Altered hepatic gene expression in liver-Cpr-null and Cpr-low mice. Mus musculus

NADPH-cytochrome P450 reductase (CPR) is important for the functions of many enzymes, such as microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. Two mouse models with deficient CPR expression in adults were recently generated in this laboratory: liver-Cpr-null (with liver-specific Cpr deletion) (Gu et al., J. Biol. Chem., 278, 25895–25901, 2003) and Cpr-low (with reduced CPR expression in all organs examined) (Wu et al. J. Pharmacol. Expt. Ther. 312, 35-43, 2005). The phenotypes included a reduced serum cholesterol level and an induction of hepatic P450 in both models, and hepatomegaly and fatty liver in the liver-Cpr-null mouse alone. Our aim was to identify hepatic gene-expression changes related to these phenotypes. Cpr-lox mice, which have normal CPR expression (Wu et al., Genesis, 36, 177-181, 2003.), were used as the control in microarray analysis. A detailed analysis of the gene-expression changes in lipid metabolism and transport pathways revealed potential mechanisms, such as an increased activation of constitutive androstane receptor (CAR) and a decreased activation of peroxisomal proliferators activated receptor alpha (PPAR-gamma) by precursors of cholesterol biosynthesis, that underlie common changes (e.g., induction of multiple P450s and inhibition of genes for fatty acids metabolism) in response to CPR-loss in the two mouse models. Moreover, we also uncovered model-specific gene-expression changes, such as the induction of a lipid translocase (CD36 antigen) and the suppression of carnitine O-palmitoyltransferase 1 (CPT1a) and acyl-CoA synthetase long-chain family member 1 (Acsl1), that are potentially responsible for the severe hepatic lipidosis observed in liver-Cpr-null, but not Cpr-low mice. Keywords = Cytochrome P450 Keywords = NADPH-cytochrome P450 reductase Keywords = transgenic mice Keywords = liver Keywords = nuclear receptor Keywords: other

NADPH-细胞色素P450还原酶（NADPH-cytochrome P450 reductase，CPR）对多种酶的功能发挥至关重要，例如微粒体细胞色素P450（microsomal cytochrome P450，P450）单加氧酶与血红素加氧酶。本实验室近期构建了两种成年个体CPR表达缺陷的小鼠模型：其一为肝特异性Cpr敲除的肝-Cpr-null小鼠（Gu等，《生物化学杂志》，278卷，25895–25901页，2003年），其二为所有检测器官中CPR表达均降低的Cpr-low小鼠（Wu等，《药理学与实验治疗学杂志》，312卷，35-43页，2005年）。两种模型均表现出血清胆固醇水平降低以及肝组织P450酶诱导的表型，而仅肝-Cpr-null小鼠出现肝肿大与脂肪肝。本研究旨在识别与上述表型相关的肝脏基因表达变化。本研究采用CPR表达正常的Cpr-lox小鼠作为微阵列分析的对照样本（Wu等，《遗传学与发育生物学杂志》，36卷，177-181页，2003年）。对脂质代谢与转运通路的基因表达变化进行细致分析后，我们揭示了两种小鼠模型在CPR缺失后出现的共同变化（如多种P450酶的诱导以及脂肪酸代谢相关基因的抑制）的潜在机制，即组成型雄甾烷受体（constitutive androstane receptor，CAR）的激活增强，以及胆固醇生物合成前体对过氧化物酶体增殖物激活受体α（peroxisomal proliferators activated receptor alpha，PPAR-γ）的激活减弱。此外，我们还发现了模型特异性的基因表达变化：例如脂质转位酶（CD36抗原，CD36 antigen）的诱导，以及肉碱O-棕榈酰转移酶1（carnitine O-palmitoyltransferase 1，CPT1a）和酰基辅酶A合成酶长链家族成员1（acyl-CoA synthetase long-chain family member 1，Acsl1）的抑制，这些变化可能是仅肝-Cpr-null小鼠而非Cpr-low小鼠出现严重肝脂质沉积的原因。关键词 = 细胞色素P450 关键词 = NADPH-细胞色素P450还原酶 关键词 = 转基因小鼠 关键词 = 肝脏 关键词 = 核受体 关键词：其他