Evidence for increased synthesis of lipoprotein(a) in the nephrotic syndrome.

1998 ◽  
Vol 9 (8) ◽  
pp. 1474-1481
Author(s):  
M G De Sain-Van Der Velden ◽  
D J Reijngoud ◽  
G A Kaysen ◽  
M M Gadellaa ◽  
H Voorbij ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Synthesis Rate ◽  
Fractional Synthesis Rate ◽  
Lipoprotein A ◽  
Control Subjects ◽  
Apolipoprotein A ◽  
Catabolic Rate ◽  
Fractional Synthesis ◽  
The Mean

In patients with the nephrotic syndrome, markedly increased levels of lipoprotein(a) (Lp(a)) concentration have been frequently reported, and it has been suggested that this may contribute to the increased cardiovascular risk in these patients. The mechanism, however, is not clear. In the present study, in vivo fractional synthesis rate of Lp(a) was measured using incorporation of the stable isotope 13C valine. Under steady-state conditions, fractional synthesis rate equals fractional catabolic rate (FCR). FCR of Lp(a) was estimated in five patients with the nephrotic syndrome and compared with five control subjects. The mean plasma Lp(a) concentration in the patients (1749+/-612 mg/L) was higher than in control subjects (553+/-96 mg/L). Two patients were heterozygous for apolipoprotein(a) (range, 19 to 30 kringle IV domains), whereas all control subjects were each homozygous with regard to apolipoprotein(a) phenotype (range, 18 to 28 kringle IV domains). The FCR of Lp(a) was comparable between control subjects (0.072+/-0.032 pools/d) and patients (0.064+/-0.029 pools/d) despite the wide variance in plasma concentration. This suggests that differences in Lp(a) levels are caused by differences in synthesis rate. Indeed, the absolute synthetic rate of Lp(a) correlated directly with plasma Lp(a) concentration (P < 0.0001) in all subjects. The present results demonstrate that increased synthesis, rather than decreased catabolism, causes elevated plasma Lp(a) concentrations in the nephrotic syndrome.

scholarly journals Lipoprotein(a) in the Nephrotic Syndrome

2000 ◽  
Vol 11 (3) ◽  
pp. 507-513
Author(s):  
CHANTAL DOUCET ◽  
VINCENT MOOSER ◽  
SOPHIE GONBERT ◽  
FRANÇOISE RAYMOND ◽  
JOHN CHAPMAN ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Plasma Concentrations ◽  
Lipoprotein A ◽  
Control Subjects ◽  
Large N ◽  
Catabolic Rate ◽  
Atherogenic Particle ◽  
Normal Urine ◽  
And Control

Abstract. Plasma levels of lipoprotein(a) (Lp(a)), an atherogenic particle, are elevated in kidney disease, which suggests a role of this organ in the metabolism of Lp(a). Additional evidence for a role of the kidney in the clearance of Lp(a) is provided by the fact that circulating N-terminal fragments of apolipoprotein(a) (apo(a)) are processed and eliminated by the renal route. To further understand the mechanism underlying such renal excretion, the levels of apo(a) fragments in plasma and urine relative to plasma Lp(a) levels were determined in patients with nephrotic syndrome (n = 15). In plasma, the absolute (24.7 ± 20.4 versus 2.16 ± 2.99 μg/ml, P < 0.0001) as well as the relative amounts of apo(a) fragments (4.6 ± 3.4% versus 2.1 ± 3.3% of total Lp(a), P < 0.0001) were significantly elevated in nephrotic patients compared with a control, normolipidemic population. In addition, urinary apo(a) excretion in patients with nephrotic syndrome was markedly elevated compared with that in control subjects (578 ± 622 versus 27.7 ± 44 ng/ml per mg creatinine, P < 0.001). However, the fractional catabolic rates of apo(a) fragments were similar in both groups (0.68 ± 0.67% and 0.62 ± 0.47% in nephrotic and control subjects, respectively), suggesting that increased plasma concentrations of apo(a) fragments in nephrotic subjects are more dependent on the rate of synthesis rather than on the catabolic rate. Molecular analysis of apo(a) immunoreactive material in urine revealed that the patterns of apo(a) fragments in nephrotic patients were distinct from those of control subjects. Full-length apo(a), large N-terminal apo(a) fragments similar in size to those present in plasma, as well as C-terminal fragments of apo(a) were detected in urine from nephrotic patients but not in urine from controls. All of these apo(a) forms were in addition to smaller N-terminal apo(a) fragments present in normal urine. This study also demonstrated the presence of Lp(a) in urine from nephrotic patients by ultracentrifugal fractionation. These data suggest that in nephrotic syndrome, Lp(a) and large fragments of apo(a) are passively filtered by the kidney through the glomerulus, whereas smaller apo(a) fragments are secreted into the urine.

