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DGAT1 Inhibitor-Induced Gene Expression in Mouse Skin

ABSTRACT: Inhibition of Diacylglycerol O-acyltransferase 1 (DGAT1) has been a mechanism of interest for metabolic disorders. DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects. One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme. In this report we describe a modeling-based approach to identify molecules with physical properties leading to differential exposure distribution. In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting. Mice were treated with DGAT1 inhibitors for 14 days and dorsal skin biopsies (3-5 mm^2) were taken. RNA was profiled on custom Affymetrix microarrays. The primary goal was to identify robust and consistent biomarkers of DGAT1 inibition in skin.

ORGANISM(S): Mus musculus

SUBMITTER: eric muise

PROVIDER: E-GEOD-49375 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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DGAT1 Inhibitor-Induced Gene Expression in Mouse Skin

Project description:Inhibition of Diacylglycerol O-acyltransferase 1 (DGAT1) has been a mechanism of interest for metabolic disorders. DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects. One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme. In this report we describe a modeling-based approach to identify molecules with physical properties leading to differential exposure distribution. In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting.

2014-02-20 | GSE49375 | GEO

Obesity facilitated colon cancer progression is mediated by increased diacylglycerol o-acyltransferases 1 and 2 (DGAT1/2) levels

Project description:Background & Aims: The obesity epidemic is associated with increased colon cancer progression. As lipid droplets (LDs) fuel tumor growth, we aim to determine the significance of diacyltransferases, DGAT1/2, responsible for LDs biogenesis, in obesity-mediated colonic tumorigenesis. Methods: Human colon cancer samples, colon cancer cells, colonospheres, and ApcMin/+ colon cancer mouse model on a high-fat diet were employed. For DGAT1/2 inhibition, enzymatic inhibitors and siRNA were used. Expression, pathways, cell cycle, and growth were assessed. Bioinformatic analysis of CUT&RUN and RNAseq data was performed. Results: DGAT1/2 levels in human colon cancer tissue are significantly elevated with disease severity and obesity (vs normal). Their levels are increased in human colon cancer cells (vs non-transformed) and further enhanced by fatty acids prevalent in obesity; augmented DGAT2 expression is MYC-dependent. Inhibition of DGAT1/2 improves FOXO3 activity by attenuating PI3K, resulting in reduced MYC-dependent DGAT2 expression and LDs accumulation, suggesting feedback. This inhibition attenuated growth in colon cancer cells and colonospheres via FOXO3/p27kip1 cell cycle arrest and reduced colonic tumors in ApcMin/+ mice on a high-fat diet. Transcriptomic analysis revealed that DGAT1/2 inhibition targeted metabolic and tumorigenic pathways in human colon cancer and colon cancer crypts, stratifying human colon cancer samples from normal. Further analysis revealed that this inhibition is predictive of advanced disease-free state and survival in colon cancer patients. Conclusion: This is a novel mechanism of DGAT1/2-dependent metabolic and tumorigenic remodeling in obesity-facilitated colon cancer, which provides a platform for the future development of effective treatments for colon cancer patients.

2024-10-14 | GSE278787 | GEO

Obesity facilitated colon cancer progression is mediated by increased diacylglycerol o-acyltransferases 1 and 2 (DGAT1/2) levels [RNA-seq]

2024-10-14 | GSE278785 | GEO

DGAT1 phosphoproteome and long-term proteome

Project description:Enhanced fatty acid (FA) synthesis and uptake underpin the sustained membrane biogenesis and ATP production required for melanoma cell growth and division1-4. However, to thrive, melanoma cells must avoid a potential reduction in cell growth signalling, rampant reactive oxygen species (ROS) generation, and the build-up of toxic lipid species that can accompany excess free FA5. Here, we uncover and address the significance of frequent amplification and up-regulation of the Diacylglycerol O-acyltransferase 1 (DGAT1) gene in melanoma, whose encoded product catalyses the final step of Triacyglyceride (TAG) synthesis. Consistent with the classification of DGAT1 as an oncogene, we found that forced DGAT1 expression in p53 mutant zebrafish melanocytes was sufficient to induce melanoma, and accelerated melanoma progression initiated by co-expression of oncogenic BRAF or NRAS. Regarding DGAT1 function in human melanoma cells, its depletion, or alternatively pharmacological inhibition, suppressed mTOR-S6K signalling and increased levels of acyl carnitine species— FA derivatives that are the limiting substrate for FA oxidation (FAO). In turn, increased FAO induced mitochondrial malfunction, ROS generation, and lipid peroxidation. However, the resultant oxidative stress induced NRF2 and SESTRIN2 (SESN2) expression, which limited the extent of cell death. Conversely, DGAT1 over-expression enhanced mTOR-S6K signalling and cell growth, and protected against ROS, particularly in hypoxic conditions. Together, our data establish DGAT1 as a bona fide oncogene essential in melanoma cells for enabling FA accumulation.

