High Fat Diet Reduces the Expression of Glutathione Peroxidase 3 in Mouse Prostate. Mus musculus

High fat diets are known to be a risk factor for prostate cancer. In this study, we investigated the effect of high fat diet on mouse prostate gene expression. C57BL/6J mice were fed either a control or high fat diet for 12 weeks. Microarray analyses were performed on mouse ventral prostate (VP) and dorsolateral prostate (DLP), followed by canonical pathway analysis and regulatory network identification. mRNA changes were confirmed by real time PCR. Approximately 2,125, and 1,194 genes responded significantly to the high fat diet in VP, DLP, respectively. Pathways and networks related to oxidative stress, glutathione metabolism, NRF-mediated oxidative stress response and NF-kappaB were all differentially regulated by high fat diet. GPx3 mRNA levels were decreased by approximately 2-fold by high fat diet in all 3 prostate lobes. In human non-transformed prostate cells (PrSC, PrEC and BPH-1), cholesterol loading decreased GPx3 expression, and increased H2O2 levels of culture medium. Troglitazone increased GPx3 expression in 3 normal prostate cells, and decreased H2O2 levels. In addition, troglitazone attenuated cholesterol-induced H2O2 increase. Tissue from prostate cancer biopsies had decreased GPx3 mRNA and its level was inversely related to the Gleason score. High fat diet alters pathways related to many genes concerned with oxidative stress. GPx3, a gene identified by this analysis, was found to be down regulated by high fat diet and appears be decreased in human prostate cancers, suggesting that GPx3 may have a possible role in modulating carcinogenesis. Overall design: Control group:5 C57BL/6J mice (Taconic, Hudson, NY), 8-weeks of age, fed control diet ad libitum for 12 weeks; Experimental group: 5 C57BL/6J mice (Taconic, Hudson, NY), 8-weeks of age, fed ad libitum high fat diet for 12 weeks.

高脂饮食已被证实为前列腺癌的危险因素。本研究旨在探究高脂饮食对小鼠前列腺基因表达的影响。将C57BL/6J小鼠分为两组，分别饲喂对照饮食与高脂饮食，干预时长为12周。对小鼠腹侧前列腺（ventral prostate, VP）与背外侧前列腺（dorsolateral prostate, DLP）进行基因芯片分析，随后开展经典通路分析与调控网络鉴定，并通过实时荧光定量PCR（real-time PCR）验证mRNA表达变化。在VP与DLP组织中，分别有约2125个与1194个基因对高脂饮食产生了显著应答。与氧化应激、谷胱甘肽代谢、NRF介导的氧化应激应答以及NF-κB相关的通路与调控网络，均因高脂饮食发生了差异调控。在3个前列腺叶中，谷胱甘肽过氧化物酶3（GPx3）的mRNA水平均因高脂饮食下调约2倍。在人类非转化前列腺细胞（PrSC、PrEC与BPH-1）中，胆固醇负荷可下调GPx3的表达，并升高培养基中的过氧化氢（H₂O₂）水平。曲格列酮（troglitazone）可在3种正常前列腺细胞中上调GPx3的表达，并降低培养基中的H₂O₂水平。此外，曲格列酮可削弱胆固醇诱导的H₂O₂水平升高。前列腺癌活检组织中的GPx3 mRNA水平出现下调，且其表达水平与格里森评分（Gleason score）呈负相关。高脂饮食可调控诸多与氧化应激相关基因的通路。本研究鉴定得到的GPx3，可因高脂饮食发生下调，且在人类前列腺癌组织中表达水平降低，提示GPx3可能在癌变调控中发挥潜在作用。实验设计：对照组：5只8周龄C57BL/6J小鼠（购自美国纽约州哈德逊市Taconic公司），自由采食对照饮食，持续12周；实验组：5只8周龄C57BL/6J小鼠（购自美国纽约州哈德逊市Taconic公司），自由采食高脂饮食，持续12周。