory), nucleo-, adsorbed and ribosome-associated proteins. The order of maximum labeling of membrane proteins was a) endoplasmic reticulum (nuclear membrane), b) Golgi apparatus, and c) plasma membrane. Rapid decreases in specific radioactivity followed maximal labeling of endoplasmic reticulum and Golgi apparatus membranes. These rapid turnover components of endoplasmic reticulum and Golgi apparatus were sufficient to account for labeling of plasma membranes via a flow mechanism. Incorporation of radioactivity into plasma membranes showed two distinct phases. The ultrastructural features underlying the biphasic pattern of incorporation into plasma membranes are discussed. Following initial incorporation and rapid turnover, membrane proteins were characterized by degradation kinetics approximating 1st order. Rates of degradation for Golgi apparatus and plasma membranes were faster than those for nuclear envelope and endoplasmic reticulum membranes. Assuming steady state conditions, an absolute synthetic rate of 7.1 mpg/min/avergage hepatocyte was calculated for membrane proteins of the plasma membrane. The results are compatible with intracellular movement and conversion of rough endoplasmic reticulum to plasma membrane via the membranes of the Golgi apparatus, i. e., membrane flow. Additionally, the kinetics indicate that membrane synthesis and transfer is restricted to specific parts of the endoplasmic reticulum and Golgi apparatus.