Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes

McCoull, William; Addie, Matthew S.; Birch, Alan M.; Birtles, Susan; Buckett, Linda K.; Butlin, Roger J.; Bowker, Suzanne S.; Boyd, Scott; Chapman, Stephen J.; Davies, Robert D. M.; Donald, Craig S.; Green, Clive P.; Jenner, C.; Kemmitt, Paul D.; Leach, Andrew G.; Moody, Graeme C.; Gutierrez, Pablo Morentin; Newcombe, Nicholas J.; Nowak, Thorsten; Packer, Martin J.; Plowright, Alleyn T.; Revill, John; Schofield, Paul N.; Sheldon, Chris; Stokes, Steve; Turnbull, Andrew V.; Wang, Steven J Y; Whalley, David; Wood, J. Matthew

doi:10.1016/j.bmcl.2012.04.117

Cited by 41 publications

(24 citation statements)

References 20 publications

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“…To inhibit diacylglycerol O‐acyltransferase 1 (DGAT1) activity, cells were treated with AZD3988 (Tocris Bioscience, Invitrogen) (McCoull et al ., 2012) or dimethyl sulfoxide (DMSO) control for 24 h in low‐glucose DMEM and no antibiotics. After treatment, cells were washed and sensitivity to palmitate‐induced apoptosis was assessed.…”

Section: Methodsmentioning

confidence: 99%

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

et al. 2018

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Breast cancer (BrCa) metabolism is geared toward biomass synthesis and maintenance of reductive capacity. Changes in glucose and glutamine metabolism in BrCa have been widely reported, yet the contribution of fatty acids (FAs) in BrCa biology remains to be determined. We recently reported that adipocyte coculture alters MCF‐7 and MDA‐MB‐231 cell metabolism and promotes proliferation and migration. Since adipocytes are FA‐rich, and these FAs are transferred to BrCa cells, we sought to elucidate the FA metabolism of BrCa cells and their response to FA‐rich environments. MCF‐7 and MDA‐MB‐231 cells incubated in serum‐containing media supplemented with FAs accumulate extracellular FAs as intracellular triacylglycerols (TAG) in a dose‐dependent manner, with MDA‐MB‐231 cells accumulating more TAG. The differences in TAG levels were a consequence of distinct differences in intracellular partitioning of FAs, and not due to differences in the rate of FA uptake. Specifically, MCF‐7 cells preferentially partition FAs into mitochondrial oxidation, whereas MDA‐MB‐231 cells partition FAs into TAG synthesis. These differences in intracellular FA handling underpin differences in the sensitivity to palmitate‐induced lipotoxicity, with MDA‐MB‐231 cells being highly sensitive, whereas MCF‐7 cells are partially protected. The attenuation of palmitate‐induced lipotoxicity in MCF‐7 cells was reversed by inhibition of FA oxidation. Pretreatment of MDA‐MB‐231 cells with FAs increased TAG synthesis and reduced palmitate‐induced apoptosis. Our results provide novel insight into the potential influences of obesity on BrCa biology, highlighting distinct differences in FA metabolism in MCF‐7 and MDA‐MB‐231 cells and how lipid‐rich environments modulate these effects.

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Section: Methodsmentioning

confidence: 99%

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

et al. 2018

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“…However, the side effects of DGAT1 inhibitors have not been fully vetted, and recent characterization of patients with DGAT1 deficiency showing severe diarrhea raise concerns about potential adverse effects [71,73]. Indeed, the DGAT1 inhibitor AZD7687 was shown to improve insulin sensitivity and induce weight loss in rodent models [202]. However, a randomized clinical trial indicates that AZD7687 induces serious gastrointestinal side effects including diarrhea [203].…”

Section: Glycerol 3-phosphate Pathway Enzymes As Therapeutic Targetsmentioning

confidence: 99%

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

Wang

Airola

Reue

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Triacylglycerols (TAG) serve as the predominant form of energy storage in mammalian cells, and TAG synthesis influences conditions such as obesity, fatty liver, and insulin resistance. In most tissues, the glycerol 3-phosphate pathway enzymes are responsible for TAG synthesis, and the regulation and function of these enzymes is therefore important for metabolic homeostasis. Here we review the sites and regulation of glycerol-3-phosphate acyltransferase (GPAT), acylglycerol-3-phosphate acyltransferase (AGPAT), lipin/phosphatidic acid phosphatase (PAP), and diacylglycerol acyltransferase (DGAT) enzyme action. We highlight the critical roles that these enzymes play in human health by reviewing Mendelian disorders that result from mutation in the corresponding genes. We also summarize the valuable insights that genetically engineered mouse models have provided into the cellular and physiological roles of GPATs, AGPATs, lipins and DGATs. Finally, we comment on the status and feasibility of therapeutic approaches to metabolic disease that target enzymes of the glycerol 3-phosphate pathway.

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“…Disfunction in this stage of lipid metabolism can lead to serious disorders, such as obesity, which is an important risk factor for cardiovascular diseases, hypertension and diabetes [3,4]. Transgenic DGAT1-deficient mice have been shown to resist induced obesity even when fed on a rich fat-based diet, in addition to showing a remarkable reduction in the accumulation of triacylglycerol in their adipose tissues [5].…”

Section: Introductionmentioning

confidence: 99%

Deconstructing the DGAT1 enzyme: Binding sites and substrate interactions

Lopes

Nobre

Cilli

et al. 2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Diacylglycerol acyltransferase 1 (DGAT1) is a microsomal membrane enzyme responsible for the final step in the synthesis of triacylglycerides. Although DGATs from a wide range of organisms have nearly identical sequences, there is little structural information available for these enzymes. The substrate binding sites of DGAT1 are predicted to be in its large luminal extramembranous loop and to include common motifs with acyl-CoA cholesterol acyltransferase enzymes and the diacylglycerol binding domain found in protein kinases. In this study, synthetic peptides corresponding to the predicted binding sites of DGAT1 enzyme were examined using synchrotron radiation circular dichroism spectroscopy, fluorescence emission and adsorption onto lipid monolayers to determine their interactions with substrates associated with triacylglyceride synthesis (oleoyl-CoA and dioleoylglycerol). One of the peptides, Sit1, which includes the FYxDWWN motif common to both DGAT1 and acyl-CoA cholesterol acyltransferase, changes its conformation in the presence of both substrates, suggesting its capability to bind their acyl chains. The other peptide (Sit2), which includes the putative diacylglycerol binding domain HKWCIRHFYKP found in protein kinase C and diacylglycerol kinases, appears to interact with the charged headgroup region of the substrates. Moreover, in an extended-peptide which contains Sit1 and Sit2 sequences separated by a flexible linker, larger conformational changes were induced by both substrates, suggesting that the two binding sites may bring the substrates into close proximity within the membrane, thus catalyzing the formation of the triacylglyceride product.

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Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes

Cited by 41 publications

References 20 publications

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

Deconstructing the DGAT1 enzyme: Binding sites and substrate interactions

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