A neomycin resistance cassette flanked by loxp sites was inserted into intron 1. Multiple functions of microsomal triglyceride transfer protein. Microsomal triglyceride transfer protein mttp is an essential chaperone that assists in the assembly of apolipoprotein bcontaining lipoproteins to transport lipids. Microsomal triglyceride transfer protein mtp gene mutations in. Mtp is an 894 amino acid 97 kda protein that forms a heterodimer with protein disulfide isomerase pdi. The secretion pattern of apobcontaining lipoproteins is likely to influence the vldl and ldl levels in plasma. Microsomal triglyceride transfer protein an overview.
Multiple point mutations within the mttp gene resulting in abl have been. Structurefunction analyses of microsomal triglyceride. Microsomal triglyceride transfer protein mtp transfers triglycerides and. The aim of this study was to decipher mechanisms that lead to increases in plasma transaminases after mtp inhibition. Abetalipoproteinemia medical dictionary onlinemedical.
We investigated effects on glucose and lipid metabolism in combination of jtt, a novel intestinespecific microsomal triglyceride transfer protein mtp inhibitor, and pioglitazone, peroxisome proliferatoractivated receptor ppar. Mutations of the microsomal triglyceridetransferprotein gene in. It is thought that pharmacological inhibition of mtp results in hepatic production of vldl, the precursor to ldl, causing a lowering of plasma ldlc levels. In this study, we describe a patient with abl inherited as a homozygous intron 9 splice acceptor g. Additionally, betaine or berberine attenuate hepatic steatosis by reducing the expression of the microsomal triglyceride transfer protein mttp in mice fed a highfat diet chang et al. Supplementary site interactions are critical for the. Mutations in the mttp gene that prevent lipid transfer and apob secretion.
We have shown that microrna mir30c regulates mttp expression but other members of the same family do not. Young 810 week mttpiko mice have improved survival when subjected to a murine model of pseudomonas aeruginosainduced sepsis. Characterization of mutations in mtp causing abetalipoproteinemia has. Further, we showed that interactions between mir30c seed sequence and the 3. Apolipoprotein b apob and microsomal triglyceride transfer protein mtp are.
Intestinespecific deletion of microsomal triglyceride. It is an unusual lipid transfer protein in that it is a complex of two proteins of molecular weight 55 kda and 97 kda. The interindividual variability in the occurrence of nonalcoholic steatohepatitis suggests, however, a genetic modulation. Microsomal triglyceride transfer protein is linked to a human disease state, abetalipoproteinemia. An autosomal recessive disorder of lipid metabolism. It is caused by mutation of the microsomal triglyceride transfer protein that catalyzes the transport of. Calculations and graphics were done using sybyl software tripos inc. The structure helps us to understand how this protein functions and gives a rationale for how previously reported mutations result in loss of function of the protein and. Gg homozygosity, or carrying a lower mtp activity than the other genotypes, predicted more severe liver histology. Mttp microsomal triglyceride transfer protein large. Expression and methylation of microsomal triglyceride. Mutations in the gene encoding the large subunit of microsomal triglyceride transfer protein mtp gene omim157147 are. Microsomal triglyceride transfer protein mtp plays an essential role in lipid metabolism, especially in the biogenesis of very lowdensity lipoproteins and chylomicrons via the transfer of.
In chronic hepatitis c, the fibrosis progression rates are extremely variable and can be influenced by factors associated with the host, virus and environment. Wikigenes mttp microsomal triglyceride transfer protein. Backgroundthe use of microsomal triglyceride transfer protein mtp. Apolipoprotein b48 on chylomicra and apolipoprotein b100 on ldl, idl, and vldl. Microsomal triglyceride transfer protein wikipedia.
Microsomal triglyceride transfer protein inhibitor drugbank. In vitro, the complex facilitates the transfer of triglyceride, phospholipid, and cholesteryl ester between membrane vesicles 2. Mutations in the mtp gene are known to lead to a deficiency in apolipoproteins b48 and b100, known as abetalipoproteinemia, in which sufferers are hypocholesterolemic. Microsomal triglyceride transfer protein springerlink. Male zucker diabetic fatty rats were divided into 4 groups. Common polymorphisms have been described that do not affect lipoproteins in nondiabetic subjects.
