Top PDF Studies on cholesterol and bile acid metabolism in relation to plasma lipoproteins

Studies on cholesterol and bile acid metabolism in relation to plasma lipoproteins

Studies on cholesterol and bile acid metabolism in relation to plasma lipoproteins

The cellular mechanisms by which apoB containing lipoproteins, chylomicrons and VLDLs, are assembled are similar. However, intestinal apoB is made as a truncated form, apoB48, which is 48% of the full-length protein expressed in the liver referred to as apoB100. ApoB48 cannot bind to the LDL receptor (LDLR). The assembly of apoB containing lipoproteins is not fully defined, but three components are recognized as necessary; apoB, microsomal transfer protein (MTP), and lipids that form the neutral lipid core and membrane. The main site of regulation of assembly is believed to be degradation of the nascent apoB polypeptide [3, 6, 7]. It has been suggested that enterocytes and hepatocytes may have different methods of apoB stabilization. As the apoB protein is translated by ribosomes it crosses into the ER, and triglycerides are added co-translationally to the elongating apoB protein (ie apoB is lipidated). To further promote lipoprotein formation MTP also shuttles cholesteryl esters and phospholipids [3]. Mature chylomicrons are released into the lymph, from where they will reach the systemic blood. Each chylomicron and VLDL particle contains one single molecule of apoB. ApoB is a non-exchangeable apoprotein and remains with the lipoprotein particle until the particle is removed from the circulation through cellular uptake. The primary function of apoB containing lipoproteins is to deliver fatty acids in the form of triglycerides to muscle for ATP biogenesis and to adipose tissue for long term storage.
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High dietary cholesterol and ovariectomy in rats repress gene expression of key markers of VLDL and bile acid metabolism in liver

High dietary cholesterol and ovariectomy in rats repress gene expression of key markers of VLDL and bile acid metabolism in liver

Furthermore, we investigated the gene expression of molecular markers of bile acids metabolism/transport, a pathway that is tightly associated with elimination of cholesterol from the liver. These included ATP-cassette binding protein G5 and G8 (Abcg5/Abcg8) that export cholesterol from hepatocytes to the bile duct, bile salt ex- port pump (Bsep) and multidrug resistance-associated transporter 2 (Mdr2) which stimulate bile acid and phospholipid transport from hepatocytes to bile canaliculi, Na + −taurocholate cotransporting polypeptide (Ntcp) in- volved in bile acid uptake in the basolateral membrane of the hepatocytes, farnasoid X receptor (Fxr) a nuclear re- ceptor involved in regulation of hepatic bile acid biosyn- thesis, and cytochrome P450 7A1 (Cyp7a1) the main enzyme that catalyses the conversion of cholesterol into bile acids. Finally, we complemented our approach by investigating the response of hepatic LDL-receptor (Ldl-r), a major determinant of removal of LDL- cholesterol particles from the circulation, LDL receptor- related protein-1 (Lrp-1) involved in the removal of plasma remnant lipoproteins [16, 17], and sterol regula- tory element-binding protein-2 (Srebp2) a transcription factor involved in the regulation of cholesterol.
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Genetics and genomics of cholesterol and polyunsaturated fatty acid metabolism in relation to coronary heart disease risk

Genetics and genomics of cholesterol and polyunsaturated fatty acid metabolism in relation to coronary heart disease risk

Bile acid and bile metabolism and plasma cholesterol BA transporters are now understood to play central roles in driving bile flow. The pathophysiological consequences of genetic mutations and polymorphisms in these genes encoding BA transporters have been reviewed recently (80, 85). The effect of genetic variation in SLCO1B1 on statin-mediated cholesterol lowering efficacy has recently been highlighted (94-97). SLCO1B1 encodes OATP1B1, one of the organic anion transporting polypeptides (OATP) expressed on the hepatic sinusoidal membrane and facilitating the uptake of BAs and also statin-class drugs (34, 80, 85). A number of polymorphisms and haplotypes have been identified in SLCO1B1 to affect the pharmacokinetic profiles of the statin-class drugs (98). Two small candidate gene studies conducted in eastern Asian subjects and one GWA study conducted in Caucasian subjects consistently reported that carriers of the C allele for rs4149056 (c.521T>C, V174A) had less reduction of total or LDL cholesterol levels with statin treatment compared to TT homozygotes (94, 95, 97). This could be explained by less efficient uptake of pravastatin, atorvastatin or simvastatin into hepatocytes in the C allele carriers compared to the TT homozygotes (97, 98). This reduced uptake of statins also explained the high risk of myopathy in the C allele carriers due to elevated systemic exposure to simvastatin in high dose users (80 mg simvastatin/day) (97). The V174A variation is predicted to be functionally ‘damaging’ in both SIFT and PloyPhen (99, 100), explaining the limited hepatic uptake of statins. The C allele of another SNP in SLCO1B1, rs11045819 (c.463C>A, P155T), is also reported to be associated with less total and LDL cholesterol reduction compared to AA genotypes in 420 elderly hypercholesterolemic French subjects after extended-release fluvastatin treatment (96). As reviewed by Lefebvre et al. (34), BAs affect HDL cholesterol levels in both human and animal studies. Given the pivotal role of BSEP in generating bile flow (34, 85), and also the results of recent meta-analysis of seven GWA studies (Supplement table 1 and 2), common genetic variants in BSEP could affect plasma HDL cholesterol levels relatively strongly.
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Effects of dietary cholesterol on cholesterol and bile acid homeostasis in patients with cholesterol gallstones

