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)

Male Wistar rats were fed commercial ration and given whole milk, skim milk, or water to drink. After 3 weeks the control group showed the greatest weight gain. Rats given whole milk had the smallest livers. Serum cholesterol levels were significantly lower in rats fed either whole or skim milk, but other serum lipids were unaffected. Liver triglyceride levels were lowest in the rats on skim milk. Activities of hepatic fatty acid synthetase, hydroxymethyl-glutaryl coenzyme A reductase and cholesterol 7alpha-hydroxylase were similar in the two milk-fed groups and considerably lower than in the controls.
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PMID:Influence of whole or skim milk on cholesterol metabolism in rats. 42 Jan 51

To determine the mechanism of the hypocholesteremic effect of estrogens noted in pigeon, studies were done on the subcellular distribution of cholesterol and the activity of beta-hydroxy-beta-methylglutaryl CoA reductase (HMG-CoA reductase) and and cholesterol 7alpha-hydroxylase in pigeon liver after long-term (6 months) estrogen administration. Estrogens significantly reduced free cholesterol concentration in microsomes and mitochondrial fraction. The concentration of cholesteryl ester was reduced in the supernatant fraction. The activity of HMG-CoA reductase was significantly reduced in the estrogen-treated birds, while cholesterol 7alpha-hydroxylase activity showed no changes. Thus, the hypocholesteremic effect of estrogen noted in pigeons could be mainly due to the inhibition of cholesterol biosynthesis in the liver.
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PMID:Effect of long-term administration of estrogens on the subcellular distribution of cholesterol and the activity of rate-limiting enzymes of cholesterol biosynthesis and degradation in pigeon liver. 60 56

Short- and long-term effects of ethanol on HMG-CoA reductase (EC 1.1.1.34) and cholesterol 7alpha-hydroxylase activities in rat liver have been investigated. Neither the reductase nor the hydroxylase activity as measured in vitro was significantly affected within 2 hr after a single intraperitoneal injection of ethanol (7 mmol per 100g body weight), whether tested at the diurnal low or the diurnal high point of activity. Although chronic ethanol feeding for 21 days did not affect the diurnal rhythm of either of these enzyme activities, it caused a 29% decrease in HMG-CoA reductase activity and a 56% decrease in cholesterol 7alpha-hydroxylase activity at the diurnal high point. The same chronic ethanol feeding caused a moderate increase in serum cholesterol and a significant increase in hepatic cholesterol concentration. On the basis of these findings, it is suggested that the decreased rate of cholesterol degradation to bile acids may play a significant role in the accumulation of cholesterol in the liver after chronic ethanol feeding.
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PMID:Short- and long-term effects of ethanol administration in vivo on rat liver HMG-CoA reductase and cholesterol 7alpha-hydroxylase activities. 86 24

The effects of chenodeoxycholic (CDC), 750 mg. per day, phenobarbital (PB), 90 or 180 mg., combined (CDC + PB), and placebo on biliary lipid composition and on the rate-limiting enzymes of hepatic cholesterol synthesis (HMG-CoA reductase) and bile acid synthesis (cholesterol 7alpha-hydroxylase) were studied. Percutaneous liver biopsies were performed after 6 months of therapy in 4 patients from each group participating in a double-blind study of gallstone dissolution. The enzyme activities were also assayed in liver obtained at laparotomy in 7 untreated gallstone patients and 4 without gallstones. 7alpha,12alpha-Dihydroxycholest-4-en-3-one-12alpha-hydroxylase, an enzyme leading to cholic acid synthesis, was determined in 4 untreated gallstone patients and 4 without gallstones. Untreated gallstone patients had 35 per cent greater HMG-CoA reductase (p less than 0.01), 37 per cent less 7alpha-hydroxylase (p less than 0.01), and 40 per cent less 12alpha-hydroxylase (p less than 0.01) than patients without gallstones. CDC, PB, and both increased biliary CDC and decreased the lithogenic index significantly (p less than 0.01) but saturated bile persisted with PB. CDC decreased HMG-CoA reductase 40 per cent (p less than 0.01) and 7alpha-hydroxylase 47 per cent (p less than 0.01). PB increased HMG-CoA reductase 112 per cent (p less than 0.01) and 7alpha-hydroxylase 20 per cent (p less than 0.01). The combination of CDC and PB increased HMGCoA reductase 40 per cent (p less than 0.01) and had no effect on 7alpha-hydroxylase. In conclusion, CDC induced desaturation of bile while decreasing HMG-CoA reductase and increasing CDC in bile. PB reduced the saturation less effectively than CDC; it increased 7alpha-hydroxylase but also increased HMG-CoA reductase.
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PMID:Effect of chenodeoxycholic acid and phenobarbital on the rate-limiting enzymes of hepatic cholesterol and bile acid synthesis in patients with gallstones. 124 92