scholarly journals Transferrin Synthesis Is Increased in Nephrotic Patients Insufficiently to Replace Urinary Losses

2001 ◽  
Vol 12 (5) ◽  
pp. 1017-1025
Author(s):  
BERTHIL H. C. M. T. PRINSEN ◽  
MONIQUE G. M. DE SAIN-VAN DER VELDEN ◽  
GEORGE A. KAYSEN ◽  
HELMA W. H. C. STRAVER ◽  
HERMAN J. M. VAN RIJN ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Iron Concentration ◽  
Microcytic Anemia ◽  
Synthesis Rate ◽  
Albumin Synthesis ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Control Subjects ◽  
General Response

Abstract. The urinary loss of transferrin is sufficient to reduce plasma transferrin concentrations in the nephrotic syndrome. Hypotransferrinemia may lead to iron loss and microcytic anemia. The mechanism responsible for the hypotransferrinemia in the nephrotic syndrome is, however, unknown. In the present study, synthesis rate of transferrin was measured in vivo in nephrotic patients (n = 7) compared with control subjects (n = 6) using L-[1-13C]-valine. Plasma transferrin and iron concentration in the patients were significantly lower than in control subjects (transferrin, 1.39 ± 0.08 versus 2.57 ± 0.11 g/L, P < 0.0001; iron, 10.2 ± 0.8 versus 21.1 ± 4.5 μmol/L, P = 0.02). Furthermore, albuminuria correlated with transferrinuria (r2 = 0.901, P = 0.001). The absolute synthesis rate of transferrin was increased in the patients (10.0 ± 1.1 versus 7.4 ± 0.7 mg/kg per d, P = 0.07), although this value failed to achieve significance. C-reactive protein, plasma iron, and proteinuria did not correlate with transferrin synthesis. In contrast, transferrin synthesis correlated with albumin synthesis (r2 = 0.648, P = 0.03; n = 7). The present study indicates that increased transferrin synthesis occurs in nephrotic patients but is insufficient to compensate for urinary losses. Because, overall, no significant relationship was found between transferrin synthesis and either C-reactive protein or iron, it is unlikely that inflammation suppresses or that iron deficiency stimulates increased transferrin synthesis in these patients. The correlation between transferrin synthesis and albumin synthesis suggests that transferrin synthesis is a component of a general response in hepatic protein synthesis in the nephrotic syndrome. This suggests that a therapeutic approach to maximize plasma transferrin concentrations in nephrotic patients should be aimed primarily at reducing urinary protein excretion.

scholarly journals Comparison of bolus injection and constant infusion methods for measuring muscle protein fractional synthesis rate in humans

Metabolism ◽  
2014 ◽  
Vol 63 (12) ◽  
pp. 1562-1567 ◽  
Author(s):  
Demidmaa Tuvdendorj ◽  
David L. Chinkes ◽  
John Bahadorani ◽  
Xiao-jun Zhang ◽  
Melinda Sheffield-Moore ◽  
...  
Keyword(s):  
Bolus Injection ◽  
Muscle Protein ◽  
Constant Infusion ◽  
Synthesis Rate ◽  
Fractional Synthesis Rate ◽  
Fractional Synthesis

scholarly journals Synthesis rate of plasma albumin is a good indicator of liver albumin synthesis in sepsis

2000 ◽  
Vol 279 (2) ◽  
pp. E244-E251 ◽  
Author(s):  
Benoît Ruot ◽  
Denis Breuillé ◽  
Fabienne Rambourdin ◽  
Gerard Bayle ◽  
Pierre Capitan ◽  
...  
Keyword(s):  
Synthesis Rate ◽  
Albumin Concentration ◽  
Liver Protein ◽  
Mrna Levels ◽  
Albumin Synthesis ◽  
Plasma Albumin ◽  
Period 2 ◽  
Fractional Synthesis ◽  
Plasma Albumin Concentration

Plasma albumin is well known to decrease in response to inflammation. The rate of albumin synthesis from both liver and plasma was measured in vivo by use of a large dose ofl-[2H3-14C]valine in rats injected intravenously with live Escherichia coli and in pair-fed control rats during the acute-phase period (2 days postinfection). The plasma albumin concentration was reduced by 50% in infected rats compared with pair-fed animals. Infection induced a fall in both liver albumin mRNA levels and albumin synthesis relative to total liver protein synthesis. However, absolute liver albumin synthesis rate (ASR) was not affected by infection. In plasma, albumin fractional synthesis rate was increased by 50% in infected animals compared with pair-fed animals. The albumin ASR estimated in the plasma was similar in the two groups. These results suggest that hypoalbuminemia is not due to reduced albumin synthesis during sepsis. Moreover, liver and plasma albumin ASR were similar. Therefore, albumin synthesis measured in the plasma is a good indicator of liver albumin synthesis.

scholarly journals Effect of ursodeoxycholic acid on lipid metabolism: through the prism of evidence from 2019.

