Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Effect of pregnancy and lactation on lipoprotein and cholesterol metabolism in the rat. 979 10

The present study describes the cholesterol absorption by hyperlipidemia atherosclerosis prone (LAP) Japanese quail to address their high susceptibility to experimental atherosclerosis. The apparent cholesterol absorption rate of LAP quail was compared with that of commercially available (CA) Japanese quail. After 14 d of cholesterol feeding by gavage, it was found that the cholesterol excretion of LAP quail was significantly lower than that of CA quail. The fecal excretion of bile acid and fat showed a similar tendency to that as shown with the case of cholesterol. The cholesterol feeding only increased the serum cholesterol level of LAP quail, and this trend holds true for the liver lipid concentration. The expression level of liver cholesterol 7alpha-hydroxylase mRNA showed no difference between LAP and CA strains under the conditions of cholesterol loading. These results showed that the cholesterol absorption by LAP quail is significantly higher than that by CA quail, which may reasonably explain the higher susceptibility of this strain to experimental atherosclerosis.
 ...
PMID:Increased cholesterol absorption by hyperlipidemia atherosclerosis prone (LAP) Japanese quail. 1123 16

Bile acid synthesis plays a critical role in the maintenance of mammalian cholesterol homeostasis. The CYP7A1 gene encodes the enzyme cholesterol 7alpha-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis. We report here a new metabolic disorder presenting with hyperlipidemia caused by a homozygous deletion mutation in CYP7A1. The mutation leads to a frameshift (L413fsX414) that results in loss of the active site and enzyme function. High levels of LDL cholesterol were seen in three homozygous subjects. Analysis of a liver biopsy and stool from one of these subjects revealed double the normal hepatic cholesterol content, a markedly deficient rate of bile acid excretion, and evidence for upregulation of the alternative bile acid pathway. Two male subjects studied had hypertriglyceridemia and premature gallstone disease, and their LDL cholesterol levels were noticeably resistant to 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. One subject also had premature coronary and peripheral vascular disease. Study of the kindred, which is of English and Celtic background, revealed that individuals heterozygous for the mutation are also hyperlipidemic, indicating that this is a codominant disorder.
 ...
PMID:Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. 1209 84

Guggulipid is an extract of the guggul tree Commiphora mukul and has been widely used to treat hyperlipidemia in humans. The plant sterol guggulsterone (GS) is the active agent in this extract. Recent studies have shown that GS can act as an antagonist ligand for farnesoid X receptor (FXR) and decrease expression of bile acid-activated genes. Here we show that GS, although an FXR antagonist in coactivator association assays, enhances FXR agonist-induced transcription of bile salt export pump (BSEP), a major hepatic bile acid transporter. In HepG2 cells, in the presence of an FXR agonist such as chenodeoxycholate or GW4064, GS enhanced endogenous BSEP expression with a maximum induction of 400-500% that induced by an FXR agonist alone. This enhancement was also readily observed in FXR-dependent BSEP promoter activation using a luciferase reporter construct. In addition, GS alone slightly increased BSEP promoter activation in the absence of an FXR agonist. Consistent with the results in HepG2, guggulipid treatment in Fisher rats increased BSEP mRNA. Interestingly, in these animals expression of the orphan nuclear receptor SHP (small heterodimer partner), a known FXR target, was also significantly increased, whereas expression of other FXR targets including cholesterol 7alpha-hydroxylase (Cyp 7a1), sterol 12alpha-hydroxylase (Cyp 8b1), and the intestinal bile acid-binding protein (I-BABP), remained unchanged. Thus, we propose that GS is a selective bile acid receptor modulator that regulates expression of a subset of FXR targets. Guggulipid treatment in rats lowered serum triglyceride and raised serum high density lipoprotein levels. Taken together, these data suggest that guggulsterone defines a novel class of FXR ligands characterized by antagonist activities in coactivator association assays but with the ability to enhance the action of agonists on BSEP expression in vivo.
 ...
PMID:Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump. 1252