DBP, a liver-enriched transcriptional activator protein of the leucine zipper protein family, accumulates according to a very strong circadian rhythm (amplitude approx. 1000-fold). In rat parenchymal hepatocytes, the protein is barely detectable during the morning hours. At about 2 p.m., DBP levels begin to rise, reach maximal levels at 8 p.m. and decline sharply during the night. This rhythm is free-running: it persists with regard to both its amplitude and phase in the absence of external time cues, such as daily dark/light switches. Also, fasting of rats for several days influences neither the amplitude nor the phase of circadian DBP expression. Since the levels of DBP mRNA and nascent transcripts also oscillate with a strong amplitude, circadian DBP expression is transcriptionally controlled. While DBP mRNA fluctuates with a similar phase and amplitude in most tissues examined, DBP protein accumulates to high concentrations only in liver nuclei. Hence, at least in nonhepatic tissues, cyclic DBP transcription is unlikely to be controlled by a positive and/or negative feedback mechanism involving DBP itself. More likely, the circadian DBP expression is governed by hormones whose peripheral concentrations also oscillate during the day. Several lines of evidence suggest a pivotal role of glucocorticoid hormones in establishing the DBP cycle. Two genes whose mRNAs and protein products accumulate according to a strong circadian rhythm with a phase compatible with regulation by DBP encode enzymes with key functions in cholesterol metabolism: HMG-coA reductase is the rate-limiting enzyme in cholesterol synthesis; cholesterol 7-alpha hydroxylase performs the rate-limiting step in the conversion of cholesterol to bile acid.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of the transcriptional activator protein DBP in circadian liver gene expression. 129 47

Specific activities of the hepatic microsomal enzymes 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase and cholesterol 7alpha-hydroxylase were studied in rats fed sterols and bile acids. The administration of bile acids (taurocholate, taurodeoxycholate, taurochenodeoxycholate) at a level of 1% of the diet for 1 wk reduced the activity of HMG CoA reductase. Taurocholate and taurodeoxycholate, but not taurochenodeoxycholate, inhibited cholesterol 7alpha-hydroxylase. Dietary sitosterol produced increases in the specific activity of HMG CoA reductase (3.6-fold) and cholesterol 7alpha-hydroxylase (1.4-fold), and biliary cholesterol concentrations in this group more than doubled. Compared with controls fed the stock diet, the simultaneous administration of sitosterol and taurochenodeoxycholate resulted in a 60% decrease of HMG CoA reductase activity and no change in cholesterol 7alpha-hydroxylase activity or biliary cholesterol concentration. Rats fed sitosterol plus taurocholate had nearly normal HMG CoA reductase activity, but cholesterol 7alpha-hydroxylase was inhibited and biliary cholesterol remained high. Bile acid secretion rates and biliary bile acid composition were similar in controls and sterol-fed animals. In all groups receiving bile acids, biliary secretion of bile acids was nearly doubled and bile acid composition was shifted in the direction of the administered bile acid. It is concluded that the composition of the bile acid pool influences the hepatic concentrations of the rate-controlling enzymes of bile acid synthesis.
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PMID:Regulatory effects of sterols and bile acids on hepatic 3-hydroxy-3-methylglutaryl CoA reductase and cholesterol 7alpha-hydroxylase in the rat. 472 73

