Targeting Acyl-CoA:Diacylglycerol Acyltransferase 1 (DGAT1) with Small Molecule Inhibitors for the Treatment of Metabolic Diseases

Biocorrection Research Unit, Pfizer, Cambridge, Massachusetts 02140, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2011; 286(48):41838-51. DOI: 10.1074/jbc.M111.245456
Source: PubMed


Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final step in triglyceride synthesis. Findings from genetically modified mice as well as pharmacological studies suggest that inhibition of DGAT1 is a promising strategy for the treatment of obesity and type 2 diabetes. Here we characterize a tool DGAT1 inhibitor compound, T863. We found that T863 is a potent inhibitor for both human and mouse DGAT1 in vitro, which acts on the acyl-CoA binding site of DGAT1 and inhibits DGAT1-mediated triacylglycerol formation in cells. In an acute lipid challenge model, oral administration of T863 significantly delayed fat absorption and resulted in lipid accumulation in the distal small intestine of mice, mimicking the effects of genetic ablation of DGAT1. In diet-induced obese mice, oral administration of T863 for 2 weeks caused weight loss, reduction in serum and liver triglycerides, and improved insulin sensitivity. In addition to the expected triglyceride-lowering activity, T863 also lowered serum cholesterol. Hepatic IRS2 protein was dramatically up-regulated in mice treated with T863, possibly contributing to improved insulin sensitivity. In differentiated 3T3-L1 adipocytes, T863 enhanced insulin-stimulated glucose uptake, suggesting a possible role for adipocytes to improve insulin sensitivity upon DGAT1 inhibition. These results reveal novel mechanistic insights into the insulin-sensitizing effects of DGAT1 inhibition in mouse models. Taken together, our study provides a comprehensive evaluation of a small molecule inhibitor for DGAT1 and suggests that pharmacological inhibition of DGAT1 holds promise in treating diverse metabolic disorders.

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    • "Metabolic hormones such as insulin play a key role in energy homeostasis by metabolizing glucose and triglycerides from the bloodstream into cells. In cases of insulin resistance, diglycerides are converted into triglycerides which accumulate into adipose tissue and are deposited as fat (Meegalla et al., 2002; Zhao et al., 2008; Cao et al., 2011). These studies are in accordance with our current findings of increased insulin, and a trend for higher TGs and DGs in patients under treatment with medium-and high-risk SGAs compared to low-risk and controls. "
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    The International Journal of Neuropsychopharmacology 02/2014; 17(08):1-10. DOI:10.1017/S1461145714000157 · 4.01 Impact Factor
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    • "In our study, we showed a decreased deposit of macrophages and apoB in the atherosclerotic lesions in mice treated with active ribozymes. Dgat1 is currently a target of small molecule inhibitors for the treatment of diverse metabolic disorders.34,35 As noted in this study, it is possible that the decreased Dgat1 expression may be the result of a negative feedback from the increased intracellular TAG levels in the liver, resulting from the inhibition of VLDL assembly by ribozyme activity. "
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    Molecular Therapy - Nucleic Acids 10/2013; 2(10):e125. DOI:10.1038/mtna.2013.53 · 4.51 Impact Factor
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    Bioorganic & medicinal chemistry letters 05/2012; 22(12):3873-8. DOI:10.1016/j.bmcl.2012.04.117 · 2.42 Impact Factor
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