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Biomedical subjects

M W Huff

Publications and source records attributed to M W Huff.

At least 73 records · Page 4Linked to original sources
PubMed1986

Divergent effects of d-norgestrel on the metabolism of rat very low density and low density apolipoprotein B.

Rats treated with the contraceptive steroid d-norgestrel have lower plasma very low density lipoprotein (VLDL)-triglycerides and higher low density lipoprotein (LDL)-cholesterol than controls. To explain these results, the kinetics of VLDL and LDL turnover were studied by injecting 125I-labeled rat-VLDL and 131I-labeled rat-LDL simultaneously into rats treated with a small dose of d-norgestrel (4 micrograms per day per kg body weight0.75 for 18 days, n = 22) and their untreated controls (n = 22). VLDL- and LDL-apoB specific activity-time curves obtained over 50 hr best conformed to a three-pool model. VLDL-apoB clearance expressed as irreversible catabolic rate (k01) was markedly enhanced in the treated versus control rats (0.57 vs. 0.34 pools hr-1), leading to a marked reduction in VLDL-apoB pool size (270 vs. 420 micrograms). However, VLDL-apoB production rates were similar in the two groups (160 vs. 140 micrograms/hr, respectively). The 125I-labeled apoB specific activity-time curve derived from the catabolism of 125I-labeled VLDL-apoB also showed enhanced clearance in d-norgestrel-treated rats. 125I-Labeled IDL-apoB and 125I-labeled LDL-apoB specific activity-time curves failed to intersect the VLDL-apoB curve at maximal heights, suggesting input of intermediate density lipoprotein (IDL) and LDL independent of VLDL catabolism in both groups. However, the extent of independent LDL-apoB production was similar in both groups. Clearance of 131I-labeled LDL-apoB following injection of 131I-labeled rat-LDL was delayed in the d-norgestrel-treated versus control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Direct synthesis of low-density lipoprotein apoprotein B in the miniature pig.

The metabolism of apoprotein B (apo B) was investigated in five miniature pigs following the injection of radiolabeled, very low-density lipoproteins (VLDL). The fractional catabolic rate (FCR) for VLDL apoprotein B was 0.71 +/- 0.10 h-1 (mean +/- SE), the rate of flux was 0.77 +/- 0.05 mg h-1 kg-1, and the pool size of apoprotein B averaged 1.26 +/- 0.20 mg kg-1. Examination of precursor-product relationships between VLDL and low-density lipoprotein (LDL) apoprotein B illustrated that a significant proportion (greater than 80%) of LDL apo B was derived from some source other than VLDL catabolism. In further experiments (n = 4), 125I-VLDL and 131I-LDL were simultaneously injected into miniature pigs. The fractional catabolic rate of LDL apo B averaged 0.055 +/- 0.008 h-1 and the flux rate 0.73 +/- 0.07 mg h-1 kg-1. These dual-label studies allowed us to calculate that an average of 16% of VLDL apoprotein B was converted to LDL and thus the remainder was cleared directly from the circulation. Simultaneous injection of radiolabeled homologous and human VLDL indicated that the catabolism of the two tracers was qualitatively similar. However, human VLDL apo B exhibited a slower fractional catabolic rate (0.42 v 0.71 h-1 P less than 0.05) and reduced rate of conversion to LDL. Therefore, low-density lipoproteins in the pig are largely produced by direct secretion into the circulation, independent of VLDL catabolism. Apo B metabolism in miniature pigs is similar to that of cynomologous and squirrel monkeys, and rats, but differs from normal humans in whom all LDL apo B is derived from VLDL catabolism.

Animals↗
PubMed1985

Mevinolin and cholestyramine inhibit the direct synthesis of low density lipoprotein apolipoprotein B in miniature pigs.

