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)

27-hydroxycholesterol (27OH-Chol) is an important endogenous oxysterol resulting from the action of sterol 27-hydroxylase (CYP27A1) on cholesterol in the liver and numerous extrahepatic tissues. It may act as a modulator of cholesterol and bile acid metabolism. The effects of 27OH-Chol on the main enzymes and receptors of cholesterol metabolism were investigated by feeding male hamsters a diet supplemented with 27OH-Chol (0.1% w/w) for 1 week. Intestinal scavenger class B, type I (SR-BI) protein level was decreased (-65%), but hepatic expression was increased (+34%). Liver 3beta-hydroxy-3beta-methyl glutaryl coenzyme A reductase (-58%), cholesterol 7alpha-hydroxylase (-54%), oxysterol 7alpha-hydroxylase (-44%), and sterol 12alpha-hydroxylase (-70%) activities were all decreased. Bile acid composition was changed (fourfold increase in the chenodeoxycholic/cholic acid ratio). This study demonstrates that dietary 27OH-Chol modulates major enzymes of cholesterol metabolism and alters the biliary bile acid profile, making it more hydrophobic, at least at this level of intake. Its effects on SR-BI protein levels are organ dependent. The properties of 27OH-Chol or its metabolites on cholesterol metabolism probably result from the activation of specific transcription factors.
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PMID:Effects of dietary 27-hydroxycholesterol on cholesterol metabolism and bile acid biosynthesis in the hamster. 1461 21

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) and cholesterol 7 alpha-hydroxylase (CYP7A1), essential enzymes of cholesterol synthesis and excretion, respectively, were isolated from a chicken liver cDNA library. When their recombinant proteins were overexpressed in HNK293 cells, corresponding enzyme activities were observed. The complete open reading frames of MHGR and CYP7A1 contained (i) 2625 base pairs (bp), predicting a protein of 875 amino acids, and (ii) 1539 bp, predicting a protein of 513 amino acids, respectively. By Northern blot analysis, chicken HMGR mRNA expression was detected in most tissues examined, however, the highest levels were found in liver, brain and ileum. CYP7A1 mRNA was detected only in the liver. Changes in chicken HMGR and CYP7A1 mRNA expression with nutritional state were examined and were shown to respond to certain nutritional treatments, i.e. fast refeeding and cholesterol supplementation. HMGR and CYP7A1 mRNA levels were significantly increased with maturation (i.e. egg producing), when compared to immature chickens. However, these stimulations were not associated with estrogen, although this does enhance triacylglycerol and very low density lipoprotein secretion by the chicken liver. The present study is the first to report the molecular characterization of HMGR and CYP7A1, key enzymes of cholesterol metabolism in avian species.
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PMID:Changes in mRNA expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol 7 alpha-hydroxylase in chickens. 1465 39

N-3 polyunsaturated fatty acids and estrogens are recognized as protective factors of atherosclerosis, however their interactions on cholesterol metabolism remain unclear. Male and female hamsters were fed for 9 weeks diets containing 12.5% lipids and rich in either alpha-linolenic acid ("linseed" diet) or saturated fatty acids ("butter" diet). Hamsters fed the "linseed" diet exhibited lower plasma concentrations of cholesterol (-29%), total LDL (-35%) and HDL (-17%), glucose (-20%), insulin (-40%) and of the LDL-cholesterol/HDL-cholesterol ratio (-27%) than those fed the "butter" diet. In the liver, cholesterol content was 2.7-fold lower in response to the "linseed" diet, whereas the concentration of HDL receptor (SR-BI) and the activities of HMGCoA reductase and cholesterol 7alpha-hydroxylase were 30 to 50% higher than with the "butter" diet. By contrast, the LDL receptor concentration did not vary with the diet. Females exhibited higher concentration of LDL (+24%), lower concentration of plasma triglycerides (-34%), total VLDL (-46%) and VLDL-cholesterol (-37%) and of biliary phospholipids (-19%). Besides, there was also an interaction between gender and diet: in males fed the "butter" diet, plasma triglycerides and VLDL concentration, were 2 to 4 fold higher than in the other groups. These data suggest that gene and/or metabolic regulations by fatty acids could interact with that of sex hormones and explain why males are more sensitive to dietary fatty acids.
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PMID:Effects of dietary alpha linolenic acid on cholesterol metabolism in male and female hamsters of the LPN strain. 1471 61

