Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of aging on the hepatic metabolism of cholesterol were studied in 1-, 6- and 24-month-old male Sprague-Dawley rats. Microsomal 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity, which regulates cholesterol biosynthesis, decreased from 835 +/- 144 (SEM) pmol/min/mg protein in the youngest group to 219 +/- 34 and 205 +/- 53 pmol/min/mg protein (p less than 0.001) in the 6- and 24-month-old groups, respectively. Cholesterol 7 alpha-hydroxylase activity, which governs bile acid synthesis, was gradually reduced from 70 +/- 14 pmol/min/mg protein in the 1-month-old group to 32 +/- 7 and 16 +/- 3 pmol/min/mg protein (p less than 0.05) in the 6- and 24-month-old groups, respectively. Acyl coenzyme A:cholesterol acyltransferase activity, which catalyzes the esterification of cholesterol, averaged 431 +/- 47 and 452 +/- 48 pmol/min/mg protein in the 1- and 6-month-old groups, respectively, and was increased to 585 +/- 55 pmol/min/mg protein (p less than 0.05) in the 24-month-old group. The level of total cholesterol showed an age-related increase from 1.56 +/- 0.16 mg/g liver in the 1-month-old group to 1.70 +/- 0.15 and 2.20 +/- 0.19 mg/g liver (p less than 0.05) in the 6- and 24-month-old groups, respectively. The increase was mainly caused by an accumulation of esterified cholesterol. We conclude that a marked decrease in HMG-CoA reductase occurs between 1 and 6 months of age; thereafter the enzyme activity stays unchanged. The activity of cholesterol 7 alpha-hydroxylase decreases progressively and drastically with age, whereas the capacity for esterifying cholesterol increases slightly.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Age-related changes in the metabolism of cholesterol in rat liver microsomes. 189 80

Hepatic cholesterol metabolism was examined in 27 Swedish patients with cholesterol gallstone disease and in 13 patients free of gallstones operated for roentgenographically suspect polyps in the gallbladder. All 40 patients underwent cholecystectomy, and a liver biopsy and gallbladder bile were obtained at surgery. The cholesterol saturation of gallbladder bile was significantly higher in patients with gallstones compared to the gallstone-free controls (131 +/- 13 vs. 75 +/- 5%, P less than 0.001). Microsomal 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity, governing cholesterol synthesis, did not differ between gallstone and gallstone-free patients (104 +/- 11 vs. and 109 +/- 22 pmol/min per mg protein, respectively). The activity of cholesterol 7 alpha-hydroxylase, catalyzing the catabolism of cholesterol to bile acids, was not significantly decreased in gallstone patients (6.2 +/- 1.1 vs. 8.0 +/- 2.0 pmol/min per mg protein). The capacity to esterify cholesterol, judged by the activity of acyl coenzyme A:cholesterol acyltransferase (ACAT), was similar in gallstone and gallstone-free patients (5.4 +/- 0.4 vs. 6.7 +/- 1.1 pmol/min per mg protein). In the presence of exogenous cholesterol, ACAT activity increased by more than fourfold in both groups. No correlation was found between the saturation of gallbladder bile and any of the mentioned enzyme activities in gallstone patients. It is concluded that distinct abnormalities in cholesterol metabolizing enzymes are not of major importance for development of gallstones in Swedish patients with cholesterol gallstone disease. The results support the contention that the etiology of cholesterol gallstones is multifactorial.
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PMID:Hepatic cholesterol metabolism in cholesterol gallstone disease. 206 75

The effect of two inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, lovastatin and monacolin L, and an inhibitor of acyl coenzyme A:cholesterol acyltransferase (ACAT), Sandoz compound 58-035, on the interaction of 125I-labeled high density lipoprotein-3 (HDL3) with isolated human enterocytes was studied. Both HMG-CoA reductase inhibitors inhibited cholesterol synthesis and 125I-labeled HDL3 binding and degradation by enterocytes; a strong correlation between changes in cholesterol synthesis and interaction of 125I-labeled HDL3 with cells was observed. Lovastatin caused reduction of the apparent number of 125I-labeled HDL3 binding sites without affecting the binding affinity. No changes of cell cholesterol content were observed after incubation of cells with lovastatin. Mevalonic acid reversed the effect of lovastatin on 125I-labeled HDL3 binding. Lovastatin blocked up-regulation of the HDL receptor in response to loading of cells with nonlipoprotein cholesterol and modified cholesterol-induced changes of 125I-labeled HDL3 degradation. Lovastatin also reduced HDL-mediated efflux of endogenously synthesized cholesterol from enterocytes. The ACAT inhibitor caused a modest increase of 125I-labeled HDL3 binding to enterocytes and significantly decreased its degradation; both effects correlated with inhibition of cholesteryl ester synthesis. The results allow us to assume that the intracellular free cholesterol pool may play a key role in regulation of the HDL receptor.
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PMID:Inhibition of cholesterol synthesis and esterification regulates high density lipoprotein interaction with isolated epithelial cells of human small intestine. 207 5

