PDF(Pubmed)
Abstract：
Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 knockout (Par-4-/-) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet. Par-4-/- and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is associated with mdm2 downregulation and activation of p53. We identified complement factor c3 as a p53-regulated gene linked to fat storage in adipocytes. Par-4 re-expression in adipocytes or c3 deletion reversed the obese mouse phenotype. Moreover, obese human subjects showed lower expression of Par-4 relative to lean subjects, and in longitudinal studies, low baseline Par-4 levels denoted an increased risk of developing obesity later in life. These findings indicate that Par-4 suppresses p53 and its target c3 to regulate obesity.
摘要：
前列腺细胞凋亡反应-4(Par-4)是一种诱导癌细胞凋亡的肿瘤抑制因子。然而,Par-4的生理功能仍然未知。在这里，我们显示常规Par-4敲除（Par-4-/-）小鼠和脂肪细胞特异性Par-4敲除（AKO）小鼠，但不是肝细胞特异性Par-4基因敲除小鼠，标准饮食肥胖。Par-4-/-和AKO小鼠表现出脂肪细胞中脂肪的吸收和储存增加。机械上,Par-4损失与mdm2下调和p53的激活有关。我们确定补体因子c3是与脂肪细胞中脂肪储存相关的p53调节基因。脂肪细胞中的Par-4再表达或c3缺失逆转了肥胖小鼠的表型。此外，肥胖的人类受试者相对于瘦受试者显示出更低的Par-4表达，在纵向研究中，较低的基线Par-4水平表明在以后的生活中患肥胖症的风险增加.这些发现表明Par-4抑制p53及其靶标c3以调节肥胖。
