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)

A microsomal triglyceride transfer protein (MTP) inhibitor, CP-346086, was identified that inhibited both human and rodent MTP activity [concentration giving half-maximal inhibition (IC50) 2.0 nM]. In Hep-G2 cells, CP-346086 inhibited apolipoprotein B (apoB) and triglyceride secretion (IC50 2.6 nM) without affecting apoA-I secretion or lipid synthesis. When administered orally to rats or mice, CP-346086 lowered plasma triglycerides [dose giving 30% triglyceride lowering (ED30) 1.3 mg/kg] 2 h after a single dose. Coadministration with Tyloxapol demonstrated that triglyceride lowering was due to inhibition of hepatic and intestinal triglyceride secretion. A 2 week treatment with CP-346086 lowered total, VLDL, and LDL cholesterol and triglycerides dose dependently with 23%, 33%, 75%, and 62% reductions at 10 mg/kg/day. In these animals, MTP inhibition resulted in increased liver and intestinal triglycerides when CP-346086 was administered with food. When dosed away from meals, however, only hepatic triglycerides were increased. When administered as a single oral dose to healthy human volunteers, CP-346086 reduced plasma triglycerides and VLDL cholesterol dose dependently with ED50s of 10 mg and 3 mg, and maximal inhibition (100 mg) of 66% and 87% when measured 4 h after treatment. After a 2 week treatment (30 mg/day), CP-346086 reduced total and LDL cholesterol and triglycerides by 47%, 72%, and 75%, relative to either individual baselines or placebo, with little change in HDL cholesterol. Together, these data support further evaluation of CP-346086 in hyperlipidemia.
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PMID:CP-346086: an MTP inhibitor that lowers plasma cholesterol and triglycerides in experimental animals and in humans. 1283 54

The flavonoid naringenin improves hyperlipidemia and hyperglycemia in streptozotocin-treated rats. In HepG2 human hepatoma cells, naringenin inhibits apolipoprotein B (apoB) secretion primarily by inhibiting microsomal triglyceride transfer protein and enhances LDL receptor (LDLr)-mediated apoB-containing lipoprotein uptake. Phosphatidylinositol 3-kinase (PI3K) activation by insulin increases sterol regulatory element-binding protein (SREBP)-1 and LDLr expression and inhibits apoB secretion in hepatocytes. Thus, we determined whether naringenin activates this pathway. Insulin and naringenin induced PI3K-dependent increases in cytosolic and nuclear SREBP-1 and LDLr expression. Similar PI3K-mediated increases in SREBP-1 were observed in McA-RH7777 rat hepatoma cells, which express predominantly SREBP-1c. Reductions in HepG2 cell media apoB with naringenin were partially attenuated by wortmannin, whereas the effect of insulin was completely blocked. Both treatments reduced apoB100 secretion in wild-type and LDLr(-/-) mouse hepatocytes to the same extent. Insulin and naringenin increased HepG2 cell PI3K activity and decreased insulin receptor substrate (IRS)-2 levels. In sharp contrast to insulin, naringenin did not induce tyrosine phosphorylation of IRS-1. We conclude that naringenin increases LDLr expression in HepG2 cells via PI3K-mediated upregulation of SREBP-1, independent of IRS-1 phosphorylation. Although this pathway may not regulate apoB secretion in primary hepatocytes, PI3K activation by this novel mechanism may explain the insulin-like effects of naringenin in vivo.
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PMID:Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation. 1451 40

Primary hyperlipidemia is caused by various molecular defects in lipid metabolism. The Research Committee on Primary Hyperlipidemia organized by the Ministry of Health and Welfare of Japan (present: the Ministry of Health, Labour and Welfare) has investigated reported mutations in Japanese patients with primary hyperlipidemia and related disorders (including hypolipidemia), and has created a database based on the questionnaire sent to the members of council board of the Japan Atherosclerosis Society. Mutations in the following genes were investigated: low density lipoprotein receptor, lecithin: cholesteryl acyltransferase, lipoprotein lipase (LPL), hepatic lipase, apolipoproteins A-I, A-II, A-IV, B, C-II, C-III and E, microsomal triglyceride transfer protein, and cholesterol ester transfer protein (CETP). Until 1998, 922 patients with primary hyperlipidemia and related disorders has been registered with the Research Committee, and 190 mutations in 15 genes had been reported, showing a marked variation in Japanese patients with primary hyperlipidemia and related disorders. So-called "common mutations" have been described in Japanese patients with familial hypercholesterolemia, LPL deficiency and CETP deficiency. The genetic defect of familial combined hyperlipidemia (FCHL) is still unknown although FCHL is speculated to be the most prevalent genetic hyperlipidemia, and further investigations should be performed to elucidate the molecular mechanisms of FCHL
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PMID:Mutations in Japanese subjects with primary hyperlipidemia--results from the Research Committee of the Ministry of Health and Welfare of Japan since 1996--. 1525 64

