Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0020473 (hyperlipidemia)
15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Partially inbred lines of laboratory opossums differ considerably in their low-density lipoprotein (LDL) cholesterol responses to dietary cholesterol and fat. Genetic analysis suggested that a single major gene is responsible for the variation in LDL cholesterol on the high cholesterol and high fat (HCHF) diet. We measured cholesterol absorption and acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity in intestine and liver to narrow the search for the major gene. We measured plasma lipoproteins and percent cholesterol absorption by the fecal isotope ratio method in high and low responding lines of opossums on basal and HCHF diets. We also measured lipids in liver and ACAT activity in liver and intestine on the HCHF diet. High and low lines exhibited no differences in percent cholesterol absorption on the basal diet. However, high responding opossums had significantly higher percent cholesterol absorption, hepatic free and esterified cholesterol, and hepatic ACAT activity than low responding opossums on the HCHF diet. Hepatic ACAT activity but not the intestinal ACAT activity was associated with hepatic cholesterol concentration and percent cholesterol absorption. Cholesterol absorption is a major determinant of diet-induced hyperlipidemia in opossums. Hepatic ACAT activity but not the intestinal ACAT may also play a role in diet-induced hyperlipidemia in opossums.
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PMID:Cholesterol absorption and hepatic acyl-coenzyme A:cholesterol acyltransferase activity play major roles in lipemic response to dietary cholesterol and fat in laboratory opossums. 1516 35

Acyl-CoA: cholesterol acyltransferase (ACAT), which plays a role in the absorption, storage, and production of cholesterol, has been explored as a potential target for pharmacological intervention of hyperlipidemia and atherosclerotic disease. In our search for ACAT inhibitors from natural sources, the petroleum ether extract of Panax ginseng showed moderate inhibition of ACAT enzyme from rat liver microsomes. Bioactivity-guided fractionations led to the isolation of one new polyacetylenic compound, (9R,10S)-epoxy-16-heptadecene-4, 6-diyne-3-one (1), in addition to the previously reported polyacetylenic compounds 2 and 3. Their chemical structures were elucidated on the basis of spectroscopic evidence (UV, IR, NMR, and MS). The compounds 1, 2, and 3 showed significant ACAT inhibition with IC(50) values of 35, 47, and 21 microM, respectively.
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PMID:Polyacetylenic compounds, ACAT inhibitors from the roots of Panax ginseng. 1571 98

The advent of statins has virtually resolved the treatment of a majority of essential hypercholesterolaemic patients. Nevertheless, other abnormalities in lipoprotein metabolism, including such lipoprotein disturbances as hypertriglyceridaemia, mixed hyperlipidaemia, accumulation of small dense low density lipoprotein (LDL), high levels of lipoprotein (a) (Lp[a]) and hypo-HDL-cholesterolaemia, although also highly atherogenic, are not as efficiently treated as essential hypercholesterolaemia. Pharmaceutical companies are improving new molecules directed against old targets (PPARalpha: fibrates) or creating original molecules directed against new targets (acyl CoA:cholesterol acyltransferase (ACAT), microsomal triglyceride transfer protein (MTP), retinoid X receptor (RXR)). Of the multitude of ACAT inhibitors, only a few have reached preliminary clinical studies: e.g., F-1394, Sch48461 and CI-1011. They reduce LDL-cholesterol and atherosclerosis development in animals, partly by directly inhibiting cholesteryl ester formation in the artery wall. BW-USC-148 is a fibric acid derivative with ACAT-inhibiting activity. The hypocholesterolaemic activity for this novel ureido fibrate analogue was found to be over 100-fold greater than that of any 'second generation' fibrate in cholesterol-fed rats, mainly through its fibrate activity (PPARalpha activation) but not its ACAT activity. Targretin (LGD1069), a member of the rexinoid family (RXR activator), was shown to decrease triglyceridaemia and to increase HDL levels in hypertriglyceridaemic rats. Microsomal triglyceride transfer protein inhibitors are potent inhibitors of the synthesis of all the atherogenic apolipoprotein B-containing particles and are under development, but in vivo data are not yet available in literature. Vitamin E, an old molecule, should be used in the near future as a potent anti-atherosclerotic treatment due to its anti-oxidant power. Results of preliminary gene therapy studies of homozygous familial hypercholesterolaemic patients and of hypo-HDL-cholesterolaemia in animals are promising but do not show hope for significant clinical use in the near future. The improvement in the understanding of the molecular mechanisms of dyslipoproteinaemia and atherosclerosis development, taken together with new strategies in drug design and drug synthesis, has led to the discovery of potent normolipidaemic drugs.
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PMID:Post-statin approaches to hyperlipidaemia. 1599 42