Dyslipidemia is a prominent feature of chronic renal failure (CRF) and a major risk factor for atherosclerosis and the progression of renal disease. CRF-induced dyslipidemia is marked by hypertriglyceridemia and a shift in plasma cholesterol from HDL to the ApoB-containing lipoproteins. Several studies have demonstrated a favorable response to administration of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (statins) in CRF. This study was intended to explore the effect of statin therapy on key enzymes and receptors involved in cholesterol metabolism. Accordingly, CRF (5/6 nephrectomized) and sham-operated rats were randomized to untreated and statin-treated (rosuvastatin 20 mg x kg(-1) x day(-1)) groups and observed for 6 wk. The untreated CRF rats exhibited increased total cholesterol-to-HDL cholesterol ratio, diminished plasma lecithin:cholesterol acyltransferase (LCAT) and the hepatic LDL receptor, elevated hepatic acyl-CoA:cholesterol acyltransferase (ACAT), and no change in hepatic HMG-CoA reductase, cholesterol 7alpha-hydroxylase, or HDL receptor (SRB-1). Statin administration lowered HMG-CoA reductase activity, normalized plasma LCAT, total cholesterol-to-HDL cholesterol ratio, and hepatic LDL receptor but did not significantly change either plasma total cholesterol, hepatic cholesterol 7alpha-hydroxylase, total ACAT activity, or SRB-1 in the CRF animals. Statin administration to the normal control rats led to significant increases in plasma LCAT and hepatic LDL receptor, significant reductions of total cholesterol-to-HDL cholesterol ratio, hepatic HMG-CoA reductase activity, and cholesterol 7alpha-hydroxylase abundance with virtually no change in plasma cholesterol concentration. Thus administration of rosuvastatin reversed LCAT and LDL receptor deficiencies and promoted a shift in plasma cholesterol from ApoB-containing lipoproteins to HDL in CRF rats.
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PMID:HMG-CoA reductase inhibition reverses LCAT and LDL receptor deficiencies and improves HDL in rats with chronic renal failure. 1550 47

1. Expression levels of four key enzymes of cholesterol metabolism, namely 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, lanosterol 14-demethylase (CYP51), cholesterol 7alpha-hydroxylase (CYP7A1) and sterol 12alpha-hydroxylase (CYP8B1), in metabolic syndrome model rats (SHR/NDmcr-cp) were examined. 2. Decreased expression of CYP51, which may be linked to the development of obesity, was found in the rats. 3. Expression of CYP8B1 was significantly higher in young rats. 4. No substantial change was observed in the mRNA levels of the dominant rate-limiting enzymes of sterol metabolism, namely HMG-CoA reductase and CYP7A1, in the rats. 5. These findings suggest that the expression levels of two key enzymes managing the downstream parts of the cholesterol-metabolizing pathways are altered in the rats, although little change was observed in the expression levels of the dominant rate-limiting enzymes of cholesterol metabolism.
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PMID:Studies on the expression levels of sterol-metabolizing enzymes in the obese model SHR/NDmcr-cp rats. 1564 92

Hypoalbuminemia is accompanied by hypercholesterolemia in both nephrotic syndrome and hereditary analbuminemia. Hypercholesterolemia is more severe in the female than in the male Nagase analbuminemic rats (NAR). The sex difference in plasma cholesterol diminishes after ovariectomy (OVX) and reappears after estrogen replacement in the NAR. The molecular mechanism responsible for the sex difference in severity of hypercholesterolemia in NAR is not known and was investigated here. To this end, hepatic hydroxylmethylglutaryl (HMG)-CoA reductase, cholesterol 7alpha-hydroxylase, and LDL receptor were determined in male, female, and OVX female NAR and Sprague-Dawley (SD) rats. Plasma cholesterol, triglycerides, and hepatic HMG-CoA reductase activities were greater in both female and male NAR than in SD rats. This was coupled with upregulation of cholesterol 7alpha-hydroxylase in both male and female NAR compared with SD controls. LDL receptor in male NAR was similar to that in male SD rats but was significantly reduced in female NAR. OVX partially, but significantly, reduced plasma cholesterol and triglyceride levels in female NAR. This was coupled with a significant rise in hepatic cholesterol 7alpha-hydroxylase and a modest increase in hepatic LDL receptor. In contrast, OVX resulted in a mild elevation of plasma cholesterol and no significant changes in total hepatic HMG-CoA reductase, cholesterol 7alpha-hydroxylase, or LDL receptor in female SD rats. Thus the greater severity of hypercholesterolemia in the female NAR appears to be due, in part, to a combination of the constrained compensatory upregulation of cholesterol 7alpha-hydroxylase and LDL receptor deficiency.
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PMID:Effects of gender on hepatic HMG-CoA reductase, cholesterol 7alpha-hydroxylase, and LDL receptor in hereditary analbuminemia. 1603 68

