Last update 01 Nov 2024

DGAT1 x NLRP3

Last update 01 Nov 2024

Basic Info

Related Targets

DGAT1NLRP3

Drugs associated with DGAT1 x NLRP3

PF-4620110

Target

DGAT1 x NLRP3

Mechanism

DGAT1 inhibitors [+1]

Active Org.-

Originator Org.

Pfizer Inc.

Active Indication-

Inactive Indication

Diabetes Mellitus, Type 2 [+1]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with DGAT1 x NLRP3

NCT01474941 / CompletedPhase 1

A Phase 1, Randomized, Double-Blind, Parallel, Placebo-Controlled, Multiple-Dose Escalation Study To Investigate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of A Modified-Release Formulation Of PF-04620110 In Otherwise Healthy Overweight Or Obese Adult Subjects

The primary purpose of this trial is to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics, of multiple oral doses of PF-04620110 as a modified-release formulation.

Start Date01 Jun 2011

Sponsor / Collaborator

Pfizer Inc.

NCT01298518 / CompletedPhase 1

A Phase 1B, Randomized, Double-Blind, Placebo-Controlled Trial To Assess The Efficacy And Safety Of 4-Week Administration Of Multiple Oral Doses Of PF-04620110 In Type 2 Diabetes Mellitus Subjects With Insufficient Glycemic Control On Metformin

PF-04620110 is a novel compound proposed for the treatment of Type 2 diabetes mellitus. The primary purpose of this trial is to evaluate the safety and tolerability, and pharmacodynamics, of multiple oral doses of PF-04620110 in T2DM patients.

Start Date01 Feb 2011

Sponsor / Collaborator

Pfizer Inc.

NCT01166217 / CompletedPhase 1

A Phase 1, Cross-over, Single-dose, Open-label Study to Estimate the Relative Bioavailability of Three Different Formulations of Pf-04620110 Under Fed/Fasted Conditions in Healthy Adult Subjects

PF-04620110 is a novel compound proposed for the treatment of Type 2 diabetes mellitus. The primary purpose of this trial is to evaluate the relative bioavailability of three different oral dose formulations of PF-04620110.

Start Date01 Jul 2010

Sponsor / Collaborator

Pfizer Inc.

[+1]

100 Clinical Results associated with DGAT1 x NLRP3

100 Translational Medicine associated with DGAT1 x NLRP3

0 Patents (Medical) associated with DGAT1 x NLRP3

Literatures (Medical) associated with DGAT1 x NLRP3

01 Jan 2019·Diabetes & Metabolism JournalQ3 · MEDICINE

PF-04620110, a Potent Antidiabetic Agent, Suppresses Fatty Acid-Induced NLRP3 Inflammasome Activation in Macrophages

Q3 · MEDICINE

ArticleOA

Author: Moon, Jong-Seok ; Kim, Seong Jin ; Lee, Jong Min ; Jo, Seung Il ; Jeong, Ji Hun ; Bae, Jung Hwan

BACKGROUNDChronic inflammation has been linked to insulin resistance and type 2 diabetes mellitus (T2DM). High-fat diet (HFD)-derived fatty acid is associated with the activation of chronic inflammation in T2DM. PF-04620110, which is currently in phase 1 clinical trials as a selective acyl-CoA:diacylglycerol acyltransferase-1 (DGAT1) inhibitor, is a potent anti-diabetic agent that may be important for the regulation of chronic inflammation in T2DM. However, the mechanisms by which PF-04620110 regulates fatty acid-induced chronic inflammation remain unclear.METHODSPF-04620110 was used in vitro and in vivo. DGAT1-targeting gRNAs were used for deletion of mouse DGAT1 via CRISPR ribonucleoprotein (RNP) system. The activation of NLRP3 inflammasome was measured by immunoblot or cytokine analysis in vitro and in vivo.RESULTSHere we show that PF-04620110 suppressed fatty acid-induced nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome activation in macrophages. In contrast, PF-04620110 did not change the activation of the NLR family, CARD-domain-containing 4 (NLRC4), or the absent in melanoma 2 (AIM2) inflammasomes. Moreover, PF-04620110 inhibited K⁺ efflux and the NLRP3 inflammasome complex formation, which are required for NLRP3 inflammasome activation. PF-04620110 reduced the production of interleukin 1β (IL-1β) and IL-18 and blood glucose levels in the plasma of mice fed HFD. Furthermore, genetic inhibition of DGAT1 suppressed fatty acid-induced NLRP3 inflammasome activation.CONCLUSIONOur results suggest that PF-04620110 suppresses fatty acid-induced NLRP3 inflammasome activation.