Effects of dietary cholesterol on cholesterol and bile acid homeostasis in patients with cholesterol gallstones

cholesterol in gallstone subjects and matched controls. Healthy women were recruited and, after confirming the presence or absence of radiolucent gallstones, they were studied on regular diets and again on the same diet supplemented with five eggs daily for 15-18 d. Studies included plasma lipids, lipoproteins and apolipoproteins, dietary records,

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Metabolism of apoprotein B of plasma very low density lipoproteins in the rat

Metabolism of apoprotein B of plasma very low density lipoproteins in the rat

As an extension of metabolic studies of the cholesteryl ester component of rat very low density lipoproteins, we have studied the metabolism of the B apoprotein component labeled by intravenous injection of [3H]lysine. The B apoprotein separated from other apoproteins by delipidation and selective precipitation with tetramethylurea could not be distinguished from B apoprotein prepared by the conventional gel filtration technique. After injection of [3H]lysine, specific activity of B apoprotein was maximal in very low density and low density lipoproteins 1 and 11/2-h later, respectively, in a manner consistent with a precursor-product relationship. When protein-labeled very low density lipoproteins were injected into rats, the relationships of specific activity again indicated that B apoprotein of very low density lipoproteins may be the sole precursor of that of low density lipoproteins. However, less than 10% of the B apoprotein that disappeared from very low density lipoproteins appeared in density lipoproteins. To evaluate the sites of removal of B
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Influence of age on the metabolism of plasma low density lipoproteins in healthy males

Influence of age on the metabolism of plasma low density lipoproteins in healthy males

comparison, they were divided into three age groups: young, 21-39 yr (n = 18), middle-aged, 40-59 yr (n = 11), and old, 60-80 yr (n = 12). The levels of plasma LDL cholesterol and LDL apo B increased from respectively 3.4 +/- 0.1 (SEM) mmol/liter and 86 +/- 2 mg/dl in the young to 4.1 +/- 0.1 mmol/liter and 95 +/- 3 mg/dl in the old (P less than 0.01), and this increase was linked to a progressively decreased (r = -0.38, P less than 0.02) fractional catabolic rate of LDL apo B (0.348 +/- 0.010 pools per day in the young vs. 0.296 +/- 0.009 pools per day in the old, P less than 0.01). The production rate of LDL apo B did not differ significantly between the groups. The reduced fractional catabolic rate of LDL apo B in the old was not associated with a decrease in binding affinity of the LDL particle to its receptor, as judged from its ability to compete for 125I-LDL fibroblast binding. When hepatic LDL receptor expression was stimulated by cholestyramine treatment in six old […]
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MAFG Is a Transcriptional Repressor of Bile Acid Synthesis and Metabolism

MAFG Is a Transcriptional Repressor of Bile Acid Synthesis and Metabolism

The MafG-dependent repression of Cyp8b1 suggests that MAFG may regulate the synthesis of cholic acid and alter the bile acid pool composition. To determine whether MAFG overex- pression could indeed change the biliary pool composition, we treated a new cohort of mice with either Ad-control or Ad- MafG adenovirus. Changes in the composition of the bile acid pool are relatively slow under normal conditions, since only 5% of the bile acids are excreted each day during multiple enterohe- patic cycles ( de Aguiar Vallim et al., 2013a; Hofmann and Hagey, 2008 ). Consequently, we fed mice either control diet (chow) or the same diet supplemented with a bile acid sequestrant (0.25% Colesevelam/Welchol) for 7 days prior to treatment with Ad-control or Ad-MafG. Bile acid sequestrants bind bile acids in the intestine, preventing their re-absorption in the ileum and promoting bile acid excretion in the feces ( Hofmann and Ha- gey, 2008 ). The result is impaired enterohepatic re-circulation of bile acids, de-repression of genes involved in bile acid synthesis, and changes in the bile acid pool size ( Hofmann and Hagey, 2008; Kong et al., 2012 ). As expected, Ad-MafG increased the hepatic expression of MAFG mRNA ( Figure 3 B) and protein ( Fig- ure 3 C and full blot in Figure S2 D), regardless of the presence or absence of the bile acid sequestrant in the diet. The bile acid sequestrant-containing diet increased basal expression of
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Cholesterol Homeostasis: Lipoproteins In Action

