JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis

Okuma, Chihiro; Ohta, Takeshi; Tadaki, Hironobu; Ishigure, Tatsuya; Sakata, Shohei; Taniuchi, Hideyuki; Sano, Ryuhei; Hamada, Hiromi; Kume, Shinji; Nishiu, Jun; Kakutani, Makoto

doi:10.1016/j.jphs.2015.06.007

Cited by 9 publications

(7 citation statements)

References 31 publications

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“…Only when both enzymes were inhibited together was there a small decrease in intracellular TG. This is different from mice that were chronically treated with an MGAT2 inhibitor that had reduced liver MGAT activity and TG content 33 , 43 . The lack of effect on TG levels in MGAT2 inhibitor-treated HepG2 cells may be due to compensation by MGAT3, which is not present in mouse liver 24 .…”

Section: Discussionmentioning

confidence: 62%

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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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Section: Discussionmentioning

confidence: 62%

“…Because MGAT2 appears to be in low abundance in the liver, it was proposed that it was a minor contributor to MGAT activity in this tissue 23 . However, mice treated chronically with an MGAT2 inhibitor had reduced DG and TG synthesis in the liver 33 .…”

Section: Introductionmentioning

confidence: 98%

The monoacylglycerol acyltransferase pathway contributes to triacylglycerol synthesis in HepG2 cells

McFie

Patel

Stone

2022

Sci Rep

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“…MGAT1 ASO was not effective in preventing inflammatory changes in mice fed the high-fat/fructose and cholesterol diet (Soufi et al, 2014). Chemical inhibitors of MGAT2 have been shown to prevent diet-induced obesity and hepatic steatosis, though this is likely linked to decreased food intake (Okuma et al, 2015a; Okuma et al, 2015b). Interestingly, the decrease in food intake was only evident in high-fat fed rodents and associated with increased incretin hormones, suggesting an interaction between enteric MGAT2 and feeding behavior.…”

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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“…11 JTP-103237, an MGAT2 inhibitor, was shown to prevent fatty liver and suppress both hepatic TG synthesis and de novo lipogenesis in a carbohydrate-induced mouse fatty liver model. 12 In that report, the inhibition of hepatic MGAT activity by JTP-103237 was assessed using 2-oleoyl and [1- 14 C]-oleoyl-CoA as substrates. The radioactivity of the MGAT product, [1- 14 C] diacylglycerol, was separated using TLC and analyzed as MGAT activity.…”

Section: Resultsmentioning

confidence: 99%

Novel LC/MS/MS and High-Throughput Mass Spectrometric Assays for Monoacylglycerol Acyltransferase Inhibitors

Masucci

Lang

et al. 2017

SLAS Discovery

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Monoacylglycerol acyltransferase enzymes (MGAT1, MGAT2, and MGAT3) convert monoacylglycerol to diacylglycerol (DAG). MGAT1 and MGAT2 are both implicated in obesity-related metabolic diseases. Conventional MGAT enzyme assays use radioactive substrates, wherein the product of the MGAT-catalyzed reaction is usually resolved by time-consuming thin layer chromatography (TLC) analysis. Furthermore, microsomal membrane preparations typically contain endogenous diacylglycerol acyltransferase (DGAT) from the host cells, and these DGAT activities can further acylate DAG to form triglyceride (TG). Our mass spectrometry (liquid chromatography-tandem mass spectrometry, or LC/MS/MS) MGAT2 assay measures human recombinant MGAT2-catalyzed formation of didecanoyl-glycerol from 1-decanoyl-rac-glycerol and decanoyl-CoA, to produce predominantly 1,3-didecanoyl-glycerol. Unlike 1,2-DAG, 1,3-didecanoyl-glycerol is proved to be not susceptible to further acylation to TG. 1,3-Didecanoyl-glycerol product can be readily solubilized and directly subjected to high-throughput mass spectrometry (HTMS) without further extraction in a 384-well format. We also have established the LC/MS/MS MGAT activity assay in the intestinal microsomes from various species. Our assay is proved to be highly sensitive, and thus it allows measurement of endogenous MGAT activity in cell lysates and tissue preparations. The implementation of the HTMS MGAT activity assay has facilitated the robust screening and evaluation of MGAT inhibitors for the treatment of metabolic diseases.

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JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis

Abstract: In the present study, JTP-103237 prevented carbohydrate-induced fatty liver and suppressed both TG synthesis and de novo lipogenesis, suggesting MGAT inhibitor may prevent carbohydrate-induced metabolic disorders, including NAFLD, obesity and diabetes.

Cited by 9 publications

References 31 publications

The monoacylglycerol acyltransferase pathway contributes to triacylglycerol synthesis in HepG2 cells

The monoacylglycerol acyltransferase pathway contributes to triacylglycerol synthesis in HepG2 cells

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

Novel LC/MS/MS and High-Throughput Mass Spectrometric Assays for Monoacylglycerol Acyltransferase Inhibitors

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