We have demonstrated that SC-435, an apical sodium codependent bile acid transporter (ASBT) inhibitor, lowers plasma low-density lipoprotein cholesterol (LDL-C) concentrations in guinea pigs. The purpose of this study was to further examine the hypocholesterolemic effects of SC-435, by measuring the activity and RNA expression of regulatory enzymes of hepatic cholesterol and lipoprotein metabolism. In addition, the use of a combination (COMBO) therapy with simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was also tested. Male Hartley guinea pigs were randomly allocated to one of three diets (n=10 per group), for 12 weeks. The control diet contained no ASBT inhibitor or simvastatin. The monotherapy diet (ASBTi) contained 0.1% of SC-435. The COMBO therapy consisted of a lower dose of SC-435 (0.03%) and 0.05% simvastatin. Cholesterol ester transfer protein (CETP) and HMG-CoA reductase mRNA abundance were determined using RT-PCR techniques. Hepatic HMG-CoA reductase and cholesterol 7alpha-hydroxylase (CYP7) activities were measured by radioisotopic methods. Compared to the control group, CETP activity was 34% and 56% lower with ASBTi and COMBO, respectively. Similarly, CETP mRNA expression was reduced by 36% and 73% in ASBTi and COMBO groups, respectively. Cholesterol 7alpha-hydroxylase and HMG-CoA reductase activities were increased approximately 2-fold with ASBTi and COMBO treatments, respectively. Likewise, HMG-CoA reductase mRNA expression was increased 33% with ASBTi treatment. These results suggest that both SC-435 monotherapy and combination therapy lower LDL cholesterol concentrations by altering both hepatic cholesterol homeostasis and the intravascular processing of lipoproteins in guinea pigs.
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PMID:SC-435, an ileal apical sodium-codependent bile acid transporter inhibitor alters mRNA levels and enzyme activities of selected genes involved in hepatic cholesterol and lipoprotein metabolism in guinea pigs. 1616 2

We examined the effects of adzuki bean resistant starch on serum cholesterol and hepatic mRNA in rats fed a cholesterol diet. The mRNA coded for key regulatory proteins of cholesterol metabolism. The control rats were fed 15 % cornstarch (basal diet, BD). The experimental rats were fed BD plus a 0.5 % cholesterol diet (CD), or a 15 % adzuki resistant starch plus 0.5 % cholesterol diet (ACD) for 4 weeks. The serum total cholesterol and VLDL + intermediate density lipoprotein + LDL-cholesterol levels in the ACD group were significantly lower than those in the CD group throughout the feeding period. The total hepatic cholesterol concentrations in the CD and ACD groups were not significantly different. The faecal total bile acid concentration in the ACD group was significantly higher than that in the BD and CD groups. Total SCFA and acetic acid concentrations in the ACD group were significantly higher than those in the CD group but there were no significant differences in the concentrations between the ACD and BD groups. The hepatic LDL-receptor mRNA and cholesterol 7alpha-hydroxylase mRNA levels in the ACD group were significantly higher than those in the CD group and the hepatic 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase mRNA level in the ACD group was significantly lower than in the CD group. The results suggest that adzuki resistant starch has a serum cholesterol-lowering function via enhancement of the hepatic LDL-receptor mRNA and cholesterol 7alpha-hydroxylase mRNA levels and faecal bile acid excretion, and a decrease in the hepatic HMG-CoA reductase mRNA level, when it is added to a cholesterol diet.
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PMID:Adzuki resistant starch lowered serum cholesterol and hepatic 3-hydroxy-3-methylglutaryl-CoA mRNA levels and increased hepatic LDL-receptor and cholesterol 7alpha-hydroxylase mRNA levels in rats fed a cholesterol diet. 1635 66

