MOGAT2: A New Therapeutic Target for Metabolic Syndrome
Abstract
:1. Introduction
1.1. TAG Biosynthesis
2. Identification and Characterization of MGATs
2.1. MGAT1
2.2. MGAT2
Genetic Manipulation | Mouse Model | Description | TAG Content | Reference | |
---|---|---|---|---|---|
Plasma | Liver | ||||
Mogat1 ASO | DIO | Weight loss was seen in all but DIO model; | n.c. | n.c. | [35,36,37] |
ob/ob | Fatty acid oxidation was increased; Lipogenesis was suppressed; | ↓ | n.c. | ||
HFD | Insulin sensitivity was improved; Hepatic inflammation was enhanced. | n.c. | ↓ | ||
Mogat2 −/− Mogat2iko | HFD | Weight and food intake was decreased; Food preference was changed to carbohydrate from fat; Plasma non-HDL cholesterol was decreased; Hepatic steatosis was prevented; Energy expenditure was increased; GLP-1 secretion was increased; Insulin sensitivity was improved. | ↓ | n.d. | [43,44] |
2.3. MGAT3
2.4. DGATs
3. Small Molecule MGAT2 Inhibitors
Company | Description | Reference |
---|---|---|
Banyu | Pyrimidine-4(3H)-one derivatives, IC50 = 56 nM, Selectivity to other acyltransferasesare unknown | WO2010/095767 |
Dainippon Sumitomo | Bicyclic pyrimidine derivative, IC50 = 2 nM, Selectivity to other acyltransferasesare unknown | WO2012091010 A1 |
Taisho | N-containing heterocyclic derivatives, IC50 = 4.1 nM, Selectivity to other acyltransferasesare unknown | WO2012124744 A1 |
Eli Lily | Phenyl methanesulfonamide derivatives, IC50 = 12 nM in vitro assay, IC50 = 17.7 nM CaCo2 cell based LC-MS assay, Selectivity to other acyltransferasesare unknown Benzyl sulfonamide derivatives, IC50 = 2.28 nM in vitro assay, IC50 = 3.8 nM CaCo2 cell based LC-MS assay, >70% reduction in TAG excursion in a dog oil bolus model, Selectivity to other acyltransferasesare unknown Morpholynyl derivatives, IC50 = 12 nM in vitro assay, IC50 = 16 nM CaCo2 cell based LC-MS assay, 43% to 64% reduction of TAG excursion in a dog oil bolus model, Selectivity to other acyltransferasesare unknown | WO 2013112323 A1 WO2014074365A1 US20150005305 |
Bristol-Myers Squibb | Aryl dihydropyridinones and piperidinones derivatives, IC50 = 14 nM in vitro assay, IC50 = 4 nM in STC-1 LC/MS assay, >1000-fold selective over other acyltransferases | WO2013/082345 [65] |
AstraZeneca | 3-ethyl-3-methyl-2,5-dioxo-
N-phenyl-2,3,4,5-tetra hydro-1H-1,4-benzodiazepine-7-sulphonamide 1, IC50 = 1.6 nMRapidfire LCMS® assay, 68% reduction of TAG excursion in a mice oil oral gavage model, >10,000-fold selective over AWAT, variable selectivity toward MGAT2 and no selectivity toward MGAT1 | [66] |
Takeda | N-phenylindoline-5-sulfonamide derivatives, IC50 = 3.4 nMRapidfire LCMS® assay, Significant reduction of TAG excursion in a mice olive oil oral gavage model, >30,000 fold selective over MGAT3, DGAT1, DGAT2 and ACAT1 | [67] |
Japan Tobacco Inc. (Minato, TKY) | 7-(4,6-Di-tert-butyl-pyrimidin-2-yl)-3-(4-tri-fluoromethoxy-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine derivative, IC50 = 19 nM in vitro assay, Significant reduction of TAG excursion in a mice olive oil oral gavage model, >300-fold selective over MGAT3, and >1000-fold selective over DGAT2, | [68] |
4. Conclusion
Acknowledgments
Conflicts of Interest
Abbreviations
NAFLD | nonalcoholic fatty liver disease; |
TAG | triacylglycerol; |
MGAT2 | acyl-coA: monoacylglycerolacyltransferase 2; |
MAG | monoacylglycerol; |
DAG | diacylglycerol; |
FA | fatty acid; |
G3P | sn-glycerol-3-phosphate; |
DGAT | acyl-coA: diacylglycerolacyltransferase; |
GPAT | glycerol-3-phosphate acyltransferase; |
LPA | lysophosphatidic acid; |
AGPAT | acylglycerol-3-phosphate acyltransferase; |
Pa | phosphatidic acid; |
Lipin/PAP | lipins/PA phsphohydrolases; |
ER | endoplasmic reticulum; |
DHAP | dihydroxyacetone phosphate; |
VLDL | very low density lipoprotein; |
GLP-1 | glucagon-like peptide-1; |
RYBG | Reux-en-Y gastric bypass; |
DIO | diet-induced obese; |
PPAR | peroxisome proliferator-activated receptor; |
ASO | antisense oligonucleotides; |
HTF-C diet | high trans FAs, fructose and cholesterol diet; |
NASH | nonalcoholic steatohepatitis. |
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Yang, M.; Nickels, J.T., Jr. MOGAT2: A New Therapeutic Target for Metabolic Syndrome. Diseases 2015, 3, 176-192. https://doi.org/10.3390/diseases3030176
Yang M, Nickels JT Jr. MOGAT2: A New Therapeutic Target for Metabolic Syndrome. Diseases. 2015; 3(3):176-192. https://doi.org/10.3390/diseases3030176
Chicago/Turabian StyleYang, Muhua, and Joseph T. Nickels, Jr. 2015. "MOGAT2: A New Therapeutic Target for Metabolic Syndrome" Diseases 3, no. 3: 176-192. https://doi.org/10.3390/diseases3030176