Avasimibe is a novel orally bioavailable ACAT inhibitor, currently under clinical development (phase III trials). It was safe when administered to rats, dogs, and humans. In vitro studies in human macrophages demonstrated that avasimibe reduces foam cell formation not only by enhancing free cholesterol efflux, but also by inhibiting the uptake of modified LDL. The concentration-dependent reduction in cellular cholesteryl ester content in these cells was not accompanied by an increase in intracellular free cholesterol, which is in agreement with a good safety profile for avasimibe. In the liver, avasimibe caused a significant reduction in the secretion of apo B and apo B-containing lipoproteins into plasma. Avasimibe induced cholesterol 7alpha-hydroxylase and increased bile acid synthesis in cultured rat hepatocytes, and its administration to rats did not produce an increase in lithogenicity index of the bile. The hypolipidemic efficacy of the compound was demonstrated in cholesterol-fed as well as in non-cholesterol-fed animals. In these models, plasma cholesterol levels were reduced, mainly due to the decrease in the non-HDL cholesterol fraction. Clinical data are scarce, but in a study performed in 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia, avasimibe, 50-500 mg/day, significantly reduced plasma total triglyceride and VLDL-cholesterol. Although total cholesterol, LDL-cholesterol, and HDL-cholesterol were unchanged, it must be stressed that animal data suggest that avasimibe may have direct antiatherosclerotic activity in addition to its cholesterol-lowering effect. Avasimibe treatment can also contribute to increase plaque stability, as it reduces the accumulation of lipids in the arterial wall, inhibits macrophage infiltration into the media and reduces matrix metalloproteinase expression and activity. Moreover, avasimibe and statins have been shown to have synergistic effects, and the combination therapy may not only inhibit atherosclerotic lesion progression but also induce lesion regression, independently of changes in plasma cholesterol.
 ...
PMID:Pharmacology of the ACAT inhibitor avasimibe (CI-1011). 1259 16

1. To develop and characterize a new animal model of hypertension and hyperlipidaemia, we cross-bred spontaneously hypertensive rats (SHR) with spontaneously hyperlipidaemic rats (HLR). 2. A new strain of spontaneously hypertensive hyperlipidaemic rats (SHHR) was established at generation 10 through selective mating of brothers and sisters (systolic blood pressure > 150 mmHg, plasma cholesterol > 150 mg/dL). Cross-bred Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats (SDWKY rats) were used as a control. 3. Adrenaline and noradrenaline levels in the plasma and adrenal medulla of male SHHR were significantly higher than those of male SDWKY rats. The tyrosine hydroxylase activity in the adrenal medulla of male SHHR was significantly higher than that of male SDWKY rats. Low-density lipoprotein expression was found in the plasma of male and female SHHR and HLR. Cholesterol 7alpha-hydroxylase mRNA expression in the liver of male SHHR was lower than that of male SDWKY rats. Endothelium lesions and lipid deposition under the endothelium were observed in the aorta of 24-month-old SHHR, especially female SHHR, but not in age-matched HLR and SDWKY rats. 4. The hypertension of this new animal model of hypertension and hyperlipidaemia may be related to increased catecholamine activity and the hyperlipidaemia may be related to changes in the expression of cholesterol 7alpha-hydroxylase mRNA and lipoprotein profiles. The SHHR may be valuable in the study of mechanisms of atherosclerosis and the evaluation of anti-atherosclerosis drugs as a new strain of cardiovascular disease.
 ...
PMID:Biochemical and morphological characterization of spontaneously hypertensive hyperlipidaemic rats. 1289 Jan 74

Human immunodeficiency virus protease inhibitors induce hyperlipidemia in many patients treated with these drugs. We examined the effects of indinavir on cholesterol and bile acid homeostatic mechanisms in a primary rat hepatocyte (PRH) culture model. In PRH, indinavir up-regulated (2.5-fold) 3-hydroxy-3-methylglutaryl-Coenzyme A reductase mRNA levels 24hr after drug addition. In these same experiments, cholesterol 7alpha-hydroxylase (CYP7A1) mRNA levels, the rate-limiting enzyme in bile acid biosynthesis, was decreased up to 10-fold. Fatty acid synthase mRNA levels were up-regulated more than 3-fold under these conditions. Indinavir did not alter CYP7A1 transcriptional activity, but decreased CYP7A1 mRNA half-life in PRH from 1.5hr to less than 0.5hr. Sterol regulatory element-binding protein-1 (SREBP-1) mature form was increased approximately 6-fold by this drug. Indinavir-induced mRNA changes and SREBP-1 mature protein levels were significantly abated by the addition of cholesterol, solubilized in beta-cyclodextrin, to culture medium. Indinavir markedly decreased endogenous cholesterol esterification and increased cholesterol in intracellular membranes in primary hepatocytes. Indinavir gavaged into intact mice also markedly increased SREBP-1 and SREBP-2 (mature forms) in hepatic nuclei. CYP7A1 mRNA was also decreased approximately 52% in indinavir-treated animals. We propose that indinavir disrupts cellular cholesterol homeostasis by increasing SREBP's and decreasing CYP7A1 mRNA.
 ...
PMID:Indinavir alters sterol and fatty acid homeostatic mechanisms in primary rat hepatocytes by increasing levels of activated sterol regulatory element-binding proteins and decreasing cholesterol 7alpha-hydroxylase mRNA levels. 1469 38

