Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1

Dow, Robert L.; Li, Jiancheng; Pence, Michael P.; Gibbs, E. Michael; LaPerle, Jennifer L.; Litchfield, John; Piotrowski, David W.; Munchhof, Michael J.; Manion, Tara B.; Zavadoski, William J.; Walker, Gregory S.; McPherson, R. Kirk; Tapley, Susan; Sugarman, Eliot; Guzmán-Pérez, Angel; DaSilva-Jardine, Paul

doi:10.1021/ml200051p

Cited by 87 publications

(86 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The discovery of PF-04620110 has been reported previously (19) and is a potent and selective small molecule inhibitor of DGAT1 with 100-fold selectivity vs. human DGAT2, ACAT1, AWAT1, AWAT2, MGAT2, and MGAT3 and mouse MGAT1. Briefly, the ability of PF-04620110 to inhibit recombinant human (38 nM), rat (94 nM), and mouse (64 nM) DGAT1 enzymatic activity was determined by measuring the incorporation of [ 3 H]n-decanoyl coenzyme A into DG to form TG.…”

Section: Methodsmentioning

confidence: 81%

“…The systemic deletion of DGAT1 as well as its acute pharmacological inhibition has been shown to elicit a blunted postabsorptive lipid profile (4,5,19,32,38,60). However, the precise trafficking of dietary lipids without functional DGAT1 has been largely unstudied.…”

mentioning

confidence: 99%

“…PF-04620110, a pyrimidooxazepinone, is a competitive inhibitor with a comparable K i in humans (19 nM), rat (64 nM), and mice (94 nM) (19,22). Additionally, we examined the temporal and spatial patterns of TG absorption in mice following administration of a single dose of PF-04620110 (19). To monitor the impact of DGAT1 inhibition on enterocyte lipid species content, lipid metabolite profiling was performed in both rat intestine and plasma and human plasma.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Pharmacological inhibition to examine the role of DGAT1 in dietary lipid absorption in rodents and humans

Maciejewski

LaPerle

Chen

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

Self Cite

View full text Add to dashboard Cite

Alterations in fat metabolism, in particular elevated plasma concentrations of free fatty acids and triglycerides (TG), have been implicated in the pathogenesis of Type 2 diabetes, obesity, and cardiovascular disease. Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a member of the large family of membrane-bound O-acyltransferases, catalyzes the final step in triacylglycerol formation. In the intestine, DGAT1 is one of the acyltransferases responsible for the reesterficiation of dietary TG. Following a single dose of a selective pharmacological inhibitor of DGAT1, PF-04620110, a dose-dependent inhibition of TG and vitamin A absorption postprandially was demonstrated in rodents and human subjects. In C57/BL6J mice, acute DGAT1 inhibition alters the temporal and spatial pattern of dietary lipid absorption. To understand the impact of DGAT1 inhibition on enterocyte lipid metabolism, lipomic profiling was performed in rat intestine and plasma as well as human plasma. DGAT1 inhibition causes an enrichment of polyunsaturated fatty acids within the TG class of lipids. This pharmacological intervention gives us insight as to the role of DGAT1 in human dietary lipid absorption.

show abstract

Section: Methodsmentioning

confidence: 81%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological inhibition to examine the role of DGAT1 in dietary lipid absorption in rodents and humans

Maciejewski

LaPerle

Chen

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

Self Cite

View full text Add to dashboard Cite

show abstract

“…12,28 To investigate distinct contributions of the 2 DGATs to hepatic triacylglycerol synthesis, deposition in LDs, and triacylglycerol secretion in VLDL, we pharmacologically inhibited their activities in primary mouse and human hepatocytes with potent, highly selective small-molecule inhibitors. 29,30 Moreover, because some studies showed that DGAT2 preferentially used endogenously synthesized FA to form triacylglycerol in HepG2 hepatoma cell line, whereas DGAT1 was primarily responsible for exogenous FA esterification, 25,31 we tracked lipids synthesized from FA made de novo or from exogenously supplied oleic acid.…”

mentioning

confidence: 99%

Roles of Acyl-CoA:Diacylglycerol Acyltransferases 1 and 2 in Triacylglycerol Synthesis and Secretion in Primary Hepatocytes