2020 ◽  
Vol 46 (1) ◽  
pp. 83-88
Author(s):  
N. B. Gubergrits ◽  
N.V. Byelyayeva ◽  
T. L. Mozhyna ◽  
G. M. Lukashevich ◽  
P. G. Fomenko
Keyword(s):  
Lipid Metabolism ◽  
Bile Acid ◽  
Bile Acids ◽  
De Novo ◽  
Gallstone Disease ◽  
Farnesoid X Receptor ◽  
Synthesis Rate ◽  
Primary Biliary Cholangitis ◽  
Fractional Synthesis Rate ◽  
Fractional Synthesis

After the discovery of the method of ursodeoxycholic acid’s (UDCA) synthesis and the publication of evidence confirming its ability to reduce the lithogenic properties of bile, active clinical use of UDCA began in the world. This drug, which has pleiotropic effect (choleretic, cytoprotective, immunomodulatory, antiapoptic, litholytic, hypocholesterolemic), has proven its effectiveness in the treatment various diseases: primary biliary cholangitis, intrahepatic cholestasis of pregnancy, gallstone disease. Being a tertiary bile acid, UDCA stimulates bile acid synthesis by reducing the circulating fibroblast growth factor 19 and inhibiting the activation of the farnesoid X-receptor (FXR), which leads to the induction of cholesterol-7α-hydroxylase, a key enzyme in the synthesis of bile acid de novo, mediating the conversion of cholesterol into bile acids. Changes in the formation of bile acids and cholesterol while taking UDCA intake is accompanied by activation of the main enzyme of cholesterol synthesis - 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Under the influence of UDCA the activity of stearoyl-Coa desaturase (SCD) in visceral white adipose tissue increases. According to studies conducted in 2019, UDCA improves lipid metabolism by regulating the activity of the ACT/mTOR signaling pathway, reduces the synthesis of cholesterol, decreases the fractional synthesis rate of cholesterol and the fractional synthesis rate of triglycerides. It has been proved that UDCA is accompanied by a decrease in the level of total cholesterol and low density lipoprotein cholesterol.

Albumin synthesis in humans increases immediately following the administration of endotoxin

2002 ◽  
Vol 103 (5) ◽  
pp. 525-531 ◽  
Author(s):  
Hans BARLE ◽  
Anna JANUSZKIEWICZ ◽  
Lars HÅLLSTRÖM ◽  
Pia ESSÉN ◽  
Margaret A. MCNURLAN ◽  
...  
Keyword(s):  
Intravenous Injection ◽  
Early Phase ◽  
The Other ◽  
Synthesis Rate ◽  
Control Group ◽  
Albumin Synthesis ◽  
Fractional Synthesis Rate ◽  
Before And After ◽  
Fractional Synthesis ◽  
Absolute Synthesis

In order to investigate the immediate (i.e. within 3h) response of albumin synthesis to the administration of endotoxin, as a model of a moderate and well controlled catabolic insult, two measurements employing L-[2H5]phenylalanine were performed in 16 volunteers. One group (n = 8) received an intravenous injection of endotoxin (4ng/kg; lot EC-6) immediately after the first measurement of albumin synthesis, whereas the other group received saline. A second measurement was initiated 1h later. In the endotoxin group, the fractional synthesis rate of albumin was 6.9±0.6%/day (mean±S.D.) in the first measurement. In the second measurement, a significant increase was observed (9.6±1.2%/day; P<0.001). The corresponding values in the control group were were 6.6±0.6%/day and 7.0±0.6%/day respectively (not significant compared with first measurement and P<0.001 compared with the second measurement in the endotoxin group). The absolute synthesis rates of albumin were 148±35 and 201±49mg·kg-1·day-1 before and after endotoxin (P<0.01). In the control group, the corresponding values were 131±21 and 132±20mg·kg-1·day-1 (not significant compared with the first measurement and P<0.01 compared with the second measurement in the endotoxin group). In conclusion, these results indicate that albumin synthesis increases in the very early phase after a catabolic insult, as represented by the administration of endotoxin.

