Triglyceride Transfer Protein

MTP is responsible for the transfer of TGs and cholesteryl esters from the endoplasmic reticulum (ER) to lipoprotein particles (VLDL in hepatocytes in the liver and chylomicrons in endocytes in the intestine) for secretion [52]. It is a heterodimer consisting of a unique large subunit essential for lipid transfer encoded by the mttp gene and a smaller subunit, the ubiquitous ER enzyme protein disulfide isomerase [53]. 

Abetalipoproteinemia or Bassen-Kornzweig syndrome, a potentially disabling, familial disease characterized by lack of plasma TGs, malabsorption of fat-soluble vitamins, liver steatosis, steatorrhea, and other symptoms, is linked to mutations in the MTP functional subunit [52,53], 

Currently, there are a number of systemic and intestine-selective MTP inhibitors, including lomitapide (23, BMS-201038, AEGR-733), implitapide (24), JTT-130, SLx-4090, and R-256918 (latter three structures not disclosed) believed to be in active development [60]. In a meta-analysis of three Phase II clinical trials, lomitapide as monotherapy or in combination with ezetimibe, atorvastatin, or fenofibrate significantly reduced LDL cholesterol (up to 35% as monotherapy and 66% in combination with atorvastatin) and was well tolerated with less than 2% discontinuation due to abnormal liver function [61]. Lomitapide has also been granted orphan drug status for the treatment of homozygous familial hypercholesterolemia [59]. Results of a Phase II study of JTT-130 for type 2 diabetes are expected in August 2010 [59,60]. 

There is emerging evidence that VLDL assembly in general and MTP function in particular are intimately tied to assembly of hepatitis C virus (HCV) infectious particles [63]. MTP inhibition and ApoB downregula-tion in turn inhibit HCV assembly and maturation [64]. This may open new therapeutic opportunities for small-molecule MTP inhibitors in the 

Enzymes involved in TG synthesis continue to represent challenging and intriguing targets for small-molecule intervention against the worldwide epidemic of obesity, metabolic syndrome, and type 2 diabetes, as well as smaller market indications from rare familial diseases to veterinary use. There is also intriguing evidence that inhibition of these enzymes may be beneficial for diseases unrelated to the area of metabolic disorders, such 

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Hoen P.A. C., Prince P., Van der Bilt E., Valentijn A. R., Meeuwenoord N.J., Princen H., Bijsterbosch M.K., van der Marel G.A., van Boom J.H., van BerkelT.J.C. Design of a targeted peptide nucleic acid prodrug to inhibit hepatic human microsomal triglyceride transfer protein expression in hepato-cytes. Bioconjug. Chem. 2002 13 295-302. 

Li, CM, Presley, B, Zhang, XM, Dashti, N, Chung, BH, Medeiros, NE, Guidry, C, and Curcio, CA, 2005. Retina expresses microsomal triglyceride transfer protein Implications for age-related maculopathy. J Lipid Res 46, 628-640. 

Microsomal triglyceride-transfer protein (MTP) plays a pivotal role in the assembly of TG-rich apolipoprotein B-containing VLDL in the liver and... 

Hussain MM, Shi J, Dreizen P (2003) Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res 44 22-32... 

A protein, originally described as cholesteryl ester exchange or transfer protein, or triglyceride transfer protein, has been purified from human and... 

Lipoprotein Assembly and Microsomal Triglyceride Transfer Protein... 

In ABL, an early step in apoB lipoprotein assembly shared by intestinal and liver cells is defective. The net result is near absence of all plasma apoB lipoproteins. ApoB synthesis from a mRNA transcript occurs, but its successful assembly into the mature lipoprotein particle does not. The inability to assemble apoB into lipoproteins was shown to be due to a defect in the mttp gene in affected individuals (Wetterau et al., 1992). Its translational product is an 894-amino acid, 97-kd, polypeptide that exists in the ER complexed with a 55-kd protein disulfide isomerase which is believed to maintain solubility, physiologic activity, and ER retention of the 97-kd peptide. The heterodimeric complex of the 97-kd and 55-kd subunits is referred to as microsomal triglyceride transfer protein (MTP) (Wetterau et al., 1992). 

Berriot-Varoqueaux N, Aggerbeck LP, et al. The role of the microsomal triglyceride transfer protein in abetalipoproteinemia. Annu Rev Nut. 20 663-697, 2000. 

Wetterau JR, Aggerbeck I.p Bouma M, et al. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science 258 999-1001,1992. 

C. Identity with Subunit of Triglyceride Transfer Protein. 142... 

AUister, E. M., Borradaile, N. M., Edwards, J. Y., Huff, M. W. (2005). Inhibition of microsomal triglyceride transfer protein expression and apolipoprotein BlOO secretion by the citms flavonoid naiingenin and by insulin involves activation of the mitogen-activated protein kinase pathway in hepatocytes. Diabetes, 54, 1676-1683. 

Casaschi, A., Wang, Q., Dang, K., Richards, A., Theriault, A. (2002). Intestinal apoUpoprotein B secretion is inhibited by the flavonoid quercetin potential role of microsomal triglyceride transfer protein and diacylglycerol acyltransferase. Lipids, 37, 647-652. 

MSH-R, melanoc5de stimulating hormone receptor MTP, microsomal triglyceride transfer protein NEFA, non-esterified fatty acids NO, nitric oxide NPY, neuropeptide Y... 

In this autosomal recessive disease, the disorder does not involve the gene on chromosome 2, which is responsible for apoprotein assembly, but the MTP gene (microsomal triglyceride transfer protein), which is localized on chromosome 4 q 22—24. In the endoplasmic reticulum, MTP transfers cholesterol esters, triglycerides and phospholipids to the nascent apoprotein B. This process is a prerequisite for the transport of the complete lipoproteins (e.g. chylomicrons, VLDL) to the Golgi complex and their secretion into the blood via subsequent exocytosis. In the case of MTP deficiency, lipoprotein particles are not secreted, with the result that any superfluous apoprotein B is broken down in the endoplasmic reticulum. (214, 216, 219, 220)... 

Wetterau, J.R., Aggerbeck, L.P., Bouma, M.E., Esenberg, C, Munck, A., Hermier, M., Gay, G., Rader, D.J., Gregg, R.E Absence of microsomal triglyceride transfer protein in individuals with abetalipopro-teinemia. Science 1992 258 999-1001... 

L. B. Nielsen, M. Veniant, and J. Boren, et ah, Genes for apolipoprotein B and microsomal triglyceride transfer protein are expressed in the heart evidence that the heart has the capacity to synthesize and secrete lipoproteins, Circulation, 1998, 98, 13-16. 

Sharp, D., et al. 1993. Cloning and gene defects in microsomal triglyceride transfer protein associated with a beta lipoproteinaemia. Nature 365(6441) 65-69. 

Without the enzyme microsomal triglyceride transfer protein (MTP), hepatic triglycerides cannot be transferred to apoB-100. Patients with dysfunctional MTP fail to make any of the apoB-containing lipoproteins (VLDL, IDL, or LDL). MTP also plays a key role in the synthesis of chylomicrons in the intestine, and mutations of MTP that result in the inability of triglycerides to he transferred to either apoB-100 in the liver or apoB-48 in the intestine prevent VLDL and chylomicron production and cause the genetic disorder abetalipoproteinemia. 

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