Rowachol, a mixture of 6 terpenes in olive oil and under investigation for dissolution of gallstones in humans, was compared with UDCA in hamsters with induced cholesterol gallstones. Eighty hamsters were allocated to eight groups of ten animals each. One group received only standard rodent chow. The other seven groups received the lithogenic regime (standard chow containing ethinyl estradiol and increased cholesterol), either alone or with 20 mg/kg/day of UDCA, or 5, 10, or 20 mg/kg/day of mixed terpenes in olive oil or 10 mg ( of terpenes) kg/day of Rowachol or 0.2 cc/day of olive oil. The animals were sacrificed after 12 weeks. Two additional groups of six hamsters each received the lithogenic regime for 12 weeks, and then were switched to the standard diet, alone or with 10 mg/kg/day of Rowachol for eight weeks at the end of which time they were sacrificed. Rowachol decreased HMGCoA reductase activity 18%, but did not dissolve gallstones. Neither the terpenes nor Rowachol altered the biliary cholesterol saturation index, bile acid pool size or the activity of cholesterol 7-alpha hydroxylase or prevented formation of gallstones. UDCA unsaturated bile, increased the total bile acid pool size 38%, depressed the activity of HMGCoA reductase 29%, and prevented formation of gallstones.
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PMID:Rowachol and ursodeoxycholic acid in hamsters with cholesterol gallstones. 714 85

Cholesterol is an essential component of all tissues, as it is a part of the structure of cell membranes, and it is an immediate precursor of a series of essential substances such as vitamins, steroid hormones, and bile acids. Under physiologic conditions, the intake and output of cholesterol in the organism is coordinated and balanced with the aim of guaranteeing the availability of adequate amounts of cholesterol to satisfy the needs of the different tissues (fig. 1). Under pathological conditions there is an imbalance between these mechanism, which leads to an increase in the circulating levels of cholesterol, leading to pathological processes such as hyperlipemias, atherosclerosis and bile stones. The liver plays a central role in the regulation of the homeostasis of cholesterol. The molecule enters the liver in the form of chylomicrons and low density lipoproteins (LDL), through lipoprotein receptors, and this is also the most important organ for the de novo biosynthesis of cholesterol from acetyl coenzyme A, by means of a cascade enzyme reaction in which the enzyme 3-hydroxy-3 methyl glutaryl CoA reductase (HMG-CoA) is the key of the entire process. Cholesterol is found in the liver in the form of cholesterol esters or as free cholesterol. The two most effective ways of eliminating body cholesterol are found in the liver, with the degradation of the compound to bile acids and the biliary secretion of cholesterol. The conversion to bile acids takes place through a series of enzymatic steps in which the formation of 7-alpha-hydroxycholesterol by the enzyme cholesterol 7-alpha-hydroxylase is the key of the process. The biliary secretion of cholesterol is 600 mg/day. Both the abundance and the universality of cholesterol in living things as its clinical implications emphasize the importance and interest of this compound.
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PMID:[Hepatic metabolism of cholesterol]. 870 15

The effect of bile acid depletion and replacement with glycodeoxycholic acid on plasma cholesterol concentrations, hepatic low-density lipoprotein (LDL) receptor binding and messenger RNA (mRNA) levels, and hepatic activities and mRNA levels for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7alpha-hydroxylase was investigated in 19 New Zealand white (NZW) and 15 Watanabe heritable hyperlipidemic (WHHL) rabbits. Bile acid depletion was produced by external bile drainage for 5 days, which maximized cholic acid synthesis. Replacement was achieved by infusing glycodeoxycholic acid intraduodenally for 24 hours so that the hepatic bile acid flux reached prefistula levels. Plasma and liver cholesterol concentrations were 13 times and 50% greater, respectively, hepatic LDL receptor-mediated binding was 26% less, and cholesterol 7alpha-hydroxylase activity and mRNA levels were 62% and 86% less in WHHL than NZW rabbits. After bile drainage, plasma cholesterol concentrations decreased 29% in NZW rabbits and 40% in WHHL rabbits and were associated with a 2.1-fold increase in hepatic LDL receptor-mediated binding in the NZW rabbits, but there was no change in the WHHL rabbits. Cholesterol 7alpha-hydroxylase activity and mRNA levels increased three and four times in NZW and WHHL rabbits, respectively, although liver cholesterol levels remained unchanged. Replacement with exogenous glycodeoxycholic acid increased plasma cholesterol concentrations 1.7 times in NZW rabbits and decreased enhanced cholesterol 7alpha-hydroxylase activity 54%, mRNA levels 86%, cholic acid synthesis 38%, and hepatic LDL receptor-mediated binding 57% in NZW rabbits. Bile acid depletion stimulated cholic acid synthesis by up-regulating cholesterol 7alpha-hydroxylase to use cholesterol and reduce plasma concentrations substantially in both NZW and WHHL rabbits, although LDL receptors did not function in WHHL rabbits. Glycodeoxycholic acid replacement inhibited elevated cholesterol 7alpha-hydroxylase, cholic acid synthesis, and hepatic LDL receptor binding to reestablish baseline plasma cholesterol levels in NZW rabbits. Hypercholesterolemia in WHHL rabbits was related to the combination of dysfunctional LDL receptors and inhibited cholesterol 7alpha-hydroxylase. Plasma cholesterol concentrations were reduced significantly when cholesterol 7alpha-hydroxylase was stimulated even in the absence of LDL receptor function.
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PMID:Increasing hepatic cholesterol 7alpha-hydroxylase reduces plasma cholesterol concentrations in normocholesterolemic and hypercholesterolemic rabbits. 885 92

