Discovery of Selective Small Molecule Inhibitors of Monoacylglycerol Acyltransferase 3

Huard, Kim; Londregan, Allyn T.; Tesz, Gregory J.; Bahnck, Kevin B.; Magee, Thomas V.; Hepworth, David; Polívková, Jana; Coffey, Steven B.; Pabst, Brandon; Gosset, J; Nigam, Anu; Kou, Kou; Sun, Hao; Lee, Kyuha; Herr, Michael; Boehm, Markus; Carpino, Philip A.; Goodwin, Bryan; Perreault, Christian; Li, Qifang; Jorgensen, Csilla C.; Tkalcevic, George T.; Subashi, Timothy A.; Ahn, Kay

doi:10.1021/acs.jmedchem.5b01008

Cited by 15 publications

(10 citation statements)

References 37 publications

(39 reference statements)

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“…Glucose was chosen for the simultaneous labeling of acyl chains and glycerol based on a recent plant-based study that demonstrated a lack of incorporation of label into fatty acids using glycerol itself (40). The incorporation of stable isotopically labeled glycerol into the TG pool as a proxy for the activity of complex lipid remodeling enzymes is an established technique (41).…”

Section: Resultsmentioning

confidence: 99%

Carbon and Acyl Chain Flux during Stress-induced Triglyceride Accumulation by Stable Isotopic Labeling of the Polar Microalga Coccomyxa subellipsoidea C169

Allen

DiRusso

Black

2017

Journal of Biological Chemistry

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Edited by George M. CarmanDeriving biofuels and other lipoid products from algae is a promising future technology directly addressing global issues of atmospheric CO 2 balance. To better understand the metabolism of triglyceride synthesis in algae, we examined their metabolic origins in the model species, Coccomyxa subellipsoidea C169, using stable isotopic labeling. Labeling patterns arising from [U- The incorporation rates of de novo synthesized FA into lipid classes were measured over a time course of nitrogen starvation. The synthesis of triglycerides, phospholipids, and galactolipids followed a two-stage pattern where nitrogen starvation resulted in a 2.5-fold increase followed by a gradual decline. Acyl chain flux into membrane lipids was dominant in the first stage followed by triglycerides. These data indicate that the level of metabolic control that determines acyl chain flux between membrane lipids and triglycerides during nitrogen stress relies primarily on the Kennedy pathway and de novo FA synthesis with limited, defined input from acyl editing reactions.

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Section: Resultsmentioning

confidence: 99%

Carbon and Acyl Chain Flux during Stress-induced Triglyceride Accumulation by Stable Isotopic Labeling of the Polar Microalga Coccomyxa subellipsoidea C169

Allen

DiRusso

Black

2017

Journal of Biological Chemistry

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“…It is unknown whether targeting MGAT3 will be effective in treating humans. MGAT3 specific inhibitors have been designed and preliminary studies in transgenic mice expressing MGAT3 have demonstrated efficacy in vivo , though further phenotypic characterization has not been reported (Huard et al, 2015).…”

Section: Peroxisome Proliferator-activated Receptor Agonists (Ppar’s)mentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases

2018

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NAFLD is closely linked with hepatic insulin resistance. Accumulation of hepatic diacylglycerol activates PKC-ε, impairing insulin receptor activation and insulin-stimulated glycogen synthesis. Peripheral insulin resistance indirectly influences hepatic glucose and lipid metabolism by increasing flux of substrates that promote lipogenesis (glucose and fatty acids) and gluconeogenesis (glycerol and fatty acid-derived acetyl-CoA, an allosteric activator of pyruvate carboxylase). Weight loss with diet or bariatric surgery effectively treats NAFLD, but drugs specifically approved for NAFLD are not available. Some new pharmacological strategies act broadly to alter energy balance or influence pathways that contribute to NAFLD (e.g., agonists for PPAR γ, PPAR α/δ, FXR and analogs for FGF-21, and GLP-1). Others specifically inhibit key enzymes involved in lipid synthesis (e.g., mitochondrial pyruvate carrier, acetyl-CoA carboxylase, stearoyl-CoA desaturase, and monoacyl- and diacyl-glycerol transferases). Finally, a novel class of liver-targeted mitochondrial uncoupling agents increases hepatocellular energy expenditure, reversing the metabolic and hepatic complications of NAFLD.

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“…The relative contributions of MGAT2 and MGAT3 to hepatic lipid metabolism are unknown. To probe the role that each enzyme has in TG synthesis and secretion in HepG2 cells we utilized the highly selective MGAT2 and MGAT3 small molecule inhibitors, Cpd24d and PF-06471553, respectively, to attenuate MGAT activity 34 , 35 . We first confirmed that these compounds effectively inhibited MGAT activity.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we tested the hypothesis that MGAT2 and/or MGAT3 can contribute to TG synthesis and secretion in the liver via the MGAT pathway. To test this, we inhibited MGAT2 and MGAT3 in HepG2 cells with highly selective small-molecule inhibitors and examined the effects on lipid metabolism 34 , 35 . We found that MGAT2, much more so than MGAT3, contributed to hepatic TG synthesis and secretion.…”

Section: Introductionmentioning

confidence: 99%

The monoacylglycerol acyltransferase pathway contributes to triacylglycerol synthesis in HepG2 cells

McFie

Patel

Stone

2022

Sci Rep

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The monoacylglycerol acyltransferase (MGAT) pathway has a well-established role in the small intestine where it facilitates the absorption of dietary fat. In enterocytes, MGAT participates in the resynthesis of triacylglycerol using substrates (monoacylglycerol and fatty acids) generated in the gut lumen from the breakdown of triacylglycerol consumed in the diet. MGAT activity is also present in the liver, but its role in triacylglycerol metabolism in this tissue remains unclear. The predominant MGAT isoforms present in human liver appear to be MGAT2 and MGAT3. The objective of this study was to use selective small molecule inhibitors of MGAT2 and MGAT3 to determine the contributions of these enzymes to triacylglycerol production in liver cells. We found that pharmacological inhibition of either enzyme had no effect on TG mass in HepG2 cells but did alter lipid droplet size and number. Inhibition of MGAT2 did result in decreased DG and TG synthesis and TG secretion. Interestingly, MGAT2 preferentially utilized 2-monoacylglycerol derived from free glycerol and not from exogenously added 2-monoacylglycerol. In contrast, inhibition of MGAT3 had very little effect on TG metabolism in HepG2 cells. Additionally, we demonstrated that the MGAT activity of DGAT1 only makes a minor contribution to TG synthesis in intact HepG2 cells. Our data demonstrated that the MGAT pathway has a role in hepatic lipid metabolism with MGAT2, more so than MGAT3, contributing to TG synthesis and secretion.

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Discovery of Selective Small Molecule Inhibitors of Monoacylglycerol Acyltransferase 3

Cited by 15 publications

References 37 publications

Carbon and Acyl Chain Flux during Stress-induced Triglyceride Accumulation by Stable Isotopic Labeling of the Polar Microalga Coccomyxa subellipsoidea C169

Carbon and Acyl Chain Flux during Stress-induced Triglyceride Accumulation by Stable Isotopic Labeling of the Polar Microalga Coccomyxa subellipsoidea C169

Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases

The monoacylglycerol acyltransferase pathway contributes to triacylglycerol synthesis in HepG2 cells

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