Proceedings of The Physiological Society
AstraZeneca (2010) Proc Physiol Soc 18, PC28
Pharmacological effect of DGAT1 inhibition on food intake and post-prandial lipaemia - determination of the mechanism of action
S. Birtles1, L. Buckett1, C. Hammond1, A. Turnbull1
1. CVGI, AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom.
Diacylglycerol acyltransferase 1 (DGAT1) functions in triglyceride synthesis and triglyceride intestinal absorption. DGAT1 catalyses the formation of triglycerides from diacylglycerol and acyl-coA and is the final committed step in the mammalian triglyceride synthesis pathway. Dietary triglycerides are emulsified and hydrolysed to fatty acids and 2-monoacylglycerol in the intestinal lumen, are then transported to the enterocyte where triglyceride is re-synthesised and incorporated into chylomicrons for secretion into lymph. DGAT1 enzyme is distributed across the metabolic tissues with high levels of mRNA expressed in human and rodent small intestine. DGAT1 global knock out mice have decreased adiposity when fed a diet high in fat and accumulate neutral-lipid droplets in the cytoplasm of the enterocyte. DGAT1 knock out mice also show a reduced rate of triacylglycerol absorption after an acute lipid challenge. We have conducted studies to evaluate the effects of a small molecule DGAT1 inhibitor. DGAT1 inhibition produces a dose-dependent decrease in post-prandial lipaemia in Han Wistar rats administered a corn oil challenge orally (n=15, EC50 = 0.02μM). Moreover it produced a decrease in the acute intake of high fat, but not low fat food (>50% decrease at 1 hour post-refeed, n=12, p=<0.001). Studies in DGAT1 knockout mice have shown that DGAT1 deficiency produces an increase in PYY and GLP-1 levels in response to a lipid load and these gut peptides represent one potential anorectic mechanism. DGAT 1 inhibition has, however, additional potential effects in the gastrointestinal tract. Indeed DGAT1 inhibitors divert fatty acids away from triglyceride synthesis into fatty acid oxidation in CaCo2 (human colonic cell line) (EC50 = 0.03μM, n=1) and HuTu80 (human duodenal cell line) (EC50 = 0.008μM, n=3) cells as assessed by uptake of 14C-oleate or 14C-palmitate and release of 14C-CO2 and 14C-acid-soluble products. These data suggest multiple potential effects of DGAT1 inhibition in the gastointestinal tract that may have therapeutic benefit in metabolic disease.
Where applicable, experiments conform with Society ethical requirements