Cholesterol Homeostasis: Lipoproteins In Action

As chylomicrons, VLDLs exchange ApoC2 and ApoE, with HDL in circulation and distribute free fatty acids to muscle and adipose tissues expressing LPL. When VLDL loses the triglycerides they become IDLs, which are either removed by the liver or further acted upon by the lipase to develop into LDL. LDL-c is taken up by the cells through LDLr which interacts mainly with ApoB100 on LDL. The extracellular portion of LDLr consists of three protein modules including a domain with seven contiguous cysteine rich repeats (referred to a LDLR type A, or LA domains) [42]. The receptor-ligand complex is endocytosed into the cells that occurs at clathrin coated pits. The acidic conditions within the cells catalyse and dissociate LDL from the LDLr. LDL particles are degraded into lipid components and amino acids by enzymes of the vesicle. Lysosomal acid lipase hydrolyses the cholesteryl esters into free cholesterol which can be incorporated into the cell membranes and transformation into other products like bile acids or steroids depending upon the cell context. The denovo synthesis of cholesterol is metabolically regulated and expression levels of HMGcoA reductase as well as LDLr are negatively controlled by intra cellular cholesterol. Sterol regulatory elements are present in the promoter regions of LDLr and HMGcoA reductase genes. Transcriptional factors like SRE binding proteins (SREBPs) are required for transcription of these genes containing SRE.
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Effect of cholestyramine on bile acid metabolism in normal man

Effect of cholestyramine on bile acid metabolism in normal man

duodenal contents after an overnight fast, indicating that a hepatic mechanism was responsible for the elevated ratios of glycine- to taurine-conjugated bile acid (G: T ratios) observed. The relative proportions of both dihydroxy bile acids, chenodeoxycholic and deoxycholic, were significantly reduced. Steatorrhea did not occur, and the total bile acid pool size determined after an overnight fast was unaltered by cholestyramine. These

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Estimation of Cholesterol and Bile Acid Turnover in Man by Kinetic Analysis

Estimation of Cholesterol and Bile Acid Turnover in Man by Kinetic Analysis

The kinetics of cholesterol and bile acid turnover were determined from an analysis of the biliary lipids after a single intravenous injection of labeled cholesterol. A compartmental model was designed for the system, and the fractional metabolic rates and fluxes were determined in one lean and two obese normal humans. Each of the normals converted about 3% per day of their rapidly miscible cholesterol pool to cholic acid and 1% per day or less to chenodeoxycholate. Cholate was catabolized at about twice the rate of the dihydroxy bile acids in these normals. Two of the normals were fed corn oil with little change in their kinetic parameters from the control state. The other normal received cholestyramine and dramatically increased the bile acid flux with little change in neutral sterol catabolism. A cirrhotic patient was also studied by this technique and noted to have kinetic parameters quite different from the normals.
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Bile Acid Induced Increase in Bile Acid Independent Flow and Plasma Membrane NaK ATPase Activity in Rat Liver

Bile Acid Induced Increase in Bile Acid Independent Flow and Plasma Membrane NaK ATPase Activity in Rat Liver

NaK-ATPase activity in canaliculi-enriched liver plasma membrane preparations from the nonobstructed lobes of selectively obstructed rats and from 48-h bile acid-loaded rats was increased by 47% and 52%, respectively, relative to controls, but was not increased in membranes from 16-h bile acid-loaded rats. Canalicular membrane 5¢-nucleotidase and Mg ATPase also were increased.

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Kinetic Studies to Elucidate Impaired Metabolism of Triglyceride-rich Lipoproteins in Humans.

Kinetic Studies to Elucidate Impaired Metabolism of Triglyceride-rich Lipoproteins in Humans.

The power of mathematical modeling to describe the metabolic pathways of lipid and lipoprotein metabolism was first demonstrated by Drs. Berman and Zech ( Grundy et al., 1979; Zech et al., 1979 ). Since then, kinetic studies combined with mathematical modeling have been used to clarify the pathogenesis of impaired lipoprotein metabolism in humans linked to accelerated CVD, obesity, and insulin resistance (Figure 2). The methodology has also been instrumental in testing how efficiently novel drugs improve the dyslipidemia. However, it’s important to emphasize that all models are based on several assumptions and simplifications. Therefore, mathematical modeling does not determine the kinetics of lipids directly; rather, they derive an indirect approximation.
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Studies on the Transport and Metabolism of Conjugated Bile Salts by Intestinal Mucosa

Studies on the Transport and Metabolism of Conjugated Bile Salts by Intestinal Mucosa

When sodium cholate or sodium glycocholate Kinetic studies of bile salt transport was in the mucosal medium together with S35Transport of S35-taurocholate was studied in taurocholate, th[r]

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Metabolism of adrenal cholesterol in man: I  In vivo studies

Metabolism of adrenal cholesterol in man: I In vivo studies

However small the synthesis of adrenal cholesterol may be, it seems more important in the zona “reticularis.” On the other hand, the inflow of plasma cholesterol and the turnover of the free adrenal compartment tend to be faster in the zona “fasciculata.” The equilibration of plasma and adrenal cholesterol can proceed unmodified under conditions of ACTH suppression.

