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Dgat1 detoxifies androgen receptor signaling to promote antitumor CD8+ T cell responses

ABSTRACT: The role of fatty acid (FA) oxidation 31 in T cell responses has been extensively studied, but whether FA esterification to triacylglycerol (TAG) regulates T cell exhaustion is unknown. Dgat1 catalyzes the rate-limiting step in TAGsynthesis. Here,we showthat deficiency in Dgat1 improvedmitochondrial metabolic fitness and expanded the pool of progenitors of CD8+ exhausted T (Tex) cells to sustain antitumor responses in femalemice. Inmalemice, however, Dgat1 deficiency synergized with androgen receptor (AR) signaling to cause FA peroxidation, endoplasmic reticulum (ER) stress, and Tex cell death. Deletion of Ar, overexpression of glutathione peroxidase 4 (Gpx4), or inhibition of ER stress-induced cell death rescued Dgat1-deficient CD8+ T cell survival and promoted antitumor responses in male mice. This study suggests that Dgat1 detoxifies AR signaling to protect against ER stress-induced cell death and maintain T cell stemness in males, and highlights sex-specific metabolic adaptations in the tumormicroenvironment.

ORGANISM(S): Mus musculus

PROVIDER: GSE307220 | GEO | 2025/12/16

REPOSITORIES: GEO

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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. A total of 28 Holstein-Friesian dairy cows in mid-lactation (DIM; 153 M-BM-1 32.8 days), milk yield (25.7 M-BM-1 3.08 kg/d) and fat content (4.3 M-BM-1 0.12%) were used in the study. Two consecutive milk samples (a.m. and p.m. milking) were obtained and pooled. One aliquot was stored at 4M-BM-0C until analysis of fat, protein and lactose percentage, and another aliquot was frozen at -20M-BM-0C until analysis for FA composition by gas chromatography. Specific details regarding the analysis of FA in milk are presented in Mach et al. (2011). Approximately 750 to 1,000 mg of mammary tissue from each cow was obtained by surgical biopsy. One part of the tissue was used for isolation of DNA and the other for extraction of the RNA. Genotyping of the DGAT1 polymorphism was performed using a TaqMan allelic discrimination method in an Applied Biosystems 7500 Real-Time PCR System (Applied Biosystems) as described by Schennink et al. (2007). The genotype at the DGAT1 locus was designated KK, KA, or AA for homozygous Lysine, heterozygous Lysine/Alanine, or homozygous Alanine, respectively. Microarray analysis was used to identify genes whose expression was affected by the DGAT1 polymorphism in the mammary gland biopsies of 11 A232A cows, 13 K232A cows, and 4 K232K cows. Total RNA from mammary gland tissue (50-100 mg) was isolated using TRIzol reagent (Invitrogen, Breda, The Netherlands), following the manufacturerM-bM-^@M-^Ys instructions. The RNA purity and concentrations were determined using a NanoDrop ND-1000 spectrophotometer (Isogen, Maarssen, the Netherlands), and the RNA quality was assessed using the BioAnalyzer 2100 (Agilent Technologies, Amsterdam, the Netherlands). The RNA of each biopsy was amplified, biotin-labeled, and hybridized to single-dye Affymetrix GeneChipM-BM-. Bovine Genome Array (#900493) by ServiceXS (Leiden, the Netherlands)

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Dgat1 detoxifies androgen receptor signaling to promote antitumor CD8+ T cell responses

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