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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.

ORGANISM(S): Mus musculus

PROVIDER: GSE49375 | GEO | 2014/02/20

SECONDARY ACCESSION(S): PRJNA213738

REPOSITORIES: GEO

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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. 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.

2014-02-20 | E-GEOD-49375 | biostudies-arrayexpress

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.

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

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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).

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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.

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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

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.

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Pleiotropic effects of the gene diacylglycerol-O-transferase 1 (DGAT1) polymorphism in the mammary gland tissue of dairy cows

Project description:The objective of this study was to determine the effect of the DGAT1 K232A polymorphism on the global mRNA expression pattern of genes in the mammary gland tissue of grazing dairy cows in order to get more insight into the effects of this polymorphism on the physiology of the mammary glandgland of grazing dairy cows. Microarray analysis was used to identify genes whose expression was affected by the DGAT1 polymorphism in the mammary gland biopsies of 9 A232A cows, 13 K232A cows, and 4 K232K cows. The Microarray Analysis of Variance (MAANOVA) and Factor Analysis for Multiple Testing method (FAMT) were used to associate the expression of the genes present on Affymettrix Bovine Genome Arrays with the DGAT1 polymorphism. The data was also analysed at the level of functional modules by gene set enrichment analysis. In this experimental setting, DGAT1 polymorphism did not modify milk yield and composition significantly, although changes occurred in the yields of C14:0, C16:1cis-9, and some long chain fatty acids in milk. The DGAT1 polymorphism resulted in 30 differentially expressed genes related to cell growth, proliferation and development, signalling, remodelling and immune system. At the functional level, the pathways most affected by DGAT1 polymorphism were related to lipid biosynthesis, which likely reflected counter mechanisms of mammary tissue to respond to changes in milk FA composition, signalling, as well as immune system responses.

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