Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight and modulates gut peptide release—Potential insight into mechanism of action

Liu, Jinqi; Gorski, Judith N.; Gold, Stephen J.; Chen, Dunlu; Chen, Shirley; Forrest, Gail; Itoh, Yoshiki; Marsh, Donald J.; McLaren, David G.; Shen, Zhu; Sonatore, Lisa M.; Carballo-Jane, Ester; Craw, Stephanie; Guan, Xiao-Ming; Karanam, Bindhu V.; Sakaki, Junichi; Szeto, Daphne; Tong, Xinchun; Xiao, Jianying; Yoshimoto, Ryo; Yu, Hong; Roddy, Thomas P.; Balkovec, James M.; Pinto, Shirly

doi:10.1002/oby.20193

Cited by 26 publications

(34 citation statements)

References 31 publications

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“…DGAT1 and DGAT2 inhibitors were from Merck & Co., Inc., Kenilworth, NJ (23, 24). The inhibitors were suspended in DMSO and used at a final concentration of 5 μM.…”

Section: Methodsmentioning

confidence: 99%

Identification and characterization of a novel DGAT1 missense mutation associated with congenital diarrhea

Gluchowski

Chitraju

Picoraro

et al. 2017

Journal of Lipid Research

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Acyl-CoA:diacylglycerol acyltransferase (DGAT)1 and DGAT2 catalyze triglyceride (TG) biosynthesis in humans. Biallelic loss-of-function mutations in human DGAT1 result in severe congenital diarrhea and protein-losing enteropathy. Additionally, pharmacologic inhibition of DGAT1 led to dose-related diarrhea in human clinical trials. Here we identify a previously unknown DGAT1 mutation in identical twins of South Asian descent. These male patients developed watery diarrhea shortly after birth, with protein-losing enteropathy and failure to thrive. Exome sequencing revealed a homozygous recessive mutation in DGAT1, c.314T>C, p.L105P. We show here that the p.L105P DGAT1 enzyme produced from the mutant allele is less abundant, resulting in partial loss of TG synthesis activity and decreased formation of lipid droplets in patient-derived primary dermal fibroblasts. Thus, in contrast with complete loss-of-function alleles of DGAT1, the p.L105P missense allele partially reduces TG synthesis activity and causes a less severe clinical phenotype. Our findings add to the growing recognition of DGAT1 deficiency as a cause of congenital diarrhea with protein-losing enteropathy and indicate that DGAT1 mutations result in a spectrum of diseases.

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“…DGAT1 and DGAT2 inhibitors were from Merck & Co., Inc., Kenilworth, NJ (23, 24). The inhibitors were suspended in DMSO and used at a final concentration of 5 μM.…”

Section: Methodsmentioning

confidence: 99%

Identification and characterization of a novel DGAT1 missense mutation associated with congenital diarrhea

Gluchowski

Chitraju

Picoraro

et al. 2017

Journal of Lipid Research

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“…Recently, we reported that small molecule DGAT1 inhibitors markedly alter incretin peptide release following oral lipid challenge. 21 Additionally, combination of DGAT1 inhibition with dipeptidyl-peptidase-4 (DPP-4) inhibition led to further enhancements in active GLP-1 in mice and dogs, suggesting potential combinability of DGAT1 inhibitors and DPP-4 inhibitors for treatment of metabolic diseases. 22 The DGAT1 inhibitor program at Merck was primarily built upon our initial discovery of a novel benzimidazole class of compounds bearing an acid moiety at the terminus of the structure (Figure 2).…”

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confidence: 99%

Potent DGAT1 Inhibitors in the Benzimidazole Class with a Pyridyl-oxy-cyclohexanecarboxylic Acid Moiety

Hong

Lai

et al. 2013

ACS Med. Chem. Lett.

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We report the design and synthesis of a series of novel DGAT1 inhibitors in the benzimidazole class with a pyridyl-oxy-cyclohexanecarboxylic acid moiety. In particular, compound 11A is a potent DGAT1 inhibitor with excellent selectivity against ACAT1. Compound 11A significantly reduces triglyceride excursion in lipid tolerance tests (LTT) in both mice and dogs at low plasma exposure. An in vivo study in mice with des-fluoro analogue 10A indicates that this series of compounds appears to distribute in intestine preferentially over plasma. The propensity to target intestine over plasma could be advantageous in reducing potential side effects since lower circulating levels of drug are required for efficacy. However, in the preclinical species, compound 11A undergoes cis/trans epimerization in vivo, which could complicate further development due to the presence of an active metabolite. KEYWORDS: DGAT1, inhibitor, benzimidazole, ACAT1, cyclohexanecarboxylic acid, lipid tolerance test, epimerization, metabolite T ype II diabetes mellitus (T2DM) and obesity, two interlinked disease conditions, have emerged as the major threats to human health globally. 1,2 In 2008, World Health Organization estimated the number of overweight and obese adults worldwide to be 1 billion and 500 million, respectively. In 2009−2010, more than one-third of the American population was classified as obese. 3 Meanwhile, a recent estimate indicates that there are about 371 million people worldwide living with diabetes. 4 Current drugs available to treat diabetes and obesity have limitations in terms of longterm efficacy and/or side effects. 5−7 The unmet need prompts significant research efforts in this area.Inhibition of DGAT1 (diglyceride acyltransferase 1) has emerged as a potential mechanism for the treatment of T2DM and obesity. 8,9 The DGAT family (diglyce diglyceride acyltransferase 1 and 2) catalyzes the formation of triglyceride (TG) from diacylglycerol and acyl-CoA, the terminal and committed step in TG synthesis. 10 DGAT1 shares only limited sequence homology with DGAT2, the other known isoform. 11 In contrast, DGAT1 has more sequence homology to acyl CoA:cholesterol acyltransferase (ACAT1 and ACAT2). ACAT plays an important role in cholesterol homeostasis. 12 The strong interest in DGAT1 started after the reports on DGAT1 knockout mouse phenotyping studies. DGAT1 knockout mice were shown to be viable and resistant to diet-induced obesity. 13 Furthermore, these mice appeared to have increased sensitivity to insulin and leptin. 14 This compelling data set has inspired major efforts in identifying small molecule DGAT1 inhibitors for potential treatment of diabetes and obesity (Figure 1