PCSK9 inhibition with alirocumab reduces lipoprotein(a) levels in nonhuman primates by lowering apolipoprotein(a) production rate

2018 ◽  
Vol 132 (10) ◽  
pp. 1075-1083 ◽  
Author(s):  
Mikaël Croyal ◽  
Thi-Thu-Trang Tran ◽  
Rose Hélène Blanchard ◽  
Jean-Christophe Le Bail ◽  
Elise F. Villard ◽  
...  
Keyword(s):  
Production Rate ◽  
Nonhuman Primates ◽  
Numerical Models ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Human Hepatocytes ◽  
Lipoprotein A ◽  
Apolipoprotein A ◽  
Pcsk9 Inhibition

Therapeutic antibodies targeting proprotein convertase subtilisin kexin type 9 (PCSK9) (e.g. alirocumab) lower low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] levels in clinical trials. We recently showed that PCSK9 enhances apolipoprotein(a) [apo(a)] secretion from primary human hepatocytes but does not affect Lp(a) cellular uptake. Here, we aimed to determine how PCSK9 neutralization modulates Lp(a) levels in vivo. Six nonhuman primates (NHP) were treated with alirocumab or a control antibody (IgG1) in a crossover protocol. After the lowering of lipids reached steady state, NHP received an intravenous injection of [2H3]-leucine, and blood samples were collected sequentially over 48 h. Enrichment of apolipoproteins in [2H3]-leucine was assessed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Kinetic parameters were calculated using numerical models with the SAAMII software. Compared with IgG1, alirocumab significantly reduced total cholesterol (TC) (−28%), LDL-C (−67%), Lp(a) (−56%), apolipoprotein B100 (apoB100) (−53%), and apo(a) (−53%). Alirocumab significantly increased the fractional catabolic rate of apoB100 (+29%) but not that of apo(a). Conversely, alirocumab sharply and significantly reduced the production rate (PR) of apo(a) (−42%), but not significantly that of apoB100, compared with IgG1, respectively. In line with the observations made in human hepatocytes, the present kinetic study establishes that PCSK9 neutralization with alirocumab efficiently reduces circulating apoB100 and apo(a) levels by distinct mechanisms: apoB primarily by enhancing its catabolism and apo(a) primarily by lowering its production.

scholarly journals The effects of breed and level of nutrition on whole-body and muscle protein metabolism in pure-bred Aberdeen Angus and Charolais beef steers

2000 ◽  
Vol 84 (3) ◽  
pp. 275-284 ◽  
Author(s):  
G. E. Lobley ◽  
K. D. Sinclair ◽  
C. M. Grant ◽  
L. Miller ◽  
D. Mantle ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Metabolism ◽  
Muscle Protein ◽  
Live Weight ◽  
Whole Body ◽  
Synthesis Rate ◽  
Eating Quality ◽  
Eye Muscle ◽  
Fractional Synthesis Rate ◽  
Fractional Synthesis

Eighteen pure-bred steers (live weight 350 kg) from each of two breeds, Aberdeen Angus (AA) and Charolais (CH), were split into three equal groups (six animals each) and offered three planes of nutrition during a 20-week period. The same ration formulation was offered to all animals with amounts adjusted at 3-week intervals to give predicted average weight gains of either 1·0 kg/d (M/M group) or 1·4 kg/d (H/H group). The remaining group (M/H) were offered the same amount of ration as the M/M group until 10 weeks before slaughter when the ration was increased to H. Data on animal performance, carcass characteristics and fibre-type composition in skeletal muscle are presented elsewhere (; ). On three occasions (17, 10 and 2 weeks before slaughter) the animals were transferred to metabolism stalls for 1 week, during which total urine collection for quantification of Nτ-methylhistidine (Nτ-MeH) elimination was performed for 4 d. On the last day, animals were infused for 11 h with [2H5] phenylalanine with frequent blood sampling (to allow determination of whole-body phenylalanine flux) followed by biopsies from m. longissimus lumborum and m. vastus lateralis to determine the fractional synthesis rate of mixed muscle protein. For both breeds, the absolute amount of Nτ-MeH eliminated increased with animal age or weight (P < 0·001) and was significantly greater for CH steers, at all intake comparisons, than for AA (P < 0·001). Estimates of fractional muscle breakdown rate (FBR; calculated from Nτ-MeH elimination and based on skeletal muscle as a fixed fraction of live weight) showed an age (or weight) decline for M/M and H/H groups of both breeds (P < 0·001). FBR was greater for the H/H group (P = 0·044). The M/H group also showed a lower FBR for the first two measurement periods (both at M intake) but increased when intake was raised to H. When allowance was made for differences in lean content (calculated from fat scores and eye muscle area in carcasses at the end of period 3), there were significant differences in muscle FBR with intake (P = 0·012) but not between breed. Whole-body protein flux (WBPF; g/d) based on plasma phenylalanine kinetics increased with age or weight (P < 0·001) and was similar between breeds. The WBPF was lower for M/M compared with H/H (P < 0·001) based on either total or per kg live weight0·75. Muscle protein fractional synthesis rate (FSR) declined with age for both breeds and tended to be higher at H/H compared with M intakes (intake × period effects, P < 0·05). Changing intake from M to H caused a significant increase (P < 0·001) in FSR. The FSR values for AA were significantly greater than for CH at comparable ages (P = 0·044). Although FSR and FBR responded to nutrition, these changes in protein metabolism were not reflected in differences in meat eating quality (Sinclair et al. 2000).

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