Previous studies established that following simultaneous injection of 125I-labeled homologous very low density lipoproteins (VLDL) and 131I-labeled homologous low density lipoproteins (LDL) into miniature pigs, a large proportion of LDL apolipoprotein B (apoB) was synthesized directly, independent of VLDL or intermediate density lipoprotein (IDL) apoB catabolism. The possibility that cholestyramine alone (a bile acid sequestrant) or in combination with mevinolin (a cholesterol synthesis inhibitor) could regulate the direct LDL apoB synthetic pathway was investigated. 125I-labeled VLDL and 131I-labeled LDL were injected into miniature pigs (n = 8) during a control period and following 18 days of cholestyramine treatment (1.0 g kg-1d-1) or following 18 days of treatment with cholestyramine and mevinolin (1.2 mg kg-1d-1). ApoB in each lipoprotein fraction was selectively precipitated using isopropanol in order to calculate specific activity. In control experiments, LDL apoB specific activity curves reached their peak values well before crossing the VLDL or IDL apoB curves. However, cholestyramine treatment resulted in LDL apoB curves reaching maximal values much closer to the point of intersection with the VLDL or IDL curves. Kinetic analyses demonstrated that cholestyramine reduced total LDL apoB flux by 33%, which was due entirely to inhibition of the LDL apoB direct synthesis pathway since VLDL-derived apoB was unaffected. In addition, the LDL apoB pool size was reduced by 30% and the fractional catabolic rate of LDL apoB was increased by 16% with cholestyramine treatment. The combination of mevinolin and cholestyramine resulted in an even more marked inhibition of the direct LDL apoB synthesis pathway (by 90%), and in two animals this pathway was completely abolished. This inhibition was selective as VLDL-derived LDL apoB synthesis was not significantly different. LDL apoB pool size was reduced by 60% due primarily to the reduced synthesis as well as a 40% greater fractional removal rate. These results are consistent with the idea that cholestyramine and mevinolin increase LDL catabolism by inducing hepatic apoB, E receptors. We have now shown that the direct synthesis of LDL apoB is selectively inhibited by these two drugs.

Animals↗
PubMed1984

Characterization and metabolic fate of two very-low-density lipoprotein subfractions separated by heparin-sepharose chromatography.

Human very-low-density lipoproteins (VLDL) have been separated into two discrete subfractions by heparin-Sepharose chromatography. The retained fraction relative to the unretained fraction is characterized by an increased cholesterol ester/triacylglycerol ratio and an increased ratio of apolipoprotein E relative to apolipoprotein C. We have subfractionated VLDL from type IV hyperlipoproteinemic subjects and characterized these subfractions with respect to (i) composition and (ii) the metabolic fate of apolipoprotein B of each subfraction. The unretained fraction accounted for an average of 42% of total VLDL in type IV subjects. A similar distribution was obtained with VLDL from Type III subjects; however, only 25% of normal VLDL is in the unretained fraction. The apolipoprotein E/apolipoprotein C ratio was 2-8-fold higher in the retained fraction. The distribution of apolipoprotein E isomorphs and the individual C apolipoproteins were similar in each fraction. Retained and unretained fractions were labelled with 125I and/or 131I and injected simultaneously into miniature pigs. Apolipoprotein B of retained fractions was catabolized at a greater rate (fractional catabolic rate = 0.98 h-1 vs. 0.54 h-1, n = 7, P less than 0.05) compared to unretained fractions. These results are consistent with the concept that reduced content of C apolipoproteins in VLDL is correlated with enhanced uptake by perfused rat livers. Apolipoprotein B from retained fractions was converted to intermediate-density lipoproteins (IDL) at a greater rate, and apolipoprotein B from both fractions were converted to low-density lipoproteins (LDL). Although the unretained fraction may be the precursor of the retained fraction, the possibility exists that each fraction is largely synthesized and catabolized independently.

Cholesterol↗
PubMed1984

Turnover of very low-density lipoprotein-apoprotein B is increased by substitution of soybean protein for meat and dairy protein in the diets of hypercholesterolemic men.

