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)

The disturbance of lipid metabolism is seen in some inherited diseases and also in patients with some kinds of underlying diseases. The presence of its disturbance can be detected by measuring the concentrations of cholesterol and triglyceride in serum. Although hyperlipidemia or hypolipidemia is the result of abnormal lipid metabolism, hyperlipidemia is of more concern to physicians because of the close association with atherosclerosis. Responsible genes for some primary (or hereditary) hyperlipidemic diseases have been confirmed as follows; LPL or apo C-II for primary chylomicronemia, LDL receptor for familial hypercholesterolemia and apo B-100 for familial defective apo B-100. However, the responsible gene remains controversial for familial combined hyperlipidemia, though AI/CIII/AIV cluster is one of the possible candidate genes. Secondary hyperlipidemia is caused by various diseases such as diabetes mellitus, renal diseases and cholestasis. This type of hyperlipidemia is improved by therapy for the underlying diseases. To date, the mechanism of lipid metabolism has been defined in a molecular basis. In fact, sterol regulatory element-binding protein (SREBP), peroxisome proliferator-activated receptor (PPAR) and ATP-binding cassette transporter subfamily A, member 1(ABCA1) were recently identified and it was demonstrated that these regulate lipid metabolism.
 ...
PMID:[Disturbance of lipid metabolism]. 1198 47

The R219K polymorphism in the ATP-binding cassette transporter 1 gene ( ABCA1) has been associated with reduced severity of atherosclerosis, fewer coronary events, decreased triglycerides and a trend to increased HDL in men with coronary heart disease (CHD). This study examined the frequency and the effect on CHD and plasma lipids of the polymorphism in patients of both sexes attending a lipid out-patient clinic. The overall frequency of the K allele was 0.26. It was lower in patients with CHD (0.21) than in those without (0.27) but this was not statistically significant. Amongst patients with elevated Lp(a) the frequency of the K allele was significantly lower in those with CHD (0.16) than in those without (0.29). There were no statistically significant differences in total cholesterol, LDL, HDL, apoB or apoAI between carriers and non-carriers. When patients with probable secondary hypertriglyceridaemia (triglycerides >1000 mg/dl), type 2 diabetes and carriers of lipoprotein lipase polymorphisms associated with hypertriglyceridaemia were excluded, the K allele was significantly associated with reduced triglycerides but only in patients with apoE 3/3 genotype. In conclusion, we provide additional evidence that the R219K polymorphism in the ABCA1 gene either directly or as a result of linkage disequilibrium with additional functional variant(s), has a protective effect against CHD and is associated with lower plasma triglycerides in sub-groups of patients with hyperlipidaemia.
 ...
PMID:The association of the R219K polymorphism in the ATP-binding cassette transporter 1 ( ABCA1) gene with coronary heart disease and hyperlipidaemia. 1270 Aug 93

The field of new lipid-lowering drug research is very active, with researchers, looking to make the currently available drugs more powerful and safer, and to develop new classes of drugs. Among the statins, development has gone the farthest for rosuvastatin and pitavastatin. Colesevelam is a new bile acid sequestrant with a better digestive tolerance. Among the new classes of drugs, the most promising molecules are the cholesterol absorption inhibitors--with ezetimibe as the first in line--and the PPAR-alpha and PPAR-gamma activators. Among the other classes, the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, and ileal bile acid transporter inhibitors, have to be mentioned. In most of the cases, those new compounds are being developed mainly as a combined treatment with statins. However, these combination therapies differ depending on the lipid abnormalities of the patient. The statin-ezitimibe and the statin-bile acid sequestrant combinations have been the most studied treatments in pure hypercholesterolaemia. On another hand, the statin-PPAR-alpha and -gamma activator combination were the first to be developed for patients with combined hyperlipidaemia or type 2 diabetes mellitus. However, the clinical benefit of ACAT or CETP inhibitors remains to be determined and the development of MTP inhibitors has been restricted so far, because of problems of digestive intolerance and hepatic steatosis. Finally, the discovery of new specific lipoprotein receptors, such as the ABCA1 and SRB1 receptors, means that we can work towards developing new potential targets for pharmacological intervention.
 ...
PMID:[New antilipemics: prospects]. 1282 7