MK-733 (simvastatin), a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, was found to inhibit the absorption of cholesterol from the gastrointestinal tract in cholesterol-fed rabbits (Ishida et al. (1988) Biochim. Biophys. Acta 963, 35-41). To clarify the mechanism of action, the effects of MK-733 on acyl coenzyme A:cholesterol acyltransferase (ACAT) and cholesterol esterase activities, which are thought to participate in the absorption of cholesterol, were examined. Dietary administration (0.03% in a 1% cholesterol diet for 7 days, approx. 10 mg/kg) of MK-733 to cholesterol-fed rabbits was found to inhibit the increase in serum total cholesterol levels, and caused a 70% reduction in ACAT activity in microsomes of intestinal mucosa relative to those observed in concurrent control rabbits. MK-733 did not affect cholesterol esterase activity in the cytosol of the intestinal mucosa. The inhibitory effect of MK-733 on cholesterol absorption in cholesterol-fed rabbits is though to be related to a reduction in microsomal ACAT activity in the intestinal mucosa.
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PMID:Effects of MK-733 (simvastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on intestinal acylcoenzyme A:cholesterol acyltransferase activity in rabbits. 274 65

Many aspects of lipid metabolism have been studied in amphibians, but seasonal lipid modulation in male and female frogs has not been investigated. We describe here the yearlong patterns of hepatic lipid content and enzyme activities related to cholesterol homeostasis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity and acyl coenzyme A:cholesterol acyltransferase (ACAT) activity in liver of the male and female frog, Rana esculenta. Lipid storage follows distinct seasonal patterns, with an increase in June that is more pronounced in the female than in the male frog. Cholesterol content and cholesterol storage as cholesteryl ester in male liver are consistent with the activity of HMG-CoA reductase and of ACAT enzymes. HMG-CoA reductase activity of the female frog shows an extra peak in fall unrelated to cholesterol storage and probably related to the production of essential compound for oogenesis.
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PMID:Cholesterol metabolism in frog (Rana esculenta) liver: seasonal and sex-related variations. 278 85

To learn whether either reduced de novo cholesterol synthesis and/or altered cholesteryl ester metabolism is responsible for the deficient progestin production induced by estrogen withdrawal from pseudopregnant rabbits, we measured the luteal activity of three enzymes: 1) 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (the rate-limiting step in de novo cholesterol synthesis), 2) cholesteryl ester hydrolase, and 3) acyl coenzyme A:cholesterol acyltransferase (ACAT) in estrogen-stimulated and estrogen-deprived rabbits. The only change in the activity of these enzymes and of the enzyme NADPH-cytochrome c reductase (a microsomal marker enzyme) after estrogen capsule removal for 12 or 24 h was a 30% decrease in HMG-CoA reductase activity after 24 h. The decrease in HMG-CoA reductase activity was not accompanied by a detectable change in either the content or localization of cellular free cholesterol. Previous data from our laboratory have demonstrated that 24 h of estrogen deprivation has no effect on inner mitochondrial membrane P-450 side-chain cleavage activity (a rate-limiting step in the conversion of cholesterol to steroid hormones). These data, and our earlier finding that estrogen deprivation leads to accumulation of cholesteryl ester in the luteal cells, indicate that estrogen maintains rabbit luteal progestin production by stimulating the transfer of cytoplasmic cholesterol to the active site of P-450 side-chain cleavage on the inner mitochondrial membrane.
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PMID:Cholesterol metabolism in estrogen-sensitive progestin synthesis by rabbit corpus luteum. 376 27

Rabbits fed low-fat, cholesterol-free diets containing casein as the sole protein source develop endogenous hypercholesterolemia (EH). To test the hypothesis that lipoprotein cholesteryl esters in EH rabbits are acyl coenzyme A:cholesterol acyltransferase (ACAT) derived, we treated EH rabbits with CI-976, a potent and selective ACAT inhibitor. In addition, since cholesterol and bile acid synthesis as well as low-density lipoprotein (LDL) receptor activity are reduced in EH rabbits, we determined whether changes in gene expression for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, 7 alpha-hydroxylase, and the LDL receptor might be associated with the efficacy due to ACAT inhibition. Compared with EH controls, CI-976-treated rabbits (50 mg/kg per day for 5 weeks) had decreased plasma total cholesterol (-43%), very-low-density lipoprotein (VLDL) cholesterol (-62%), LDL cholesterol (-43%), plasma apolipoprotein B (-23%), liver cholesteryl esters (-39%), LDL size, VLDL and LDL cholesteryl ester content (percent of total lipids), cholesteryl oleate/cholesteryl linoleate ratios in VLDL and LDL (25% to 30%), and ex vivo liver ACAT activity. The triglyceride/cholesteryl ester ratio increased twofold to fourfold in these apolipoprotein B-containing lipoproteins. Endogenous cholesterol absorption appeared to be unaffected by drug treatment. CI-976 failed to alter specific hepatic mRNAs involved in cholesterol metabolism, but comparisons among dietary control groups revealed a marked reduction in 7 alpha-hydroxylase mRNA, no change in LDL receptor mRNA, and an increase in HMG-CoA reductase mRNA in EH rabbits compared with normal chow-fed controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:ACAT inhibition decreases LDL cholesterol in rabbits fed a cholesterol-free diet. Marked changes in LDL cholesterol without changes in LDL receptor mRNA abundance. 814 58