The effect of dietary protein source on the kinetics of plasma very low-density lipoprotein (VLDL) (Sf 60 to 400) in hypercholesterolemic men was investigated. Using a crossover design, five subjects received sequentially either 1) a high polyunsaturated fat, low cholesterol control diet containing mixed protein from meat, dairy products, and plant sources or 2) an all-plant protein experimental diet in which the meat and dairy protein of the former diet was replaced by soybean protein and soy milk. There was no significant change in the mean values for fasting serum cholesterol and triglycerides over the 6-wk period of administration of the control versus experimental diets. The kinetics of VLDL (Sf 60 to 400) apolipoprotein B were studied at the end of each dietary period after reinjection of 125I-labeled autologous VLDL (Sf 60 to 400). The VLDL apolipoprotein B pool size was similar during the experimental and control protocols; however, the fractional catabolic rate was consistently higher during the experimental protocol (8.5 +/- 1.3 versus 6.5 +/- 1.2 day-1, p less than 0.01) and the production rate of apoprotein B was higher than control in four of five subjects (mean values 18.6 +/- 3 versus 12.6 +/- 1 mg/day/kg, respectively). Administration of an all-plant protein diet significantly increased the fractional turnover rate of VLDL apolipoprotein B, even when no changes in VLDL ago B pool size or VLDL lipid concentrations were observed.

Adult↗
PubMed1982

Changes in the plasma lipoprotein distribution of apolipoproteins C-II, C-III1, C-III2 and apolipoprotein B after heparin-induced lipolysis.

The group of C apolipoproteins are involved in the catabolism of triacylglycerol-rich lipoproteins, C-II activating triacyglycerol lipolysis and C-III possibly preventing premature removal of the particle. In normal subjects, C-II, C-III1 and C-III2 exchange between very low density (VLDL) and high density lipoprotein (HDL) at similar rates and catabolism appears to occur with HDL. In the present studies in one normal and in four subjects with moderate-to-severe hypertriglyceridemia, the metabolism of the C apolipoproteins was studied before and during maximal lipolysis induced with heparin. Radioiodinated triacylglycerol-rich lipoproteins were injected and the specific activity-time curves for C-II, C-III1, C-III2 and B proteins were analyzed in triacylglycerol-rich lipoproteins and HDL. Heparin infusion caused rapid and proportional transfer of each C apolipoprotein from triacylglycerol-rich lipoproteins to HDL. In the two most hyperlipemic men, a substantial fraction (over 90%) of apolipoprotein C mass lost from triacylglycerol-rich lipoproteins was not recoverable in HDL, whereas in the normal subject this was less than 15% and intermediate in the other two hypertriglyceridemic men. This indicates a new potential catabolic pathway for C apolipoproteins, direct loss from the circulation during remnant particle removal, which was also evident from B apolipoprotein studies. Furthermore, unlike in the normal subject transfer of C apolipoprotein radioactivity from triacylglycerol-rich lipoproteins to HDL was greater than that of mass, also suggesting heterogeneity in C apolipoprotein catabolism. The studies show that C apolipoprotein metabolism may be disturbed in severely hypertriglyceridemic subjects: the lack of conservation of these proteins within HDL may exacerbate the degree of hyperlipoproteinemia.

Adult↗
PubMed1982

Metabolism of apolipoproteins CII, CIII1, CIII2 and VLDL-B in human subjects consuming high carbohydrate diets.

Simultaneous kinetics of apoproteins CII, CIII1 and CIII2 and VLDL-B were determined in six normal subjects initially while consuming a control diet and subsequently while consuming a high carbohydrate diet. Mean triglyceride levels in plasma and VLDL were significantly increased, from 110 to 173 mg/dl and 40 to 114 mg/dl respectively, by the high carbohydrate diet. Specific radioactivity of each C peptide was determined, following injection of 125I-VLDL, in both VLDL and HDL from plasma samples taken over 48 hr using a technique involving analytical isoelectric focusing. Specific activity vs time curves for VLDL and HDL were almost superimposable on either diet, suggesting that CII, CIII1 and CIII2 were catabolized as a group. The high carbohydrate diet resulted in a significant increase in the mass of each C peptide which was brought about by an increase in production since no change in fractional removal rate (FRR) was observed. The pool size of VLDL apo B was also significantly increased and was a function of both increased production as well as decreased FRR. The proportion of CIII2 mass relative to those of CII and CIII1 was lower in both VLDL and HDL with the high carbohydrate diet. These observations indicate that the metabolism of the B and C apoproteins are independent of each other and do not respond in the same manner to changes in VLDL triglyceride and that increased triglyceride synthesis and secretion stimulates C apoprotein production.