The objective of this study was to determine the effect of two amino-terminal apolipoprotein A-I (apoA-I) deletions on high-density lipoprotein (HDL) biosynthesis and lipid homeostasis. Adenovirus-mediated gene transfer showed that the apoA-I[Delta(89-99)] deletion mutant caused hypercholesterolemia, characterized by increased plasma cholesterol and phospholipids, that were distributed in the very low density/intermediate density/low-density lipoprotein (VLDL/IDL/LDL) region, and normal triglycerides. The capacity of the mutant protein to promote ATP-binding cassette transporter A1- (ABCA1-) mediated cholesterol efflux and to activate lecithin:cholesterol acyltranserase (LCAT) was approximately 70-80% of the wild-type (WT) control. The phospholipid transfer protein (PLTP) activity of plasma containing the apoA-I[Delta(89-99)] mutant was decreased to 32% of the WT control. Similar analysis showed that the apoA-I[Delta(62-78)] deletion mutant in apoA-I-deficient mice caused combined hyperlipidemia characterized by increased triglycerides, cholesterol, and phospholipids in the VLDL/IDL region. There was enrichment of the VLDL/IDL with mutant apoA-I that resulted in reduction of in vitro lipolysis. The capacity of this mutant to promote ABCA1-mediated cholesterol efflux was normal, and the capacity to activate LCAT in vitro was reduced by 53%. The WT apoA-I and the apoA-I[Delta(62-78)] mutant formed spherical HDL particles, whereas the apoA-I[Delta(89-99)] mutant formed discoidal HDL particles. We conclude that alterations in apoA-I not only may have adverse effects on HDL biosynthesis but also may promote dyslipidemia due to interference of the apoA-I mutants on the overall cholesterol and triglycerides homeostasis.
 ...
PMID:Deletions of helices 2 and 3 of human apoA-I are associated with severe dyslipidemia following adenovirus-mediated gene transfer in apoA-I-deficient mice. 1575 88

Hyperlipidemias and small dense LDLs in patients with high-triglyceride low-HDL syndromes lead to a prolonged half life of apoB-containing particles. This is associated with reactive oxygen species (ROS) activation and leads to formation of oxidized LDL (Ox-LDL). Generators of ROS in macrophages (MACs) include myeloperoxidase (MPO)-mediated respiratory burst and raft-associated NADPH-oxidase. The intracellular oxidant milieu is involved in cellular signaling pathways, like ion-transport systems, protein phosphorylation, and gene expression. Lipid oxidation through ROS can amplify foam cell formation through Ox-LDL uptake, leading to formation of ceramide (Cer)-rich lipid membrane microdomains, and is associated with expansion of the lysosomal compartment and an upregulation of ABCA1 and other genes of the AP3 secretory pathway. Ox-LDL may also affect cell-surface turnover of Cer-backbone sphingolipids and apoE-mediated uptake by LRP-family members. In contrast, HDL-mediated lipid efflux causes disruption of lipid membrane microdomains and prevents foam cell formation. Oxidation of HDL through MPO leads to a failure of lipid efflux and enhancement of MAC loading. Therefore, lipid rafts and oxidation processes are important in regulation of MAC foam cell formation and atherosclerosis, and the balance between oxidant and antioxidant intracellular systems is critically important for efficient MAC function.
 ...
PMID:Role of redox regulation and lipid rafts in macrophages during Ox-LDL-mediated foam cell formation. 1760 Apr 63

Various dietary factors affect postprandial metabolism yet precise mechanisms have not necessarily been pinpointed. The effects of various meal components on postprandial lipemia lead to the following question: do we need a standardized oral lipid tolerance test? A number of transporters, enzymes, receptors and hormones directly influence and act as "gatekeepers" of these processes. Each protein appears to have specific and individual functional roles in the overall process and selected developments in these areas will be reviewed. Within the intestinal cells, FABP2 (fatty acid-binding protein 2) and MTP (microsomal triglyceride transfer protein) are required for the formation of chylomicrons. Niemann-Pick C1-like 1 (NPC1-L1) plays an important role in cholesterol absorption and provides a pharmacological target. Hormones such as GLP1 and GLP2 influence this absorption process. Within the periphery, lipoprotein lipase (LPL) is a key gatekeeper of clearance. Of the massive amounts of fatty acids released by LPL, 36% escape peripheral adipose and muscle uptake and fatty acid overload can result in LPL product inhibition. Acylation stimulating protein (ASP) and insulin are two key hormones in maintaining efficient tissue uptake and re-esterification of fatty acids while TNFalpha negatively influences this process. In both ASP deficient (C3 KO) and C5L2 KO mice, postprandial lipemia increased with reduced adipose tissue storage. This is compensated by increased energy expenditure and muscle lipid oxidation. Clearance of hepatic remnants is controlled through many factors, including SR-B1 and ABCA1. Intestinal, peripheral and hepatic gatekeepers serve important and individual roles in regulating postprandial lipemia and provide potential targets for regulation.
 ...
PMID:Intestinally derived lipids: metabolic regulation and consequences--an overview. 1869 44

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.
 ...
PMID:Modulation of intestinal cholesterol absorption by high glucose levels: impact on cholesterol transporters, regulatory enzymes, and transcription factors. 1877 61