Acyl-coenzyme A:cholesterol acyltransferase (ACAT) 1 and ACAT2 play an important role in cellular cholesterol esterification and thus modulate intestinal cholesterol absorption and hepatic lipoprotein secretion. The relative expression levels of ACAT1 and ACAT2 in human tissues differ from those in other animals, including nonhuman primates. The present study compared the relative expression levels of ACAT1 and ACAT2 in baboons with high and low lipemic responses to dietary lipids. We isolated RNA and prepared cDNA from frozen liver and small intestine from high- and low-responding pedigreed baboons necropsied after consuming a high-cholesterol and high-fat diet for 18 months. The expression of ACAT1 and ACAT2 was measured by TaqMan real-time quantitative PCR normalized to 18s ribosomal RNA. The expression of ACAT1 was higher than that of ACAT2 in the liver, whereas the expression of ACAT2 was higher than that of ACAT1 in the duodenum and jejunum. There was no difference in the expression of ACAT1 or ACAT2 in the liver and intestine between high- and low-responding baboons except that the expression of ACAT1 was higher in the duodenum of high responders than in that of low responders. Western blot analysis also showed a higher level of ACAT1 protein in the duodenum of high responders than in that of low responders. There was a significant correlation between duodenal ACAT expression levels and total plasma cholesterol concentration in baboons. These results suggest that differences in ACAT1 expression may affect plasma cholesterol concentration and partly affect diet-induced hyperlipidemia.
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PMID:Expression levels of ACAT1 and ACAT2 genes in the liver and intestine of baboons with high and low lipemic responses to dietary lipids. 1608 Dec 63

According to the Vital Statistics Report published by the Japanese Ministry of Health and Welfare, heart disease and cerebrovascular disease are the main causes of death in Japan. The main pathological finding in these diseases is atherosclerosis and the main risk factors, besides the patient's age and diathesis, include hyperlipidemia, hypertension, diabetes, obesity and smoking. Among the aforementioned various risk factors, hyperlipidemia play a crucial role at the stage of atherosclerosis. The main pathological findings in atherosclerosis include abnormal reactions of neutrophils, lymphocytes and monocytes/macrophages, vascular smooth muscle cells and vascular endothelial cells, and the accumulation of cholesterol ester in the arterial wall. Previously, Mg(2+) deficit and the lower blood concentration of Mg(2+) was a frequent in patients with the main risk factors, hyperlipidemia, hypertension, diabetes, and obesity. Magnesium is necessary the activity of lecithin cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL), which lowers triglyceride levels and raises HDL-cholesterol levels. Moreover, Mg(2+)-ATP is also the controlling factor for the rate-limiting enzyme in the cholesterol biosynthesis, which associated with cholesterol levels. In this article, we first discuss the effect of Mg(2+) deficit on atherosclerosis, especially hyperlipidemia in bloodstream and liver. Then, based on recent studies including our own, we describe the Mg(2+) deficit and the relationships between risk factors for atherosclerosis, hypertension, oxidative stress, cholesterol reverse transport system, and the molecular mechanisms, especially peroxisome preoliferator-activated receptor (PPAR), which have the pleiotropic effect in atherosclerosis. The mechanism is likely the effect of Mg(2+) on atherosclerosis.
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PMID:[Lipid metabolism and magnesium]. 1627 15