Apolipoprotein C-II↗
PubMed1981

Metabolism of C-apolipoproteins: kinetics of C-II, C-III1 and C-III2, and VLDL-apolipoprotein B in normal and hyperlipoproteinemic subjects.

The turnover and metabolism of the individual C apolipoproteins (C-II, C-III1, and C-III2) were studied following the injection of 125I-labeled VLDL into 15 normal and hyperlipoproteinemic subjects. The C apolipoproteins from very low density lipoprotein (VLDL) and high density lipoprotein (HDL) were separated by analytical isoelectric focusing, and subsequent densitometric scanning and radioassay of the stained bands yielded values for specific activity. In 13 of 15 subjects, kinetics of C-II, C-III1, and C-III2 were best described by a one-pool model, whereas two subjects showed biexponential kinetics. The specific activity-time curves for VLDL and HDL were super-imposable, indicating rapid exchange of all C apolipoproteins in hyperlipidemic as well as in normal subjects. In each subject the half-life was similar for C-II, C-III1, and C-III2, which suggests similar synthesis and catabolic mechanisms for each C apolipoprotein. The mass of exchangeable C-II (range 1.0-5.8 mg/kg), C-III1 (2.6-20 mg/kg), and C-III2 (2.0-13 mg/kg) increased with plasma triglyceride concentrations. Values for flux of C-II were 1.0-2.8 mg/d per kg, for C-III1 1.6-5.6 mg/d per kg, and for C-III2 1.2-3.1 mg/d per kg, but they were not related to levels of plasma triglyceride. However the irreversible fractional catabolic rates were inversely related to C apolipoprotein (and triglyceride) mass, suggesting that expansion in C apolipoprotein pool size is related to slower removal, due to the longer residence time of triglyceride-rich VLDL particles in plasma. This was confirmed by similar findings for B apolipoprotein kinetics in VLDL carried out simultaneously.

Adult↗
PubMed1980

Effects of dietary proteins and amino acid mixtures on plasma cholesterol levels in rabbits.

Amino acid mixtures corresponding to either casein or egg yolk protein when fed to rabits ina low fat, cholesterol-free semipurified diet, produced the same degree of hypercholesterolemia as the proteins themselves. Amino acid mixtures corresponding to soy protein isolate or sunflower protein gave low plasma cholesterol levels, but not as low as those obtained with the intact proteins. Experiments were designed to identify amino acids responsible for the differential in plasma cholesterol produced by casein or soy protein amino acid mixtures. Plasma cholesterol levels obtained with a casein amino acid mixture containing half the amounts of essential amino acids were significantly higher than he corresponding soy protein mixture. Feeding trials based on systematic modifications to the casein and soy protein mixtures indicated that interaction between essential and non-essential amino acids was important in determining plasma cholesterol levels. In further experiments, protein components were formulated by adding amino acids to casein to give a mixture corresponding to soy proteins, or by adding amino acids to soy protein, or by adding amino acids to soy protein to give a mixture equivalent to casein. These diets failed to reverse plasma cholesterol levels which suggests differences in digestion and absorption of proteins relative to amino acid mixtures.

Amino Acids↗
PubMed1980

Effects of dietary protein on turnover, oxidation, and absorption of cholesterol, and on steroid excretion in rabbits.

Rabbits fed a low fat, cholesterol-free, semipurified diet containing casein became hypercholesterolemic (congruent to 300 mg/dl) after 5 weeks on diet. Rabbits on a similar diet containing soy protein isolate had low plasma cholesterols comparable to those on commercial feed (40--60 mg/dl). Cholesterol turnover, which conformed to a two-pool model, were determined by analysis of the decay of plasma cholesterol specific activity after a single intravenous injections of [26-14C]cholesterol. Rabbits on the soy protein diet or commercial feed showed a much faster rate of cholesterol turnover and a reduced size of pool A compared to rabbits on the casein diet. They also oxidized [26-14C]cholesterol to respiratory 14CO2 at much faster rates. Analysis of fecal steroid by gas--liquid chromatography indicated that bile acid and neutral steroid excretion was increased on the soy protein and commercial diets, relative to the casein diet. Cholesterol was absorbed to a greater extent on the casein diet. Addition of 15% (w/w) butter to the semipurified diets had little effect on the above parameters of cholesterol metabolism. Comparison of cholesterol turnover measured by kinetic analysis, combined sterol balance, or analysis of fecal steroids by gas--liquid chromatography, showed that all three methods gave similar results. Measurement of bile acid production by oxidation of [26-14C]cholesterol to respiratory 14CO2 also gave results comparable to those obtained by analysis of fecal bile acids.