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Studies on the influence of dietary cholesterol on cholesterol metabolism in the isotopic steady state in man

Studies on the influence of dietary cholesterol on cholesterol metabolism in the isotopic steady state in man

It is obvious that if the turnover 0.74 g per day enormously exceeded specific activity of the serum cholesterol never cholesterol intake 0.08 g per day, and it may equals that of the di[r]

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Regulation of Cholesterol Metabolism in the Dog: II  EFFECTS OF COMPLETE BILE DIVERSION AND OF CHOLESTEROL FEEDING ON POOL SIZES OF TISSUE CHOLESTEROL MEASURED AT AUTOPSY

Regulation of Cholesterol Metabolism in the Dog: II EFFECTS OF COMPLETE BILE DIVERSION AND OF CHOLESTEROL FEEDING ON POOL SIZES OF TISSUE CHOLESTEROL MEASURED AT AUTOPSY

Gross and microscopic morphology of all organs and tissues was examined. Abnormal findings were limited to the biliary tract and the urinary collecting system of the two bile- diverted dogs: multiple bilirubinate gallstones were found, and mild pyelitis and ureteritis were present on the side of the […]

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Cholesterol and bile acid balance in Macaca fascicularis  Effects of alfalfa saponins

Cholesterol and bile acid balance in Macaca fascicularis Effects of alfalfa saponins

endogenous and exogenous neutral steroids and bile acids, and decreased the percent distribution of fecal deoxycholic and lithocholic acids. The fecal excretion of fat was also slightly increased, but steatorrhea did not occur. We saw no signs of toxicity in the monkeys after 6 or 8 wk of saponin ingestion. The data suggest that alfalfa top saponins may be of use in the treatment of patients with hypercholesterolemia, but long-term studies on possible toxicity are needed before this therapy can be recommended for humans.

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Plasma lipoproteins in familial lecithin: cholesterol acyltransferase deficiency: structure of low and high density lipoproteins as revealed by electron microscopy

Plasma lipoproteins in familial lecithin: cholesterol acyltransferase deficiency: structure of low and high density lipoproteins as revealed by electron microscopy

The high density lipoproteins (HDL) also are heterogeneous. The majority of particles are disc-shaped structures 150-200 A in diameter. The discs are mainly present in stacks which have a periodicity of 50-55 A and a variable length. Each disc appears to be made up of a rosette of smaller globular units 50 A in diameter. The appearance of these large molecular weight HDL contrasts with that of normal HDL, which are 70-100 A in diameter and

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Kinetic studies of plasma free fatty acid and triglyceride metabolism in man

Kinetic studies of plasma free fatty acid and triglyceride metabolism in man

Plasma transport of free fatty acids (FFA) and triglyceride fatty acids (TGFA) was studied in seven subjects with normal lipid metabolism, one case of total lipodystrophy, and one case of familial hyperlipemia (Type V). Studies were carried out after intravenous injection of radioactive FFA, of lipoproteins previously labeled in vitro in the triglyceride moiety, or both. Computer techniques were used to evaluate a series of multicompartmental models, and a general model is proposed that yields optimum fitting of experimental data for both FFA and TGFA. The results show that as much as 20-30% of FFA leaving the plasma compartment in normal subjects is transported to an exchanging extravascular pool and quickly reenters the plasma pool as FFA. The rate of irreversible delivery of FFA from plasma to tissues averaged 358 µEq/min in normals. The lipodystrophy patient, despite the virtual absence of adipose tissue (confirmed at autopsy), had a plasma FFA concentration and a total FFA transport, both more than twice normal. Total TGFA transport ranged from 25 to 81 µEq/min in four normal controls. The rate constant for TGFA turnover in the patient with Type V hyperlipemia was so small that total transport could not be quantified from the data available; the TGFA half-life was over 500 min.
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Studies on the organic acid metabolism of plants in relation to the flooding tolerance of their roots

Studies on the organic acid metabolism of plants in relation to the flooding tolerance of their roots

STUDIES ON THE ORGANIC ACID METABOLISM OF PLANTS IN RELATION TO THE FLOODING TOLERANCE OF THEIR ROOTS Peter David Tyler A Thesis Submitted for the Degree of PhD at the University of St A[r]

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