Plant sterols compete with cholesterol (cholest-5-en-3beta-ol) for intestinal absorption to limit absorption and lower plasma concentrations of cholesterol. Stigmasterol (24-ethyl-cholesta-5,22-dien-3beta-ol; Delta(22) derivative of sitosterol [24-ethyl-cholest-5-en-3beta-ol]), but not campesterol (24-methyl-cholest-5-en-3beta-ol) and sitosterol, is reported to inhibit cholesterol biosynthesis via inhibition of sterol Delta(24)-reductase in human Caco-2 and HL-60 cell lines. We studied the effect of feeding 0.5% stigmasterol on plasma and liver sterols and intestinal cholesterol and sitosterol absorption in 12 wild-type Kyoto (WKY) and 12 Wistar rats. After 3 weeks of feeding, cholesterol and sitosterol absorption was determined in 6 rats from each group by plasma dual-isotope ratio method. After 3 more weeks, plasma and hepatic sterols and hepatic enzyme activities were determined in all rats. After feeding stigmasterol, baseline plasma cholesterol was 1.3 times and plant sterols 3 times greater in WKY compared with Wistar rats. Stigmasterol feeding lowered plasma cholesterol by approximately 11%, whereas plasma campesterol and sitosterol levels were virtually unchanged in both rat strains, and stigmasterol constituted 3.2% of plasma sterols in WKY rats and 1% in Wistar rats. After 6 weeks of feeding, cholesterol and sitosterol absorption decreased 23% and 30%, respectively, in WKY, and 22% and 16%, respectively, in the Wistar rats as compared with untreated rats. The intestinal bacteria in both rat strains metabolized stigmasterol to mainly the 5beta-H stanol (>40%), with only small amounts of 5alpha-H derivative (approximately 1.5%), whereas the C-22 double bond was resistant to bacterial metabolism. Hepatic stigmasterol levels increased from 11 microg/g liver tissue to 104 mug/g in WKY rats and from 5 microg/g liver tissue to 21 microg/g in Wistar rats. 3-Hydroxy-3-methylglutaryl coenzyme A reductase activity was suppressed 4-fold in the WKY and almost 1.8-fold in Wistar rats, cholesterol 7alpha-hydroxylase activity was suppressed 1.6-fold in the WKY and 3.5-fold in Wistar rats, whereas cholesterol 27-hydroxylase activity was unchanged after feeding. In conclusion, stigmasterol, when fed, lowers plasma cholesterol levels, inhibits intestinal cholesterol and plant sterol absorption, and suppresses hepatic cholesterol and classic bile acid synthesis in Wistar as well as WKY rats. However, plasma and hepatic incorporation of stigmasterol is low.
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PMID:Stigmasterol reduces plasma cholesterol levels and inhibits hepatic synthesis and intestinal absorption in the rat. 1648 71

Soybean [Glycine max (L.) Merrill] is known to have hypocholesterolemic effects; however, the function and mechanism of its digestion-resistant fraction (RF) in cholesterol reduction is not clearly understood. In the present study, we investigated the hypocholesterolemic effects of the RF from soybean in C57BL/6J and apolipoprotein E (apoE)-deficient mice. RFs were prepared either from raw or preheated crops to measure compositional changes in RF during cooking. Preheating reduced the RF yields and the resistant starch (RS) fraction in RF. After 1 week of feeding, the raw soybean RF (5%, w/w) was the most effective in lowering plasma cholesterol concentrations by 27% (P<.05) in apoE-deficient (apoE-/-) mice. A smaller but significant reduction was found in C57BL/6J mice. The RF from preheated soybean tended to have lower hypocholesterolemic effects than did the RF from raw soybean in apoE-/- mice. This suggests the RS may be a key hypocholesterolemic component from soybean RF. RF consumption (5%, w/w) dramatically increased hepatic low-density lipoprotein receptor and cholesterol 7alpha-hydroxylase expression in both apoE-/- and C57BL/6J mice followed by increased bile acid excretion. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase was only marginally altered. Our results show that the RF, especially from raw soybean containing high level of RS, significantly reduces plasma cholesterol concentrations under hyperlipidemic condition. The cholesterol was reduced by multiple mechanisms such as increased hepatic cholesterol uptake, cholesterol degradation into bile acids and bile acid excretion.
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PMID:Digestion-resistant fraction from soybean [Glycine max (L.) Merrill] induces hepatic LDL receptor and CYP7A1 expression in apolipoprotein E-deficient mice. 1651 41


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