The high prevalence of cholesterol gallstone disease in hypertriglyceridemic patients may be associated with frequent metabolic defects in cholesterol and bile acid syntheses and in the concomitant formation of bile supersaturated with cholesterol. This study had the two aims: 1) to assess whether the defects as well as the degree of biliary cholesterol supersaturation in patients with hyperlipoproteinemia (HLP) can be estimated by the simultaneous determination of plasma mevalonate (MVL) and 7alpha-hydroxy-4-cholesten-3-one (C4); and 2) to assess the possible application of an estimated cholesterol saturation index ([CSI]E) as a means of evaluating the clinical effects of simvastatin on biliary lipid composition. Biliary cholesterol supersaturation was observed in patients with both IIa and IV HLP types. Consistent with the high activity and steady-state messenger RNA level of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, plasma MVL was significantly higher in 86 patients with HLP (38 type IIa, 44.1 +/- 2.4 nmol/L and 48 type IV, 56.7 +/- 2.3; P < .01) than in 41 normolipidemic subjects (34.2 +/- 1.5), closely correlating with the molar percentage of cholesterol in bile (r = .61, P = .0001; n = 86). On the other hand, consistent with the high activity and messenger RNA level of cholesterol 7alpha-hydroxylase, plasma C4 was significantly higher in patients with HLP (type IIa, 28.8 +/- 2.3 nmol/L and type IV, 38.3 +/- 2.7; P < .01) than in normolipidemic subjects (17.4 +/- 1.5). Plasma C4 was closely correlated with plasma MVL (r = .40, P = .0001; n = 86), but was inversely correlated with the molar percentage of bile acids in bile (r = .49, P = .0001; n = 86). Assuming that cholesterol supersaturation in patients with HLP may be governed by both an enhanced cholesterol secretion (closely reflected by plasma MVL) and a decreased secretion of bile acids (closely reflected by plasma C4), the multivariate linear regression-analyses revealed that an index defined as estimated CSI ([CSI]E) (%) in patients with HLP was given by the following equation using plasma MVL and C4 (nmol/L): [CSI]E = 1[MVL] + 0.7[C4] + 44.4. Biliary cholesterol supersaturation in patients treated with simvastatin improved in a manner parallel to the time course of decreases in plasma MVL and C4. The [CSI]E before and at the end of treatment were correlated with biliary CSI. These results indicate that defects of hepatic cholesterogenesis, and bile acid synthesis, and the degree of biliary cholesterol supersaturation in patients with HLP can be estimated exactly by the simultaneous determination of plasma MVL and C4; furthermore [CSI]E may be adopted for clinical use as a convenient index of biliary CSI.
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PMID:Simultaneous determination of plasma mevalonate and 7alpha-hydroxy-4-cholesten-3-one levels in hyperlipoproteinemia: convenient indices for estimating hepatic defects of cholesterol and bile acid syntheses and biliary cholesterol supersaturation. 898 59


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