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)

Microsomal triglyceride transfer protein (MTP) plays a central role on secretion of lipoprotein from the liver and the intestine. MTP catalyzes the transfer of triglyceride, cholesteryl ester and phosphatidylcholine between membranes and lipoproteins. In human, defect of MTP activity, result from mutations encoding the MTP large subunit, is the primary cause of abetalipoproteinemia. To investigate the association between hyperlipidemia with obese and MTP, We used Otsuka Long-Evans Tokushima Fatty rat, an animal model of obesity with visceral fat accumulation, hyperlipidemia. In animals, very-low density lipoprotein-triglyceride levels were elevated compared with the control rats. Hepatic mRNA levels of acyl-coenzyme A synthetase, and MTP were also elevated. These results suggest that the enhanced expression of both ACS and MTP genes associated with visceral fat accumulation may be involved in the pathogenesis of hyperlipidemia in obese animal models.
 ...
PMID:[The role of microsomal triglyceride transfer protein in metabolism of apo B-containing lipoprotein]. 1063 97

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.
 ...
PMID:Post-statin approaches to hyperlipidaemia. 1599 42

Microsomal triglyceride transfer protein (MTP) is needed to assemble chylomicrons in the endoplasmic reticulum (ER) of enterocytes. We explored the role of an ER stress protein, inositol-requiring enzyme 1beta (IRE1beta), in regulating this process. High-cholesterol and high-fat diets decreased intestinal IRE1beta mRNA in wild-type mice. Ire1b(-/-) mice fed high-cholesterol and high-fat diets developed more pronounced hyperlipidemia because these mice secreted more chylomicrons and expressed more intestinal MTP, though not hepatic MTP, than wild-type mice did. Chylomicron secretion and MTP expression also were increased in primary enterocytes isolated from cholesterol-fed Ire1b(-/-) mice. There was no correlation between ER stress and MTP expression. Instead, cell culture studies revealed that IRE1beta, but not its ubiquitous homolog IRE1alpha, decreased MTP mRNA through increased posttranscriptional degradation. Conversely, knockdown of IRE1beta enhanced MTP expression. These studies show that IRE1beta plays a role in regulating MTP and in chylomicron production.
 ...
PMID:IRE1beta inhibits chylomicron production by selectively degrading MTP mRNA. 1846 Mar 35

Microsomal triglyceride transfer protein (MTP) is involved in the synthesis of very low density lipoprotein in the liver. Its deficiency results in abetalipoproteinemia. MTP inhibitors target the assembly and secretion of apolipoprotein B-containing lipoproteins. These agents may potentially play a role, alone or in combination, in the treatment of hypercholesterolemia or hypertriglyceridaemia. Clinical applications of MTP inhibitors initially focused primarily on high-dose monotherapy in order to produce substantial reductions in LDL-cholesterol levels but these proved to induce significant hepatic steatosis and transaminase elevations. However, likely orphan indications for MTP inhibitors, where a different risk-benefit profile applies, include patients with homozygous familial hypercholesterolemia where statins often show a low response. Development of MTP inhibitors has continued to enter clinical trials at lower doses or in formulations aimed at utilizing their efficacy while avoiding their side effects. These have shown promising results in reducing cholesterol, triglycerides and apolipoprotein B with a far lower incidence of, often, transient side-effects. The clinical efficacy and safety of MTP inhibition in patients with hyperlipidaemia remains to be fully determined and to be proven in both surrogate and clinical endpoint trials but there may be a role for these agents in orphan indications for rarer severe hyperlipidaemias.
 ...
PMID:New lipid modulating drugs: the role of microsomal transport protein inhibitors. 2141 29

The plasma level of apolipoprotein B (apoB) is among the strongest risk factors for coronary artery disease. Microsomal triglyceride transfer protein (MTP) plays a key role in the lipidation of nascent apoB and the secretion of apoB-containing lipoproteins enriched with triglycerides and is thus a promising target for the treatment of hyperlipidemia. Yet, the development of MTP inhibitors to lower plasma lipid concentrations has been hindered by adverse effects on hepatic steatosis. A study recently published in Nature Medicine identifies microRNA-30c (miR-30c) as a potent repressor of MTP that controls plasma apoB-containing lipoprotein levels, in addition to decreasing hepatic lipid synthesis through direct targeting of lysophosphatidylglycerol acyltransferase 1 (LPGAT1). These findings identify miR-30c as a novel therapeutic target that coordinately reduces lipid biosynthesis and lipoprotein secretion to suppress circulating apoB lipoproteins, while sparing the liver from steatosis.
 ...
PMID:Small RNA overcomes the challenges of therapeutic targeting of microsomal triglyceride transfer protein. 2374 31

Metabolic diseases including nonalcoholic steatohepatitis develop due to various environmental factors. In particular, the westernization of food is closely related to the development of these diseases. In this study, we investigated pathophysiological changes in the livers of Zucker fatty (ZF) rats induced by feeding Western diets. Male ZF rats were fed a sucrose/fat/cholesterol-enriched diet (Western diet, WD) or standard diet (SD) for 18 weeks, from 7 to 25 weeks of age. Body weight, food intake, and biochemical parameters were periodically measured, histopathological analyses were performed at 25 weeks, and mRNA expression in the liver was determined. ZF rats fed the WD (ZF-WD rats) developed obesity, hyperinsulinemia, hyperglycemia, and hyperlipidemia, and their alanine aminotransferase and aspartate aminotransferase levels increased compared with those of ZF rats fed the SD (ZF-SD rats). Hepatic lesions including fibrosis and necrosis were observed in the ZF-WD rats at 25 weeks; however, fibrosis and necrosis were not observed in the ZF-SD rats. Oxidative stress markers also increased in the livers of ZF-WD rats. Hepatic mRNA expression related to inflammation and fibrosis increased in the ZF-WD rats; however, mRNA expression related to lipid synthesis decreased. Microsomal triglyceride transfer protein mRNA levels in the ZF-WD rats also decreased. In Zucker lean rats fed the WD, similar changes were observed in the liver; however, the hepatic changes were not serious compared with ZF-WD rats. In conclusion, hepatic lesions, such as inflammation, fibrosis, and necrosis, were observed in the ZF-WD rats. The sucrose/fat/cholesterol-enriched diet induced significant lipotoxicity in the livers of animals in this insulin-resistant model.
 ...
PMID:Hepatic lesions induced by feeding Western diets to Zucker fatty rats, an insulin-resistant model. 3039 32