2023-03-10 | PXD017487 | Pride

Comparison of hepatic gene expression between short-term calorie restricted wild-type and Dgat1 deficient middle-aged female mice

Project description:Leanness is associated with increased lifespan and is linked to favorable metabolic conditions promoting life extension. We show here that deficiency of the lipid synthesis enzyme acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), which reduces body fat in mice, promotes longevity. Female DGAT1-deficient mice were protected from age-related increases in body fat, non-adipose tissue triglycerides, and markers of inflammation in white adipose tissue. These metabolic changes were accompanied by an increased mean and maximal lifespan of ~25% and ~10%, respectively. The gene expression profile of DGAT1-deficient mice was not highly correlated with calorie restriction of sex and age matched wild-type littermates. Our findings indicate that loss of DGAT1-mediated lipid synthesis results in leanness, protects against age-related metabolic consequences, and thus extends longevity. Liver gene expression profiles between short-term calorie restricted wild-type (WTCR) and Dgat1 deficient (KO) middle-aged (15-16 mo) female mice were compared to determine if calorie restriction and Dgat1 deficiency rely on common regulatory pathways for the promotion of longevity. Both CR and KO were compared to middle-aged wild-type female littermates fed a standard chow diet ad libitum (WTAL).

2012-02-09 | E-GEOD-26267 | biostudies-arrayexpress

JMJD6-DGAT1 Signaling Regulates Lipid Metabolism and Tumorigenesis in ccRCC

Project description:Clear cell renal cell carcinoma (ccRCC) represents a lethal disease and classically resistant to cytotoxic chemotherapy, highlighting the importance of identifying new therapeutic vulnerabilities. We performed a functional siRNA screening for all 2-oxoglutarate (2-OG)-dependent enzymes in ccRCC using 3-D soft agar colony formation assay, and combined with TCGA data, we identified Jumonji domain-containing 6 (JMJD6) as an essential gene for ccRCC tumorigenesis. Downregulation of JMJD6 abolished ccRCC colony formation in vitro and inhibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq and RNA-seq identified that JMJD6 can transcriptionally regulate the expression of diacylglycerol O-acyltransferase 1 (DGAT1) by co-occupying the target gene promoter with H3K4me3. Downregulation of JMJD6 caused decreased expression of DGAT1 at both mRNA and protein level. Inhibition or depletion of DGAT1 induced decreased cell growth in vitro or inhibited tumor growth in vivo. Mechanistically, decreased DGAT1 caused decreased LD formation in ccRCC, while restoration of JMJD6 expression can restore DGAT1 level, and LD formation as well as cell growth. In summary, JMJD6 is essential for ccRCC lipid storage and tumorigenesis through a DGAT1-dependent signaling. Therefore, the JMJD6-DGAT1 axis serves as a potential therapeutic avenue for ccRCC.

2022-06-27 | GSE182888 | GEO

Comparison of hepatic gene expression between short-term calorie restricted wild-type and Dgat1 deficient middle-aged female mice

2012-02-09 | GSE26267 | GEO

Gene expression analysis of Merkel Cell Carcinoma

Project description:Merkel cell carcinoma (MCC) is a polyomavirus-associated skin cancer that is frequently lethal and lacks established prognostic biomarkers. The purpose of this study was to use gene expression analysis to identify biomarkers that may improve prognostic accuracy and provide insight into MCC biology. We profiled 35 tumors from 34 patients. Tumors were macrodissected from surrounding stroma. RNA isolation was performed with RNeasy or Allprep Mini kits (Qiagen, Alameda, CA), and RNA quality assessed by Agilent Bioanalyzer analysis. RNAs were profiled on the Human Rosetta Custom Affymetrix 2.0 chip.

2010-12-15 | E-GEOD-22396 | biostudies-arrayexpress

Transcript profiles of developing Arabidopsis dgat1-1 mutant seed

Project description:Global transcript profiling of Arabidopsis dgat1-1 seed at different stages of embryo development was used to identify differentially expressed genes in the mutant compared to wild-type (Col-0) seed. These genes provided information about the remodeling of lipid metabolism and TAG synthesis in response to the lack of DGAT1 activity.

2019-08-20 | GSE123303 | GEO

DGAT1 regulates retinol-dependent regulatory T cell generation and mediates autoimmune encephalomyelitis

Project description:This file contains gene microarray data from FACS purified mouse memory phenotype CD4+ T cells (CD44hiCD45RBloCD25-), which were isolated from lymph node and spinal cord tissues of mice with experimental autoimmune encephalomyelitis (EAE), a widely studied model of human multiple sclerosis (MS). Memory phenotype CD4+ T cells infiltrating the CNS during EAE expressed high levels of mRNA for Dgat1 encoding diacylglycerol-O-acyltransferase-1 (DGAT1). We studied the biology of DGAT1 in EAE models and in assays of T cell differentiation and function.

2016-05-03 | GSE80978 | GEO

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