Microsomal triglyceride transfer protein mtp is an intracellular lipid transfer complex consisting of a unique 97 kd subunit, which possess lipid transfer activity, and the multifunctional 58kd protein disulfide isomerase pdi 1. Mttp microsomal triglyceride transfer protein large subunit. Microsomal triglyceride transfer protein 164 t c gene. Microsomal triglyceride transfer protein mtp plays an essential role in lipid metabolism, especially in the biogenesis of very lowdensity lipoproteins and chylomicrons via the transfer of neutral lipids and the assembly of apobcontaining lipoproteins. Because the microsomal triglyceride transfer protein is expressed in the intestine and is required for chylomicron assembly and secretion, 9 inhibition of the protein could cause steatorrhea. A missense mutation dissociates triglyceride and phospholipid. Genetic variation in the microsomal triglyceride transfer. Identification of a novel mutation of mtp gene in a patient with. It is caused by a mutation in microsomal triglyceride transfer protein resulting in deficiencies in the apolipoproteins b48 and b100, which are used in the synthesis and exportation of chylomicrons and vldl respectively. A microsomal triglyceride transfer protein inhibitor used to lower cholesterol associated with homozygous familial hypercholesterolemia hofh, reducing risk of cardiovascular events such as myocardial infarction and stroke. Microsomal triglyceride transfer protein polymorphisms and. A deficiency in microsomal triglyceride transfer protein mtp causes the human lipoprotein deficiency syndrome abetalipoproteinemia. Mttp microsomal triglyceride transfer protein whole gene. Microsomal triglyceride transfer protein deficiency microsomal triglyceride transfer protein deficiency disease.
The microsomal triglyceride transfer protein mtp, which catalyses the transport of triglyceride, cholesteryl ester and phospholipid between phospholipid surfaces, is a heterodimer composed of the multifunctional protein, protein disulphide isomerase, and a unique large subunit with an. Mtp activity assay kit supplied by roar biomedical, inc. Abetalipoproteinemia caused by maternal isodisomy of. Microsomal triglyceride transfer protein mtp regulates the assembly of chylomicrons in the intestine and verylowdensity lipoprotein vldl in the liver. Microsomal triglyceride transfer protein inhibition. Novel mutations in the microsomal triglyceride transfer. This protein facilitates the transfer of triglyceride tg, cholesteryl ester ce and phosphatidylcholine pc between phospholipid surfaces. The microsomal triglyceride transfer protein mtp is an intracellular lipid transfer protein that catalyzes the transport of triglyceride tg, cholesteryl ester ce, and phospholipid molecules between membranes. Microsomal triglyceride transfer protein mtp was first identified as a major cellular protein capable of transferring neutral lipids between membrane vesicles.
Abetalipoproteinemia abl is a rare autosomal recessive deficiency of apobcontaining lipoproteins caused by a microsomal triglyceride transfer protein mtp deficiency. Their effect in diabetes has not been described in a caucasian population. Microsomal triglyceride transfer protein and its role in apob. Microsomal triglyceride transfer protein mtp is an intracellular lipidtransfer protein found in the endoplasmic reticulum and which is responsible for transferring lipid molecules onto apob. In ashkenazi jewish patients there is a conserved haplotype and a common mtp mutation, p. Combination therapy of an intestinespecific inhibitor of. Microsomal triglyceride transfer protein mtp is a unique lipid transfer protein essential for the assembly of triglyceriderich lipoproteins by the liver and intestine. Mtp encodes the large subunit of the heterodimeric microsomal triglyceride transfer protein. Polymorphism in microsomal triglyceride transfer protein. A common functional polymorphism in the promoter region of. Microsomal triglyceride transfer protein mtp is a lipid transfer protein that is required for the assembly and secretion of very low density lipoproteins by the liver and chylomicrons by the intestine. Aimsthe aim of this study was to evaluate the effect of microsomal triglyceride transfer protein inhibitor lomitapide in patients with homozygous familial hypercholesterolaemia. Mutations that lead to the absence of a functional 97kda subunit cause abetalipoproteinemia, an autosomal recessive disease characterized by a defect in the assembly. In this prospective, randomized trial aegr733 provided a dosedependent reduction in ldl cholesterol, reaching a 30% reduction with 10 mg daily monotherapy and.
The microsomal triglyceride transfer protein is responsible for transferring triglycerides onto apolipoprotein b within the liver in the assembly of verylowdensity lipoprotein vldl, the. Its role as an essential chaperone for the biosynthesis of apolipoprotein b apobcontaining triglyceriderich lipoproteins was established after the realization that abetalipoproteinemia patients carry mutations in the mttp gene. Novel abetalipoproteinemia missense mutation highlights the. Microsomal triglyceride transfer protein large subunit is a protein that in humans is encoded by the mttp gene. Microsomal triglyceride transfer protein mtp facilitates the transport of dietary and endogenous fat by the intestine and liver by assisting in the assembly and secretion of triglyceriderich apolipoprotein bcontaining lipoproteins. Application mtp activity assay kit has been used to measure the activity of microsomal triglyceride transfer protein mtp. Lipoproteins are assembled in the endoplasmic reticulum er of liver and intestinal cells. Microsomal triglyceride transfer protein mtp plays a critical role in the assembly of lipoproteins.