The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that functions as an endogenous sensor for bile acids and regulates cholesterol and fatty acid metabolism. The effect of FXR activation on aortic plaque formation was assessed by feeding apolipoprotein E-deficient (ApoE-/-) mice with the synthetic FXR ligand INT-747, a cheno-deoxycholic acid derivative, at doses of 3 and 10 mg x kg(-1) x day(-1), or with rosiglitazone, a peroxisome proliferator-activated receptor-gamma ligand, at the dose of 10 mg x kg(-1) x day(-1) for 12 wk. Administration of INT-747 reduced formation of aortic plaque area by 95% (P < 0.01), and a similar antiplaque activity was exerted by administration of rosiglitazone. INT-747 administration to ApoE-/- mice reduced aortic expression of IL-1beta, IL-6, and CD11b mRNA, while it upregulated the expression of FXR and its target gene, the small heterodimer partner (SHP). FXR activation reduced the liver expression of sterol regulatory element binding protein 1c, resulting in reduced triglyceride and cholesterol content in the liver and amelioration of hyperlipidemia. FXR expression, mRNA and protein, was detected in human macrophages and macrophage cell lines. FXR activation by natural and synthetic ligands in these cell types attenuated IL-1beta, IL-6, and TNF-alpha gene induction in response to Toll-like receptor 4 activation by LPS. Using spleen monocytes from wild-type and FXR-/- mice, we demonstrated that FXR gene ablation exacerbates IL-6 and TNF-alpha generation by LPS-stimulated macrophages. FXR was also able to reduce cholesterol uptake on macrophages by regulation of CD36 and ABCA1 expression. We found that FXR and SHP are expressed in the aorta and macrophages and that FXR ligands might have utility in prevention and treatment of atherosclerotic lesions.
 ...
PMID:Antiatherosclerotic effect of farnesoid X receptor. 1902 91

Insulin resistance and type 2 diabetes (T2D) are characterized by hyperlipidemia. The aim of the present study was to elucidate whether T2D contributes to abnormal cholesterol (CHOL) homeostasis. Experiments were carried out in the small intestine and liver of Psammomys obesus, a model of nutritionally induced T2D. Our results show that diabetic animals exhibited a lower intestinal CHOL uptake, which was associated with a decrease in 1) the gene and protein expression of Niemann-Pick C1 like 1 that plays a pivotal role in CHOL incorporation in the enterocytes; and 2) mRNA of ATP-binding cassette transporters (ABC)A1 that mediates CHOL efflux from intestinal cells to apolipoprotein A-I and high-density lipoprotein. No changes were observed in the other intestinal transporters scavenger receptor-class B type I (SR-BI) and annexin 2. On the other hand, in diabetic animals, a significant mRNA decrease was noticed in intestinal ABCG5 and ABCG8 responsible for the secretion of absorbed CHOL back into the lumen. Furthermore, jejunal PCSK9 protein was diminished and low-density lipoprotein receptor was raised, along with a significant down-regulation in jejunal 3-hydroxy-3-methylglutaryl-coenzyme A reductase in P. obesus with T2D. Finally, among the transcription factors tested, only an increase in liver X receptors alpha and a decrease in peroxisome proliferator-activated receptors delta/beta mRNAs were detected in the intestine. In the liver, there was 1) an augmentation in the protein mass of Niemann-Pick C1 like 1, SR-BI, and annexin 2; 2) an up-regulation of SR-BI mRNA; 3) a fall in ABCG8 protein content as well as in ABCG5 and ABCA1 mRNA; and 4) an augmentation in liver X receptors alpha and peroxisome proliferator-activated receptors beta/delta mRNA, together with a drop in sterol regulatory element binding protein-2 protein. Our findings show that the development in P. obesus with T2D modifies the whole intraenterocyte and hepatocyte machinery responsible for CHOL homeostasis.
 ...
PMID:Intestinal and hepatic cholesterol carriers in diabetic Psammomys obesus. 2013 Jan 16

The relationship between alimentary lipemia and coronary disease is of great interest in view of the epidemiological and experimental evidence that underlies it. The modulation of such phenomena is influenced by both genetic and environmental factors, thus explaining their extraordinary individual variance. Over the last two decades there has been an explosion of research in this area, with often conflicting findings reported in the literature. In this study we have presented the current evidence linking a number of candidate genes (APOA1/C3/A4/A5 cluster, ABCA1, CETP, GCKR, HL, IL-6, LPL, PLIN, and TCF7L2) to the modulation of the postprandial lipid metabolism. Increased knowledge of how these and other genes influence postprandial response should increase the understanding of personalised nutrition.
 ...
PMID:Update on genetics of postprandial lipemia. 2043 7


1 2 3 Next >>