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Cytochrome P4501B1 and basal liver PPARa activity

细胞色素 P4501B1 和基础肝脏 PPARa 活性

基本信息

批准号：
8296906
负责人：
COLIN ROBERT JEFCOATE
金额：
$ 32.38万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8296906
关键词：
ADD-1 protein Address Adhesions Adipocytes Adipose tissue Adult Affect Agonist Alleles Amino Acids Binding Biological Factors Blood capillaries Breeding CYP1B1 gene Carbohydrates Cells Clinical Research Complex Cytochrome P450 Data Development Developmental Process Diabetes Mellitus Diet Dietary Fats Discontinuous Capillary Effectiveness Embryo Embryonic Development Endothelial Cells Endothelium Event Exhibits FGF21 gene Fat-Restricted Diet Fatty Acids Fatty Liver Fatty acid glycerol esters Fetal Liver Fetus Fibroblasts Gene Cluster Gene Expression Generations Genes Glaucoma Glycogen Goals Hepatic Hepatocyte Human In Vitro Infiltration Intervention Lead Ligands Link Liver Liver neoplasms Mass Spectrum Analysis Measures Mediating Metabolism Mitochondria Morphogenesis Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Stress Pathway interactions Peripheral Peroxisome Proliferator-Activated Receptors Regulation Research Role Serum Serum Markers Signal Transduction Site Source Stromal Cells Tamoxifen Testing Therapeutic Time Tissues Variant Weaning adenoma angiogenesis base capillary cell type cytokine endonuclease fatty acid metabolism fatty acid oxidation feeding flavanoid hormone regulation imprint improved in utero in vivo inhibitor/antagonist insulin sensitivity lipid biosynthesis liquid chromatography mass spectrometry liver metabolism macrophage metabolomics non-alcoholic oxidation promoter response stellate cell

项目摘要

DESCRIPTION (provided by applicant): Cytochrome P450 1b1 (Cyp1b1) participates in embryogenesis and is expressed in endothelia, fibroblasts and adipocytes. Genes involved in liver fatty acid metabolism are remarkably affected by deletion of Cyp1b1 in mice, despite only minimal expression in hepatocytes. Two gene clusters, distinguished by responses to dietary fat, are both suppressed by Cyp1b1 deletion and regulated by PPAR? Preliminary data that indicates that Cyp1b1 participates in the generation of endogenous PPAR? ligands will be explored further. Cyp1b1 deletion also suppresses diet-induced obesity and non-alcoholic hepatic steatosis. The increased liver fatty acid metabolism may be associated with decreased oxidative stress, as indicated by improved insulin sensitivity. Cyp1b1 may, therefore, be an unexpected contributor to Type 2 diabetes. Many dietary flavanoids are potent inhibitors of Cyp1b1. Select Cyp1b1 inhibitors, including natural compounds, may have therapeutic value for diabetes. Human Cyp1b1 suppression also enhances liver adenomas, consistent with a role in developmental processes. The proposed research compares the liver gene expression, metabolism responses and adiposity changes in WT and Cyp1b1-ko mice administered low fat/high carbohydrate or high fat/low carbohydrate diets. The goal is to determine how hepatocytes can be indirectly affected by Cyp1b1 metabolism in other cell types, particularly the endothelia of liver sinusoids and adipose tissue. The expression of Cyp1b1 in non-parenchymal liver cells and in fetal liver will be characterized. In order to define the site and timing of Cypb1 intervention, we have introduced a Floxed Cyp1b1 allele into mice. This will ultimately provide the means for controlled Cyp1b1 deletions in mice. We will use this defining set of liver and adipose responses to determine the effectiveness of Cyp1b1 deletions specifically targeted to endothelia by Tie2-Cre. We have shown that Cyp1b1 deletion affects the functions of endothelial cells and suppresses angiogenesis in vivo. Cyp1b1 deletion may cause these adult changes through active participation of Cyp1b1 in the fetal liver development that imprints adult liver regulation. Cre-targeting of Floxed Cyp1b1 will be activated through a tamoxifen-dependent promoter at selected times during development, in order to test whether this early expression contributes to the general deletion effects. Metabolomic studies using 2D-NMR and mass spectrometry analyses on, respectively, liver and serum extracts will focus on establishing that Cyp1b1 deletion increases mitochondrial fatty acid oxidation and glycogen synthesis, while lowering oxidative stress. The roles of PPAR? and PPAR? loss in these liver gene changes of Cyp1b1-ko mice will be tested by comparisons to effects of deleting these PPAR genes in mouse liver. Serum markers applicable to clinical studies will be used in probing these liver changes. PUBLIC HEALTH RELEVANCE: Loss of Cytochrome P450 1B1 (CYP1B1) in humans is linked to Glaucoma and Liver tumors. CYP1B1 variants are common in humans. We find that CYP1B1 losses can counter obesity and improve insulin sensitivity. These studies address how CYP1B1 deletion remarkably increases liver fat oxidation and glycogen synthesis through suppression of PPAR?activity. The pathway offers therapeutic possibilities, including through dietary compounds that bind to CYP1B1.