Lian

et al. 2015

ATVB

View full text Add to dashboard Cite

Objective-Very low-density lipoprotein assembly and secretion are regulated by the availability of triacylglycerol.Although compelling evidence indicates that the majority of triacylglycerol in very low-density lipoprotein is derived from re-esterification of lipolytic products released by endoplasmic reticulum-associated lipases, little is known about roles of acyl-CoA:diacylglycerol acyltransferases (DGATs) in this process. We aimed to investigate the contribution of DGAT1 and DGAT2 in lipid metabolism and lipoprotein secretion in primary mouse and human hepatocytes. Approach and Results-We used highly selective small-molecule inhibitors of DGAT1 and DGAT2, and we tracked storage and secretion of lipids synthesized de novo from [ 3 H]acetic acid and from exogenously supplied [ 3 H]oleic acid. Inactivation of individual DGAT activity did not affect incorporation of either radiolabeled precursor into intracellular triacylglycerol, whereas combined inactivation of both DGATs severely attenuated triacylglycerol synthesis. However, inhibition of DGAT2 augmented fatty acid oxidation, whereas inhibition of DGAT1 increased triacylglycerol secretion, suggesting preferential channeling of separate DGAT-derived triacylglycerol pools to distinct metabolic pathways. Inactivation of DGAT2 impaired cytosolic lipid droplet expansion, whereas DGAT1 inactivation promoted large lipid droplet formation. Moreover, inactivation of DGAT2 attenuated expression of lipogenic genes. Finally, triacylglycerol secretion was significantly reduced on DGAT2 inhibition without altering extracellular apolipoprotein B levels. Conclusions-Our data suggest that DGAT1 and DGAT2 can compensate for each other to synthesize triacylglycerol, but triacylglycerol synthesized by DGAT1 is preferentially channeled to oxidation, whereas DGAT2 synthesizes triacylglycerol destined for very low-density lipoprotein assembly. an indirect transfer of triacylglycerol for VLDL maturation. 11 It has been established that the majority (60%-80%) of triacylglycerol in VLDL is derived from re-esterification of lipolytic products in hepatocytes. [12][13][14] This sinuous supply of triacylglycerol for VLDL maturation overcomes the inability of triacylglycerol stored in cytosolic lipid droplets (LDs) to cross the lipid bilayer of the endoplasmic reticulum (ER) and provides a mechanism for the regulation of VLDL secretion independently of plasma FA and intracellular triacylglycerol concentration. 15 We have previously shown that lipases involved in the hydrolysis of preformed triacylglycerol include ER-localized carboxylesterase 1d/triacylglycerol hydrolase and arylacetamide deacetylase [16][17][18] ; however, it has not been determined which DGAT catalyzes the re-esterification of diacylglycerol to support VLDL maturation.Topological studies separated DGAT activities in hepatic microsomes into overt, cytosolic side-localized, and latent, lumenal side-localized. [19][20][21] This led to a hypothesis that the overt DGAT activity might be responsible for the synthesis of tria...

show abstract

“…Numerous specifi c inhibitors of DGAT1 have been developed as potential treatments for type 2 diabetes and obesity ( 136 ), based on the favorable metabolic phenotypes (enhanced insulin sensitivity and resistance to weight gain) observed in Dgat1 Ϫ / Ϫ mice. Several have been tested in animals and recapitulated the favorable outcomes predicted by the genetically engineered mice, including delayed gastric emptying and fat absorption, blunted postprandial plasma TAG, increased GLP-1 levels, enhanced fatty acid oxidation, reduced liver TAG, improved insulin sensitivity, and weight loss (137)(138)(139)(140)(141)(142)(143).…”

Section: Specific Inhibitors Of the Mag Pathwaymentioning

confidence: 99%

Intestinal triacylglycerol synthesis in fat absorption and systemic energy metabolism

Yen

Nelson

Yen

2015

Journal of Lipid Research

111

View full text Add to dashboard Cite

cell membranes. The biosynthesis of TAG thus serves many physiological functions. Because it is highly reduced and anhydrous, TAG is the primary energy substrate stored in adipose tissues to sustain animals during fasting. TAG is also synthesized in the liver for the assembly and secretion of VLDL to transport neutral lipids to other tissues, as well as in the mammary gland for the formation of milk fat globules to deliver fatty acids and other lipid-soluble nutrients to mammalian neonates.In the intestine, TAG synthesis is prominent for its role in the absorption of dietary fat ( 2, 3 ). TAG forms the bulk of animal fats and plant oils. It accounts for approximately 95% of dietary fat, depending on the food sources, with the rest as phospholipids and trace amounts of sterols, lipid-soluble vitamins, and other lipophilic components. Because of its hydrophobicity, TAG does not traverse the cellular membrane. Its absorption involves hydrolysis to fatty acids and monoacylglycerol (MAG) in the intestinal lumen, lipid uptake by the enterocytes, resynthesis of TAG, and assembly and secretion of ApoB-containing chylomicrons for delivery of TAG and other lipid-soluble nutrients. Like with most nutrients, the absorption of TAG occurs mostly in the proximal half of the intestine and less so in the distal intestine, where specifi c compounds, such as bile acids and vitamin B12, are absorbed. The activity of TAG synthesis coincides with the absorption of dietary fat along the length of the intestine, and it is more active in Press, September 17, 2014 DOI 10.1194 Abbreviations: ACSL, acyl-CoA synthetase; AGPAT, 1-acylglycerol-3-phosphate acyltransferase; ATGL, adipose triglyceride lipase; CD36, cluster of differentiation; CGI-58, comparative gene identifi cation-58; Cideb, cell death-inducing DNA fragmentation factor 45 (DFF45) -like effector b; DAG, diacylglycerol; DGAT, acyl-CoA:diacylglycerol acyltransferase; ER, endoplasmic reticulum; FABP, fatty acid binding protein; GLP-1, glucagon-like peptide 1; GPAT, glycerol-3-phosphate acyltransferase; G3P, glycerol-3-phosphate; IFABP, intestine-type fatty acid binding protein; LFABP, liver-type fatty acid binding protein; MAG, monoacylglycerol; MBOAT, membrane-bound O-acyltransferase; MGAT, acylCoA:monoacylglycerol acyltransferase; MTP, microsomal triacylglycerol transfer protein; PA, phosphatidic acid; PAP, phosphatidic acid phosphatase; TAG, triacylglycerol (triglyceride ). Published, JLR Papers in

show abstract

Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1

Cited by 87 publications

References 26 publications

Pharmacological inhibition to examine the role of DGAT1 in dietary lipid absorption in rodents and humans

Pharmacological inhibition to examine the role of DGAT1 in dietary lipid absorption in rodents and humans

Roles of Acyl-CoA:Diacylglycerol Acyltransferases 1 and 2 in Triacylglycerol Synthesis and Secretion in Primary Hepatocytes

Intestinal triacylglycerol synthesis in fat absorption and systemic energy metabolism

Contact Info

Product

Resources

About