In the mucosal layer of the small intestine, we found nearly identical gradients of CRBP(II), retinal reductase, and LRAT levels down the duodenal-ileal axis, suggesting coordinate regulation of these three proteins. In all cases the level of binding protein or enzyme activity was greatest in the proximal intestine and then decreased sharply in the distal half. This pattern fits with the known capacity of the intestine to absorb vitamin A. In addition, the retinal reductase activity was found predominantly in the intestinal mucosa, while LRAT activity was found in both the intestinal mucosa and muscle. An even distribution of LRAT activity along the longitudinal axis of the intestinal muscle was consistent with an even distribution of CRBP in that tissue. In conjunction with LRAT activity and CRBP, we found endogenous retinyl ester stores in the intestinal muscle layer. The patterns of retinyl ester produced by LRAT in vitro and found in vivo were similar, with retinyl palmitate predominating and a high percentage comprised of retinyl stearate. We also observed a bile salt-independent retinyl ester hydrolase activity in intestinal muscle whose distribution paralleled the retinyl ester stores and LRAT levels. This hydrolase appears to be distinct from retinyl ester hydrolases described from other organs as its activity was insensitive to retinyl ester chain length, the presence of bile salts, or the addition of apo-CRBP. This activity was inhibited by diethyl-p-nitrophenyl-phosphate (IC50 100 microM) and diethylpyrocarbonate (IC50 10 microM), demonstrating a requirement for active serine and histidine residues. In addition, we describe an activity present in some intestinal microsomal preparations that can perturb determinations of reductase and LRAT activity and must be avoided.
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PMID:Intestinal vitamin A metabolism: coordinate distribution of enzymes and CRBP(II). 822 37

Sitosterolemia (phytosterolemia) is a rare autosomal recessively inherited disorder that is characterized by premature coronary artery disease, xanthomas, and increased plasma plant sterols and 5alpha-stanols. Affected individuals show an increased absorption of both cholesterol and sitosterol from the diet, decreased bile clearance of these sterols and their metabolites resulting in markedly expanded whole body cholesterol and sitosterol pools. Biochemical studies have shown that the regulation of the cholesterol biosynthetic pathway may be abnormal in this condition. In particular, the activities and mRNA for the biosynthetic enzymes, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and HMG-CoA synthase are low in liver biopsy specimens isolated from affected individuals, suggesting replete intracellular cholesterol pools. However, the membrane expression of hepatocyte low density lipoprotein receptors was increased, suggesting discordant regulation. Segregation analyses in three families for the genes for HMG-CoA reductase, HMG-CoA synthase, and LDL-receptor excluded these as sites of mutation. In view of the previously described discordant regulation of the above genes in sitosterolemia, the two major regulatory genes for this pathway, sterol regulatory element binding proteins (SREBP-1 and -2), were also examined. These genes did not segregate with the disease and were thus excluded. Two other genes involved in cholesterol absorption and chylomicron secretion, namely acyl coenzyme A:cholesterol acyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP) were also examined for segregation and similarly excluded. Although the gene defect in sitosterolemia therefore remains to be elucidated, important candidate genes have been excluded.
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PMID:Sitosterolemia: exclusion of genes involved in reduced cholesterol biosynthesis. 961 Jul 73

Origins of hyperlipidemia and cholestasis that occur during pregnancy were investigated by examining expression of key elements related to plasma and hepatic cholesterol metabolism during pregnancy, lactation, and post-lactation in the rat model. Among major findings were: during pregnancy, the activities of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase, acyl coenzyme A:cholesterol acyltransferase, acyl coenzyme A:diacylglycerol acyltransferase, cholesterol 7alpha-hydroxylase, cholesterol ester hydrolases, low density lipoprotein receptors, LRP, and mdr2 were significantly lower or similar to non-pregnant controls while SR-B1 was elevated. Once lactation began, reductase, cholesterol acyltransferase, 7alpha-hydroxylase activities, low density lipoprotein receptors, and mdr2 increased while SR-B1 decreased. In later stages of lactation most hepatic elements returned to near control levels. Plasma cholesterol levels were higher than control at birth and during lactation with increase in LDL-size particles. By 24 h post-lactation, plasma triglycerides were 3.7-fold higher while cholesterol remained unchanged. Very large lipoproteins were present while LDL-size particles were now absent. Hepatic cholesterol acyltransferase had decreased to 27% of control while diacylglycerol acyltransferase increased 3-fold and low density lipoprotein receptors doubled. Most elements were normalized 3 weeks after weaning except for LRP and low density lipoprotein receptors which were elevated. These studies provide an integrated picture of expression of key elements of hepatic and plasma cholesterol metabolism during pregnancy and lactation and advance understanding of hyperlipidemia and cholestasis during these states.
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PMID:Effect of pregnancy and lactation on lipoprotein and cholesterol metabolism in the rat. 979 10


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