The rate-limiting enzyme in the conversion of cholesterol into bile acids is cholesterol 7alpha-hydroxylase (CYP7A1). An A to C substitution 278 bp upstream in the promoter of the CYP7A1 gene was found to be associated with variations in serum lipid levels in normolipidaemic populations. In the present study, we investigated the involvement of this polymorphism in four different lipid disorders: hypertriglyceridaemia (HTG), combined hyperlipidaemia (CH), familial dysbetalipoproteinaemia (FD) and familial hypercholesterolaemia (FH). In a normolipidaemic male population, homozygous for the apoE3 isoform, an association was found between the AA genotype and higher levels of serum triglycerides (AA: +34%, P = 0.036). In HTG patients, the AA genotype was associated with significantly higher concentrations of total cholesterol (+23%, P = 0.005). There was a tendency towards increased levels of serum triglycerides (+39%, P = 0.06), VLDL-triglycerides (+48%, P = 0.053) and VLDL-cholesterol (+35%, P = 0.059). No significant associations were found between serum lipid levels and the CYP7A1 polymorphism in patients with CH, FD and FH. Our results show that the A-278C polymorphism in the CYP7A1 gene has an effect on triglyceride levels in normolipidaemic males and on cholesterol levels in patients with hypertriglyceridaemia..
 ...
PMID:Modulating effect of the A-278C promoter polymorphism in the cholesterol 7alpha-hydroxylase gene on serum lipid levels in normolipidaemic and hypertriglyceridaemic individuals. 1524 83

To investigate the efficacy of the intake of vinegar for prevention of hyperlipidaemia, we examined the effect of dietary acetic acid, the main component of vinegar, on serum lipid values in rats fed a diet containing 1 % (w/w) cholesterol. Animals were allowed free access to a diet containing no cholesterol, a diet containing 1 % cholesterol without acetic acid, or a diet containing 1 % cholesterol with 0.3 % (w/w) acetic acid for 19 d. Then, they were killed after food deprivation for 7 h. Cholesterol feeding increased serum total cholesterol and triacylglycerol levels. Compared with the cholesterol-fed group, the cholesterol and acetic acid-fed group had significantly lower values for serum total cholesterol and triacylglycerols, liver ATP citrate lyase (ATP-CL) activity, and liver 3-hydroxy-3-methylglutaryl-CoA content as well as liver mRNA levels of sterol regulatory element binding protein-1, ATP-CL and fatty acid synthase (P<0.05). Further, the serum secretin level, liver acyl-CoA oxidase expression, and faecal bile acid content were significantly higher in the cholesterol and acetic acid-fed group than in the cholesterol-fed group (P<0.05). However, acetic acid feeding affected neither the mRNA level nor activity of cholesterol 7alpha-hydroxylase. In conclusion, dietary acetic acid reduced serum total cholesterol and triacylglycerol: first due to the inhibition of lipogenesis in liver; second due to the increment in faecal bile acid excretion in rats fed a diet containing cholesterol.
 ...
PMID:Dietary acetic acid reduces serum cholesterol and triacylglycerols in rats fed a cholesterol-rich diet. 1661 81

A rice bran oil (RBO) diet can reduce plasma lipids; this was attributed to the specific components, gamma-oryzanol and gamma-tocotrienol, which individually were shown to be hypocholesterolemic; however, the mechanism of their effects on diabetic hyperlipidemia and the development of diabetes is not known. Rats with streptozotocin/nicotinamide-induced type 2 diabetes were divided into control, RO10, and RO15 groups, and fed cholesterol-free diets containing 0, 10, and 15 g RBO with 0, 352, and 528 g gamma-oryzanol and 0, 6.0 and 9.0 mg gamma-tocotrienol/100 g diet for 4 wk. Diabetic rats fed the RBO diet had greater insulin sensitivity (P = 0.02) than rats fed the control diet. Diabetic rats fed the RBO diet also had lower plasma triglyceride (P = 0.003), LDL cholesterol (P = 0.028), and hepatic triglyceride concentrations (P = 0.04), as well as greater fecal neutral sterol and bile acid excretion than those fed the control diet. After 4 wk, there was an approximately 100% (P < 0.001) increase in the abundance of hepatic cholesterol 7alpha-hydroxylase, an 89% (P < 0.001) increase in the hepatic LDL-receptor, and a 50% (P < 0.001) increase in hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA in rats fed the RBO diet compared with those fed the control diet. These findings support the conclusion that a rice bran oil-containing diet can significantly suppress hyperlipidemic and hyperinsulinemic responses in diabetic rats. The high contents of gamma-oryzanol and gamma-tocotrienol in RBO can lead to increased fecal neutral sterol and bile acid excretion, via upregulation of cholesterol synthesis and catabolism.
 ...
PMID:A rice bran oil diet increases LDL-receptor and HMG-CoA reductase mRNA expressions and insulin sensitivity in rats with streptozotocin/nicotinamide-induced type 2 diabetes. 1670 6


1 2 3 4 5 6 7 Next >>