Analysis of the role of microsomal triglyceride transfer. The mttp gene provides instructions for making a protein called microsomal triglyceride transfer protein. This study provides a structure for microsomal triglyceride transfer protein, a key protein in lipid metabolism and transport. To further elucidate the nature of the lipid molecule binding and transport site on mtp, we have studied the relative rates at which mtp. The crystal structure of human microsomal triglyceride transfer protein. Molecular screening of the microsomal triglyceride. However, the role of mtp in the assembly and secretion of vldl in the liver is not precisely understood. It plays an important role in the assembly and secretion of apolipoproteins b apob containing lipoproteins as chylomicrons in the intestine, and of very low density lipoproteins vldls in the liver 35. Microsomal triglyceride transfer protein mtp gene mutations in canadian subjects with abetalipoproteinemia. Ccp4 software suite 71 was used for phasing and refinement. Disease description an autosomal recessive disorder of lipoprotein metabolism. The disease is caused by mutations affecting the gene represented in this entry.
To clarify the genetic basis of clinical diversity of abl, mutations of the mtp gene have been screened in 4 unrelated patients with abl. Microsomal triglyceride transfer protein mtp plays an essential role in lipid. Microsomal triglyceride transfer protein mtp is a member of a group of proteins that are able to transfer of lipids between membranes. Microsomal triglyceride transfer protein mtp physically interacts with apob, which may help it translocate across the er membrane. It most likely also transfers different lipids to translating apob to form secretion competent primordial lipoproteins.
A nonsense mutation in the a sheet, asn780tyr, does not affect its. This protein helps produce betalipoproteins, which are molecules that are made up of proteins including one called apolipoprotein b, cholesterol, and particular types of fats called phospholipids and triglycerides. Molecular and functional analysis of two new mttp gene mutations. Mutations of the microsomal triglyceridetransferprotein gene in abetalipoproteinemia. Microsomal triglyceride transfer protein mtp is necessary for the assembly and secretion of vldl and when the protein is not functional, such as in abetalipoproteinaemia, a steatohepatitis occurs. Abstractmicrosomal triglyceride transfer protein mtp is required for the assembly and cellular secretion of apolipoprotein b apob containing lipoproteins from the liver and intestine. Mttp microsomal triglyceride transfer protein human. By initial opportunistic screening for polymorphic sites in the regulatory region of the.
Structurefunction analyses of microsomal triglyceride transfer. It is not clear, for instance, whether mtp is required to move the. Association between microsomal triglyceride transfer. The microsomal triglyceride transfer protein mttp, a lipid transfer protein encoded by the mttp gene, is located in the luminal side of the endoplasmic reticulum 1, 2. The aim of this study was first to seek new mtp gene variants and. Mice with conditional, intestinespecific deletion of microsomal triglyceride transfer protein mttpiko exhibit a complete block in chylomicron assembly together with lipid malabsorption. The role of microsomal triglyceride transfer protein.
Mutation in the mtp gene leads to abetalipoproteinemia. Inhibition of microsomal triglyceride transfer protein in. The microsomal triglyceride transfer protein mtp is a heterodimer composed of the ubiquitous multifunctional protein, protein disulfide isomerase, and a unique 97kda subunit. Microsomal triglyceride transfer protein large subunit.
Abetalipoproteinemia is a disorder that interferes with the normal absorption of fat and fatsoluble vitamins from food. Protein disulfide isomerase pdi completes the heterodimeric microsomal triglyceride transfer protein, which has been shown to play a central role in lipoprotein assembly. Microsomal triglyceride transfer protein is an endoplasmic reticulum resident heterodimeric complex of a unique functional mtp subunit and ubiquitously expressed protein disulfide isomerase subunit that transfers various lipids, interacts with apob and associates with lipid vesicles. Treatmentrelated hepatic steatosis was predictable from studies in animals, variable among study subjects. Protein disulfide isomerase completes the heterodimeric microsomal triaglyceride transfer protein, which has been shown to play a central role in lipoprotein assembly. The only registered microsomal triglyceride transfer protein mtp inhibitor until now is lomitapide orally administered. Click on a disease name to see all genes associated with that disease. Mtp inhibitors lower plasma lipids, but they increase plasma transaminases and hepatic fat. Microsomal triglyceride transfer protein inhibitor. Microsomal triglyceride transfer protein mtp is responsible for the hepatic assembly of vldl particles through the transfer of triglycerides to apolipoprotein b.
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