Flavonoids have been identified as the antidiabetic components in a number of traditional ethnic remedies. However, the mechanisms whereby these compounds exert their hypoglycemic and hypolipidemic action in type-2 diabetes have rarely been investigated. Therefore, this study investigated the effect of the flavonoids hesperidin and naringin on glucose and lipid regulation in C57BL/KsJ-db/db mice. Hesperidin and naringin both significantly increased the glucokinase mRNA level, while naringin also lowered the mRNA expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver. In addition, the hepatic glucose transporter 2 protein expression was significantly reduced, while the expression of adipocyte glucose transporter 4 and hepatic and adipocyte peroxisome proliferator-activated receptor gamma were elevated in the hesperidin and naringin groups when compared with the control group. Furthermore, hesperidin and naringin effectively lowered the plasma free fatty acid and plasma and hepatic triglyceride levels, and simultaneously reduced the hepatic fatty acid oxidation and carnitine palmitoyl transferase activity. These changes were seemingly attributable to a suppression of the hepatic fatty acid synthase, glucose-6-phosphate dehydrogenase, and phosphatidate phosphohydrolase activities and an increase in the fecal triglycerides. The two flavonoids also led to a decrease in the plasma and hepatic cholesterol levels that may have been partly due to the decreased hepatic 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase and acyl CoA: cholesterol acyltransferase (ACAT) activities and increased fecal cholesterol. Consequently, the current results suggest that hesperidin and naringin are beneficial for improving hyperlipidemia and hyperglycemia in type-2 diabetic animals by partly regulating the fatty acid and cholesterol metabolism and affecting the gene expression of glucose-regulating enzymes.
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PMID:Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice. 1642 99

The anti-diabetic efficacy of Du-zhong (Eucommia ulmoides Oliver) leaves water extract (WDZ) was investigated in type 2 diabetic animals. The WDZ was given to C57BL/KsJ-db/db mice as a dietary supplement based on 1% dried whole Du-zhong leaves (0.187 g WDZ/100 g standard diet) for 6 weeks. The WDZ supplementation significantly lowered the blood glucose level and enhanced the glucose disposal in an intraperitoneal glucose tolerance test. The plasma insulin and C-peptide levels were significantly higher in the WDZ group than in the control group, while the glucagon level was lower. The hepatic glucokinase activity was significantly higher in the WDZ group, whereas, the glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities were significantly lower. The WDZ supplementation also significantly lowered the hepatic fatty acid synthase, HMG-CoA reductase and ACAT activities compared to the control group, while it elevated the lipoprotein lipase activity in the skeletal muscle. The WDZ also altered the plasma and hepatic lipid levels by lowering the cholesterol and triglyceride concentrations, while elevating the plasma HDL-cholesterol level. Therefore, these results suggest that WDZ may partly ameliorate hyperglycemia and hyperlipidemia with type 2 diabetes through increasing glycolysis, suppressing gluconeogenesis and the biosynthesis of fatty acid and cholesterol in the liver.
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PMID:Hypoglycemic and hypolipidemic action of Du-zhong (Eucommia ulmoides Oliver) leaves water extract in C57BL/KsJ-db/db mice. 1668 93

Hyperlipidemia is a well-established risk factor for atherogenesis and cardiovascular disease. Statins have been the cornerstone of treatment for hyperlipidemia in recent years and have significantly contributed to the improvement of cardiovascular disease therapy. However, novel antihyperlipidemic agents that have been developed over the last decade possess the capacity to significantly reduce plasma lipoproteins. This review analyzes the pharmacological profile, effectiveness and safety of some promising drugs that are either already in clinical use (eg, ezetimibe and nicotinic acid) or under study (eg, acyl-CoA cholesterol acyltransferase inhibitors, cholesteryl ester transfer protein inhibitors and apolipoprotein A-IMilano).
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PMID:Prospects for the development of novel anti-hyperlipidemic drugs. 1872

