Target Validation Information
Target ID T46628
Target Name Microsomal triglyceride transfer protein, large subunit
Target Type
Successful
Drug Potency against Target BMS-201038 Drug Info IC50 = 8 nM [552456]
DIRLOTAPIDE Drug Info IC50 = 2.9 nM [528651]
Action against Disease Model Implitapide Implitapide was shown to suppress MTP activity using a recombinant h uMan form complexed with protein disulphide isomerase(IC50=10 nM )and inhibit secretion of apoB-containing VLDL-like lipoproteins from a h uMan hepatoma cell(HepG2) with an IC 50 value of 1.1 nM. [536042] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations A deficiency in microsomal triglyceride transfer protein (MTP) causes the h uMan lipoprotein deficiency syndrome abetalipoproteinemia. However, the role of MTP in the assembly and secretion of VLDL in the liver is not precisely understood. It is not clear, for instance, whether MTP is required to move the bulk of triglycerides into the l uMen of the endoplasmic reticul uM (ER) during the assembly of VLDL particles. To define MTP's role in hepatic lipoprotein assembly, we recently knocked out the mouse MTP gene (Mttp). Unfortunately, achieving our objective was thwarted by a lethal embryonic phenotype. In this study, we produced mice harboring a "floxed" Mttp allele and then used Cre-mediated recombination to generate liver-specific Mttp knockout mice. Inactivating the Mttp gene in the liver caused a striking reduction in VLDL triglycerides and large reductions in both VLDL/LDL and HDL cholesterol levels. The Mttp inactivation lowered apo B-100 levels in the plasma by >95% but reduced plasma apo B-48 levels by only approximately 20%. Histologic studies in liver-specific knockout mice revealed moderate hepatic steatosis. Ultrastructural studies of wild-type mouse livers revealed n uMerous VLDL-sized lipid-staining particles within membrane-bound compartments of the secretory pathway (ER and Golgi apparatus) and few cytosolic lipid droplets. In contrast, VLDL-sized lipid-staining particles were not observed in MTP-deficient hepatocytes, either in the ER or in the Golgi apparatus, and there were n uMerous cytosolic fat droplets. We conclude that MTP is essential for transferring the bulk of triglycerides into the l uMen of the ER for VLDL assembly and is required for the secretion of apo B-100 from the liver [536042]
References
Ref 536042Implitapide, a microsomal triglyceride transfer protein inhibitor, reduces progression of atherosclerosis in apolipoprotein E knockout mice fed a Western-type diet: involvement of the inhibition of postprandial triglyceride elevation. Biol Pharm Bull. 2005 Feb;28(2):247-52.
Ref 5524565-Carboxamido-1,3,2-dioxaphosphorinanes, potent inhibitors of MTP. Bioorg Med Chem Lett. 2004 Oct 18;14(20):5067-70.
Ref 528651Bioorg Med Chem Lett. 2007 Apr 1;17(7):1996-9. Epub 2007 Jan 17.In vitro and in vivo profile of 5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), a novel potent MTP inhibitor for obesity.

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