High levels of plasma apolipoprotein B-100 (apoB-100), the principal apolipoprotein of LDL, are associated with cardiovascular disease. We hypothesized that suppression of apoB-100 mRNA by an antisense oligonucleotide (ASO) would reduce LDL cholesterol (LDL-C). Because most of the plasma apoB is made in the liver, and antisense drugs distribute to that organ, we tested the effects of a mouse-specific apoB-100 ASO in several mouse models of hyperlipidemia, including C57BL/6 mice fed a high-fat diet, Apoe-deficient mice, and Ldlr-deficient mice. The lead apoB-100 antisense compound, ISIS 147764, reduced apoB-100 mRNA levels in the liver and serum apoB-100 levels in a dose- and time-dependent manner. Consistent with those findings, total cholesterol and LDL-C decreased by 25-55% and 40-88%, respectively. Unlike small-molecule inhibitors of microsomal triglyceride transfer protein, ISIS 147764 did not produce hepatic or intestinal steatosis and did not affect dietary fat absorption or elevate plasma transaminase levels. These findings, as well as those derived from interim phase I data with a human apoB-100 antisense drug, suggest that antisense inhibition of this target may be a safe and effective approach for the treatment of humans with hyperlipidemia.
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PMID:An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis. 1571 85

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

Japan Tobacco Inc is developing JTT-130, an orally active microsomal triglyceride transfer protein inhibitor, for the potential treatment of hyperlipidemia. By August 2005, the compound was undergoing a phase II clinical trial in Japan, as well as a phase I trial in Europe.
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PMID:Drug evaluation: The MTP inhibitor JTT-130 as a potential treatment for hyperlipidemia. 1682 Nov 63

The development of cholesterol-lowering drugs, including a statins, bile acid sequestrants and cholesterol absorption inhibitors has expanded the options for cardiovascular prevention. Recent treatment guidelines emphasise that individuals at substantial risk for atherosclerotic coronary heart disease should meet defined lipid targets. Combination therapy with drugs that have different and complementary mechanisms of action is often needed to achieve these goals. Existing approaches to the treatment of hypercholesterolaemia are still ineffective in halting the progression of coronary artery disease in some patients despite combination therapies. Other patients are resistant to, or intolerant of, conventional pharmacotherapy and remain at high-risk of atherosclerotic cardiovascular disease, so that alternative approaches are needed. New agents, including inhibitors of microsomal triglyceride transfer protein (MTP), may play a future role, either alone or in combination, in the treatment of hyperlipidaemias. This review focuses on novel approaches to treat dyslipidaemias via the inhibition of MTP. Patients most suitable for use of MTP inhibitors include those with hepatic hypersecretion of apoB, including the metabolic syndrome, Type 2 diabetes mellitus and familial combined hyperlipidaemia, as well as homozygous and heterozygous familial hypercholesterolaemia. However, certain safety issues with these agents need resolving, particularly fatty liver disease.
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PMID:MTP inhibition as a treatment for dyslipidaemias: time to deliver or empty promises? 1722 33

This article sets out the clinical context of the research presented by Samaha et al. in an accompanying article in this issue. Hyperlipidemia is a common and important risk factor for cardiovascular disease. Current lipid-lowering therapies, particularly statins, lead to substantial decreases in cardiovascular disease morbidity and mortality, but use has been limited by safety or efficacy issues. The way has, therefore, been paved for the pharmaceutical development and clinical investigation of new lipid-lowering therapies. The clinical trial by Samaha et al. examines the safety and efficacy of microsomal triglyceride transfer protein inhibition for lowering lipids. Joy and Hegele explore the difficulties of translating microsomal triglyceride transfer protein inhibition into clinical practice because of the trade-off between efficacy and potential adverse effects. They also stress the need for outcome studies, rather than biochemical or surrogate studies, as the final arbiter for the clinical use of this new treatment.
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PMID:Microsomal triglyceride transfer protein inhibition-friend or foe? 1850 54

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.
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PMID:Intestinally derived lipids: metabolic regulation and consequences--an overview. 1869 44

New lipid-lowering agents include microsomal triglyceride transfer protein (MTP) inhibitors, which may have a role in the treatment of hypercholesterolemia. Clinical applications of MTP inhibitors have been focused primarily on high-dose monotherapy to produce substantial reductions in LDL-cholesterol levels (particularly for patients with homozygous familial hypercholesterolemia). However, this strategy has been associated with a high rate and severity of gastrointestinal and hepatic adverse events that has prohibited the use of these agents. Data suggest the LDL-cholesterol-lowering efficacy of low-dose lomitapide (AEGR-733, formerly BMS-201038), under development by Aegerion Pharmaceuticals Inc, in patients with familial hypercholesterolemia, both as a single agent and in combination with commonly prescribed lipid-lowering therapies. MTP inhibition with lomitapide may offer a treatment option for patients who cannot tolerate statin therapy or who experience insufficient LDL-cholesterol reduction with available therapies. However, the safety concerns for MTP inhibitors for the treatment of hyperlipidemia must be fully addressed, and the assessment of the risk-to-benefit ratio for MTP inhibitors in patients at different levels of cardiovascular-disease risk is required before clinical use of this class of drugs may be recommended.
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PMID:Lomitapide, a microsomal triglyceride transfer protein inhibitor for the treatment of hypercholesterolemia. 2012 62


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