Cyclosporine A (CsA)-induced nephrotoxicity hampers the immense therapeutic potential of such a powerful immunosuppressant. The present study was conducted with an aim to explicate the contribution of sulphated polysaccharides (SPS) in abating the lipid abnormalities induced by CsA in the rat kidney. Hyperlipidemia associated with nephrotic syndrome may play a role in the worsening of renal function. Male albino Wistar rats sorted into four groups were used for the study. CsA was given at a dose of 25 mg/kg body weight, orally for 21 days. Significant alterations in the lipid profile as well an increase in the activity of cholesterol ester synthase, coupled with a decrease in cholesterol ester hydrolase and lipoprotein lipase enzyme activities were noted in the plasma and kidneys of CsA-administered rats. A marked increase in the lipoprotein fractions, low-density lipoprotein (LDL) and very low density lipoprotein (VLDL), along with a decrease in the HDL level were found in CsA-administered rats. The degree of nephrotoxicity allied with lipid discrepancies was evident from augmented urinary excretion of urea, uric acid and creatinine. Further, an enhanced susceptibility of the apo B-containing lipoproteins (LDL + VLDL) to oxidation in vitro, induced by copper ions was also found in the plasma of CsA given groups. While SPS co-treated groups (5 mg/kg body weight, subcutaneously) revealed a normalized lipid profile and lipid metabolizing enzymes, the supplementation of SPS also brought back the elevated urinary constituents close to that of the controls and substantially minimized the oxidative changes. With these observations, it may be concluded herein that SPS may be an ideal choice as a renoprotective and hypolipidemic agent against CsA-induced hyperlipidemic nephropathy.
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PMID:Protective role of sulphated polysaccharides in abating the hyperlipidemic nephropathy provoked by cyclosporine A. 1701 61

Growing evidence suggests that the small intestine may contribute to excessive postprandial lipemia, which is highly prevalent in insulin-resistant/Type 2 diabetic individuals and substantially increases the risk of cardiovascular disease. The aim of the present study was to determine the role of high glucose levels on intestinal cholesterol absorption, cholesterol transporter expression, enzymes controlling cholesterol homeostasis, and the status of transcription factors. To this end, we employed highly differentiated and polarized cells (20 days of culture), plated on permeable polycarbonate filters. In the presence of [(14)C]cholesterol, glucose at 25 mM stimulated cholesterol uptake compared with Caco-2/15 cells supplemented with 5 mM glucose (P < 0.04). Because combination of 5 mM glucose with 20 mM of the structurally related mannitol or sorbitol did not change cholesterol uptake, we conclude that extracellular glucose concentration is uniquely involved in the regulation of intestinal cholesterol transport. The high concentration of glucose enhanced the protein expression of the critical cholesterol transporter NPC1L1 and that of CD36 (P < 0.02) and concomitantly decreased SR-BI protein mass (P < 0.02). No significant changes were observed in the protein expression of ABCA1 and ABCG8, which act as efflux pumps favoring cholesterol export out of absorptive cells. At the same time, 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity was decreased (P < 0.007), whereas ACAT activity remained unchanged. Finally, increases were noted in the transcription factors LXR-alpha, LXR-beta, PPAR-beta, and PPAR-gamma along with a drop in the protein expression of SREBP-2. Collectively, our data indicate that glucose at high concentrations may regulate intestinal cholesterol transport and metabolism in Caco-2/15 cells, thus suggesting a potential influence on the cholesterol absorption process in Type 2 diabetes.
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PMID:Modulation of intestinal cholesterol absorption by high glucose levels: impact on cholesterol transporters, regulatory enzymes, and transcription factors. 1877 61


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