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“…metabolic profile upon high fat diet feeding, including decreased body weight gain, increased insulin sensitivity, and reduced hepatic lipid accumulation (32,(37)(38)(39)(40). However, in contrast, when maintained on high fat diets, Gpat3 Ϫ/Ϫ mice exhibit weight gain in line with wild-type animals and accumulate excess hepatic lipid in the form of TG, DAG, and CE.…”

Section: Discussionmentioning

confidence: 99%

“…The reason for this difference is unclear; however, it could relate to divergent effects on enteroendocrine hormone release. Thus, although inhibition of DGAT1 is associated with suppression of GIP and robust increases in GLP-1 and the anorectic hormone peptide YY (PYY) (38,41), loss of GPAT3 results in elevated levels of circulating GIP. We were unable to discern an effect on GLP-1 levels in Gpat3 Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Novel Intestinal Glycerol-3-phosphate Acyltransferase Pathway and Its Role in Lipid Homeostasis

Khatun

Clark

Vera

et al. 2016

Journal of Biological Chemistry

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Dietary triglycerides (TG) are absorbed by the enterocytes of the small intestine after luminal hydrolysis into monacylglycerol and fatty acids. Before secretion on chylomicrons, these lipids are reesterified into TG, primarily through the monoacylglycerol pathway. However, targeted deletion of the primary murine monoacylglycerol acyltransferase does not quantitatively affect lipid absorption, suggesting the existence of alternative pathways. Therefore, we investigated the role of the glycerol 3-phosphate pathway in dietary lipid absorption. The expression of glycerol-3-phosphate acyltransferase (GPAT3) was examined throughout the small intestine. To evaluate the role for GPAT3 in lipid absorption, mice harboring a disrupted GPAT3 gene (Gpat3 ؊/؊ ) were subjected to an oral lipid challenge and fed a Western-type diet to characterize the role in lipid and cholesterol homeostasis. Additional mechanistic studies were performed in primary enterocytes. GPAT3 was abundantly expressed in the apical surface of enterocytes in the small intestine. After an oral lipid bolus, Gpat3 ؊/؊ mice exhibited attenuated plasma TG excursion and accumulated lipid in the enterocytes. Electron microscopy studies revealed a lack of lipids in the lamina propria and intercellular space in Gpat3 ؊/؊ mice. Gpat3 ؊/؊ enterocytes displayed a compensatory increase in the synthesis of phospholipid and cholesteryl ester. When fed a Western-type diet, hepatic TG and cholesteryl ester accumulation was significantly higher in Gpat3 ؊/؊ mice compared with the wild-type mice accompanied by elevated levels of alanine aminotransferase, a marker of liver injury. Dysregulation of bile acid metabolism was also evident in Gpat3-null mice. These studies identify GPAT3 as a novel enzyme involved in intestinal lipid metabolism.The ability of an organism to efficiently extract energy-rich nutrients from its diet is critical for survival. Triglycerides (TG) 2 are energy-dense lipid molecules; however, their biophysical properties preclude direct absorption in the gut. The primary site for the absorption of TG and other dietary lipids is the small intestine. Lipid absorption is a multistep process that begins with the intraluminal emulsification of fat by bile acids, which in turn facilitates hydrolysis by multiple lipases. TG hydrolysis leads to the liberation of monoacylglycerol (MAG) and free fatty acid (FFA). Absorption of these hydrolyzed products occurs in the epithelial monolayer lining the villi and involves both passive diffusion and facilitated transport. After absorption, FFAs are primarily reesterified into TG and either temporarily stored as cytosolic lipid droplets (CLDs) or packaged into chylomicrons and secreted into the lymphatic vessels of the lamina propria through the basolateral surface of enterocytes (1). There are two primary routes for TG synthesis, namely, the MAG and glycerol 3-phosphate (G3P) pathways. Both pathways produce diacylglycerol (DAG) as a common intermediate. In the MAG pathway DAG is directly synthesized from sn-2 MAG throug...

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Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight and modulates gut peptide release—Potential insight into mechanism of action

Cited by 26 publications

References 31 publications

Identification and characterization of a novel DGAT1 missense mutation associated with congenital diarrhea

Identification and characterization of a novel DGAT1 missense mutation associated with congenital diarrhea

Potent DGAT1 Inhibitors in the Benzimidazole Class with a Pyridyl-oxy-cyclohexanecarboxylic Acid Moiety

Characterization of a Novel Intestinal Glycerol-3-phosphate Acyltransferase Pathway and Its Role in Lipid Homeostasis

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