01 Dec 2017·Journal of Applied ToxicologyQ4 · MEDICINE

Increased incidence of non‐alcoholic fatty liver disease in male rat offspring exposed to fluoxetine during fetal and neonatal life involves the NLRP3 inflammasome and augmented de novo hepatic lipogenesis

Q4 · MEDICINE

Article

Author: De Long, Nicole E. ; Hardy, Daniel B. ; Ma, Noelle ; Holloway, Alison C.

AbstractUp to 10% of women take selective serotonin reuptake inhibitors (SSRI) during pregnancy. Children exposed to SSRIs in utero have an increased risk of being overweight suggesting that fetal exposure to SSRIs can cause permanent metabolic changes. We have previously shown in rats that fetal and neonatal exposure to the SSRI antidepressant fluoxetine results in metabolic perturbations including increased hepatic triglyceride content; a hallmark of non‐alcoholic fatty liver disease (NAFLD). Therefore, the aim of this study was to identify the mechanism(s) underlying the fluoxetine‐induced increase in intrahepatic triglyceride content. Female nulliparous Wistar rats were given vehicle or fluoxetine (10 mg/kg/day) orally for 2 weeks prior to mating until weaning. At 6 months of age, we assessed whether SSRI exposure altered components of the hepatic triglyceride biosynthesis pathway in the offspring and examined the molecular mechanisms underlying these changes. Male SSRI‐exposed offspring had a significant increase in the steady‐state mRNA levels of Elovl6 and Dgat1 and core components of the NLRP3 inflammasome (apoptosis‐associated speck‐like protein containing a caspase activation recruitment domain [ASC] and caspase‐1). Augmented expression of Asc in the SSRI‐exposed offspring coincided with increased histone acetylation in the proximal promoter region. Given that we have previously demonstrated that antenatal exposure to SSRIs can lead to fatty liver in the offspring, this raises concerns regarding the long‐term metabolic sequelae of fetal SSRI exposure. Moreover, this study suggests that elevated hepatic triglyceride levels observed in the SSRI‐exposed offspring may be due, in part, to activation of the NLRP3 inflammasome and augmentation of de novo lipogenesis.

CellsQ3 · BIOLOGY

The Absence of NLRP3-inflammasome Modulates Hepatic Fibrosis Progression, Lipid Metabolism, and Inflammation in KO NLRP3 Mice during Aging

Q3 · BIOLOGY

ArticleOA

Author: Gallego, Paloma ; Castejón-Vega, Beatriz ; del Campo, José A. ; Cordero, Mario D.

Aging is associated with metabolic changes and low-grade inflammation in several organs, which may be due to NLRP3 inflammasome activation. Methods: Here, we asked whether age-related liver changes such as lipid metabolism and fibrosis are reduced in aged mice lacking the NLRP3 inflammasome. We report reduced protein levels of lipid markers (MTP, FASN, DGAT1), SOD activity, oxidative stress marker PTPRG, and the fibrotic markers TPM2β, COL1-α1 associated with increased GATA4, in NLRP3 deficient mice. Fibrotic, lipid, and oxidative reduction in liver tissues of mice was more pronounced in those old KO NLRP3 mice than in the younger ones, despite their greater liver damage. These results suggest that absence of the NLRP3 inflammasome attenuates age-related liver fibrotic pathology in mice, suggesting that pharmacological targeting may be beneficial.

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