描述（由申请方提供）：细胞色素P450 1b 1（Cyp 1b 1）参与胚胎发生，并在内皮细胞、成纤维细胞和脂肪细胞中表达。参与肝脏脂肪酸代谢的基因在小鼠中被Cyp 1b 1的缺失显著影响，尽管在肝细胞中只有最小的表达。两个基因簇，区别于饮食脂肪的反应，都抑制Cyp 1b 1缺失和调节的过氧化物酶体增殖物激活受体？初步数据表明，Cyp 1b 1参与产生内源性的过氧化物酶体增殖体激活受体？将进一步探索配体。Cyp 1b 1缺失还抑制饮食诱导的肥胖和非酒精性肝脂肪变性。肝脏脂肪酸代谢增加可能与氧化应激降低有关，如胰岛素敏感性改善所示。因此，Cyp 1b 1可能是2型糖尿病的一个意想不到的贡献者。许多膳食类黄酮是Cyp 1b 1的有效抑制剂。选择Cyp 1b 1抑制剂，包括天然化合物，可能对糖尿病有治疗价值。人类Cyp 1b 1抑制也增强肝腺瘤，与发育过程中的作用一致。这项研究比较了WT和Cyp 1b 1-ko小鼠的肝脏基因表达、代谢反应和肥胖变化，这些小鼠被给予低脂/高碳水化合物或高脂/低碳水化合物饮食。目的是确定肝细胞如何间接受到其他细胞类型中Cyp 1b 1代谢的影响，特别是肝窦和脂肪组织的内皮。Cyp 1b 1在非实质肝细胞和胎肝中的表达将被表征。为了确定Cypb 1干预的位点和时机，我们将Floxed Cyp 1b 1等位基因引入小鼠。这将最终提供在小鼠中控制Cyp 1b 1缺失的方法。我们将使用这组定义的肝脏和脂肪反应来确定Tie 2-Cre特异性靶向内皮细胞的Cyp 1b 1缺失的有效性。我们已经表明，Cyp 1b 1缺失影响内皮细胞的功能，并抑制体内血管生成。Cyp 1b 1缺失可能通过Cyp 1b 1在胎儿肝脏发育中的积极参与而引起这些成人变化，而胎儿肝脏发育是成人肝脏调节的标志。在发育过程中的选定时间，通过他莫昔芬依赖性启动子激活Floxed Cyp 1b 1的Cre靶向，以测试这种早期表达是否有助于一般缺失效应。代谢组学研究使用2D-NMR和质谱分析，分别对肝脏和血清提取物将集中在建立Cyp 1b 1缺失增加线粒体脂肪酸氧化和糖原合成，同时降低氧化应激。PPAR的作用？而PPAR？Cyp 1b 1-ko小鼠的这些肝脏基因变化的损失将通过与在小鼠肝脏中删除这些PPAR基因的影响进行比较来测试。适用于临床研究的血清标志物将用于探测这些肝脏变化。公共卫生相关性：人类细胞色素P450 1B 1（CYP 1B 1）的缺失与青光眼和肝肿瘤有关。CYP 1B 1变体在人类中很常见。我们发现，CYP 1B 1的损失可以对抗肥胖和改善胰岛素敏感性。这些研究阐明了CYP 1B 1缺失如何通过抑制PPAR显著增加肝脏脂肪氧化和糖原合成？活动该途径提供了治疗的可能性，包括通过结合CYP 1B 1的饮食化合物。