Animals↗
PubMed1979

Plasma lipoprotein changes in suckling and weanling rabbits fed semipurified diets.

The distribution and composition of the plasma lipoproteins were studied in suckling rabbits and in rabbits either weaned to or fed as young adults cholesterol-free, semipurified diets containing protein of animal (casein) or plant (soy protein isolate) origin. The raised cholesterol levels of the suckling period resulted in an increase of very low density and intermediate density lipoproteins in a making similar to that seen in adult rabbits fed a high fat diet supplemented with cholesterol. Young rabbits fed the cholesterol-free, semipurified, diet containing casein also became hypercholesterolemic but, in this case, the increased cholesterol was found primarily in lipoproteins of intermediate density. Cholesterol levels remained low in those rabbits fed the soy protein isolate diet, and the lipoprotein distribution was somewhat similar to that of chow-fed animals. It appears that the raised cholesterol levels during the suckling period result in different lipoprotein patterns to those produced in young adult animals by a cholesterol-free, semipurified diet.

Aging↗
PubMed1979

Influence of diet on plasma cholesterol concentrations in suckling and weanling rabbits.

Rabbits were weaned to different semipurified diets to determine which characteristics of the diet were required to maintain the hypercholesterolemia of the suckling period. Gradual weaning to a diet similar in fat, cholesterol, protein and carbohydrate content to rabbit milk maintained and enhanced the hypercholesterolemia. Reduction of the cholesterol content, and to some extent the fat content of this diet, decreased the plasma cholesterol level, but the type of dietary protein did not alter the results. After weaning, however, animals fed milk protein (casein) in the absence of dietary cholesterol became hypercholesterolemic, whereas those fed plant protein (soy protein isolate) remained normocholesterolemic.

Animal Population Groups↗
PubMed1978

Dietary fiber and cholesterol metabolism in rabbits and rats.

Rabbits fed semipurified diets have elevated plasma cholesterol levels, and they oxidize [26-14C]cholesterol to expired 14CO2 more slowly than rabbits on a natural ingredient diet. Addition of several different types of fibrous material to a semipurified diet failed to prevent the hypercholesterolemic response. Rats on semipurified diets also oxidized [26-14C]cholesterol more slowly and tended to have somewhat higher plasma cholesterol levels than rats on commercial feed. Cholesterol oxidation was not stimulated by addition of fibrous materials to the semipurified diet, but rats fed a semipurified diet containing raw potato starch oxidized cholesterol at a rate comparable to that of rats on commercial diet. Raw potato starch was poorly digested by the rats. Cooked potato starch was well digested and failed to stimulate the rate of oxidation of cholesterol. A semipurified diet containing raw potato starch did not produce a hypercholesterolemic response in rabbits, even though the raw starch was well digested.

Animal Feed↗
PubMed1978

Hypocholesterolemic effect of substituting soybean protein for animal protein in the diet of healthy young women.

The effect of dietary protein on the level of plasma cholesterol in young, healthy, normolipidemic women was investigated in two separate studies by feeding either a conventional diet containing mixed protein, or a plant protein diet in which the animal protein of the first diet was replaced by soy protein meat analogues and soy milk. The diets were similar with respect to carbohydrate, fat and sterol composition. The first study, lasting 73 days and involving six subjects, gave an indication that plasma cholesterol levels were lower on the plant protein diet. The second study, which incorporated a number of improvements based on experience, lasted 78 days and used a cross-over design involving two groups of five subjects each. In this study, the mean plasma cholesterol level was found to be significantly lower on the plant protein diet.

Adult↗