Project description:Examination of transcriptional changes associated with diet-induced obesity in tumor-infiltrating CD45+ leukocytes from syngeneic MC38 colorectal tumors.
Project description:Multiple cancers, including colorectal cancer (CRC), are more frequent and often more aggressive in obese individuals. Here, we show that macrophages accumulate within tumors of obese CRC patients and in obese CRC mice and promote accelerated tumor growth. These changes are initiated by oleic acid accumulation and subsequent tumor cell-derived acid production, and driven by signaling through GPR65, an acid-sensing receptor on CRC-associated macrophages. We demonstrate a similar role for GPR65 in hepatocellular carcinoma (HCC) in obese mice. Tumors in obese patients with CRC or HCC also exhibit increased GPR65 expression, suggesting that the mechanism revealed here likely contributes to tumor growth in a range of obesity-associated cancers and represents a potential therapeutic target.
Project description:The composition of the diet affects many processes in the body, including body weight and endocrine system. We have previously shown that dietary fat also affects the immune system. Mice fed high fat diet rich in polyunsaturated fatty acids survive S. aureus infection to a much greater extent than mice fed high fat diet rich in saturated fatty acids. Here we present data regarding the dietary effects on protein expression in spleen from mice fed three different diets, I) low fat/chow diet (LFD, n = 4), II) high fat diet rich in saturated fatty acids (HFD-S, n = 4) and III) high fat diet rich in polyunsaturated fatty acids (HFD-P, n = 4). We performed mass spectrophotometry based quantitative proteomics analysis of isolated spleen by implementing the isobaric tags for relative and absolute quantification (iTRAQ) approach. Mass spectrometry data were analyzed using Proteome Discoverer 2.4 software using the search engine mascot against Mus musculus in SwissProt. 924 proteins are identified in all sets (n = 4) for different dietary effects taken for statistical analysis using Qlucore Omics Explorer software. Only 20 proteins were found to be differentially expressed with a cut-off value of false discovery rate < 0.1 (q-value) when comparing HFD-S and HFD-P but no differentially expressed proteins were found when LFD was compared with HFD-P or HFD-S. The identified proteins and statistical analysis comparing HFD-S and HFD-P diets are available as a supplementary file S1. We identified a subset of proteins that showed an inverse expression pattern between two high fat diets. These differentially expressed proteins were further classified by gene ontology for their role in biological processes and molecular functions. Mass spectrometry raw data are also available via ProteomeXchange with identifier PXD020365.
Project description:Nonalcoholic steatohepatitis (NASH) is a common cause of liver cirrhosis and hepatocellular carcinoma (HCC). However, effective therapeutic strategies for preventing and treating NASH-mediated liver cirrhosis and HCC are lacking. Cholesterol is closely associated with vascular endothelial growth factor (VEGF), a key factor that promotes HCC. Recent reports have demonstrated that statins could prevent HCC development. In contrast, we have little information on ezetimibe, an inhibitor of cholesterol absorption, in regards to the prevention of NASH-related liver cirrhosis and HCC. In the present study, a steatohepatitis-related HCC model, hepatocyte-specific phosphatase and tensin homolog (Pten)-deficient (PtenΔhep ) mice were fed a high-fat (HF) diet with/without ezetimibe. In the standard-diet group, ezetimibe did not reduce the development of liver tumors in PtenΔhep mice, in which the increase of serum cholesterol levels was mild. Feeding of a HF diet increased serum cholesterol levels markedly and subsequently increased serum levels of VEGF, a crucial component of angiogenesis. The HF diet increased the number of VEGF-positive cells and vascular endothelial cells in the tumors of PtenΔhep mice. Kupffer cells, macrophages in the liver, increased VEGF expression in response to fat overload. Ezetimibe treatment lowered cholesterol levels and these angiogenetic processes. As a result, ezetimibe also suppressed inflammation, liver fibrosis and tumor growth in PtenΔhep mice on the HF diet. Tumor cells were highly proliferative with HF-diet feeding, which was inhibited by ezetimibe. In conclusion, ezetimibe suppressed development of liver tumors by inhibiting angiogenesis in PtenΔhep mice with hypercholesterolemia.
Project description:Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic disease manifested in hepatic steatosis, inflammation, fibrosis, etc., which affects over one-quarter of the population around the world. Since no effective therapeutic drugs are available to cope with this widespread epidemic, the functional research of genes with altered expression during NAFLD helps understand the pathogenesis of this disease and the development of new potential therapeutic targets for drugs. In the current work, we discovered via the analysis of the Gene Expression Omnibus (GEO) dataset that cysteine sulfinic acid decarboxylase (CSAD) decreased significantly in NAFLD patients, which was also confirmed in multiple NAFLD mouse models (HFD-fed C57BL/6J, db/db and HFHFrHC-fed C57BL/6J mice). Next, CSAD's function in the progression of NAFLD was explored using AAV-mediated liver-directed gene overexpression in an HFD-fed mouse model, where the overexpression of CSAD in the liver could alleviate NAFLD-associated pathologies, including body weight, liver/body weight ratio, hepatic triglyceride and total cholesterol, and the degree of steatosis. Mechanically, we found that the overexpression of CSAD could increase the expression of some genes related to fatty acid β-oxidation (Acad1, Ppara, and Acox1). Furthermore, we also detected that CSAD could improve mitochondrial injury in vitro and in vivo. Finally, we proposed that the effect of CSAD on lipid accumulation might be independent of the taurine pathway. In conclusion, we demonstrated that CSAD is involved in the development of NAFLD as a protective factor, which suggested that CSAD has the potential to become a new target for drug discovery in NAFLD.
Project description:The composition of the diet affects many processes in the body, including body weight and endocrine system. We have previously shown that dietary fat also affects the immune system. Mice fed high fat diet rich in polyunsaturated fatty acids survive S. aureus infection to a much greater extent than mice fed high fat diet rich in saturated fatty acids. Here we present data regarding the dietary effects on protein expression in spleen from mice fed three different diets, I) low fat/chow diet (LFD, n=4), II) high fat diet rich in saturated fatty acids (HFD-S, n=4) and III) high fat diet rich in polyunsaturated fatty acids (HFD-P, n=4). We performed mass spectrophotometry based quantitative proteomics analysis of isolated spleen by implementing the isobaric tags for relative and absolute quantification (iTRAQ) approach. Mass spectrometry data were analysed using Proteome Discoverer 2.4 software using the search engine mascot against Mus musculus in SwissProt. 924 proteins are identified in all sets (n=4) for different dietary effects taken for statistical analysis using Qlucore Omics Explorer software. Only 20 proteins were found to be differentially expressed with a cut-off value of false discovery rate < 0.1 (q-value) when comparing HFD-S and HFD-P but no differentially expressed proteins were found when LFD was compared with HFD-P or HFD-S. We identified a subset of proteins that showed an inverse expression pattern between two high fat diets. These differentially expressed proteins were further classified by gene ontology for their role in biological processes and molecular functions.
Project description:Examination of transcriptional changes associated with diet-induced obesity in CD8+ T lymphocytes that infiltrate syngeneic MC38 tumors.