Reciprocal and coordinate regulation of serum amyloid A versus apolipoprotein A-I and paraoxonase-1 by inflammation in murine hepatocytes
Reciprocal and coordinate regulation of serum amyloid A versus apolipoprotein A-I and paraoxonase-1 by inflammation in murine hepatocytes
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DOI：
10.1161/01.atv.0000227472.70734.ad
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发表时间：
2006-08-01
影响因子：
8.7
通讯作者：
Chait, Alan
中科院分区：
文献类型：
--
作者：
Han, Chang Yeop;Chiba, Tsuyoshi;Chait, Alan
目的-在炎症期间，HDL 的血清淀粉样蛋白 A (SAA) 含量增加，而载脂蛋白 A-I (apoA-I) 和对氧磷酶-1 (PON-1) 含量减少。目前尚不清楚 SAA 是否在物理上取代了 apoA-I，或者这些变化是否源自 HDL 载脂蛋白基因的协调但逆转录调节。由于细胞因子刺激肝脏炎症标志物的表达，我们研究了它们在调节SAA、apoA-I和PON-1表达中的作用。方法和结果-细胞因子混合物（肿瘤坏死因子[TNF]-α、白细胞介素[IL]-1β和IL-6）同时诱导SAA并抑制apoA-I和PON-1表达水平。在用核因子 kappa B (NF-kappa B) 抑制剂（吡咯烷二硫代氨基甲酸酯、SN50 和超阻遏抑制剂 kappa B 过度表达）预处理的细胞中，或在暴露于过氧化物酶体增殖物激活受体-α (PPAR α) 配体（WY-14643 和 非诺贝特）。与这些发现一致的是，与野生型小鼠相比，PPARα缺陷小鼠的原代肝细胞中SAA的基础水平升高，而apoA-I和PON-1降低。此外，在缺乏 PPAR α 的情况下，WY-14643 和非诺贝特对 SAA、apoA-I 或 PON-1 表达均没有任何影响。结论 - 这些结果表明细胞因子通过 NF-κ B 反式激活增加 SAA 的表达，同时通过抑制 PPAR α 激活来减少 apoA-I 和 PON-1 的表达。炎症可能通过肝脏中的协调但逆转录调节，而不是通过 SAA 对 apoA-I 进行物理置换，将 HDL 从头转化为更容易导致动脉粥样硬化的形式。
Objectives-During inflammation, the serum amyloid A (SAA) content of HDL increases, whereas apolipoprotein A-I (apoA-I) and paraoxonase-1 (PON-1) decrease. It remains unclear whether SAA physically displaces apoA-I or if these changes derive from coordinated but inverse transcriptional regulation of the HDL apolipoprotein genes. Because cytokines stimulate the hepatic expression of inflammatory markers, we investigated their role in regulating SAA, apoA-I, and PON-1 expression.Methods and Results-A cytokine mixture (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1 beta, and IL-6) simultaneously induced SAA and repressed apoA-I and PON-1 expression levels. These effects were partially inhibited in cells pretreated with either nuclear factor kappa B (NF-kappa B) inhibitors (pyrrolidine dithiocarbamate, SN50, and overexpression of super-repressor inhibitor kappa B) or after exposure to the peroxisome proliferator-activated receptor-alpha (PPAR alpha) ligands (WY-14643 and fenofibrate). Consistent with these findings, the basal level of SAA was increased, whereas apoA-I and PON-1 decreased in primary hepatocytes from PPAR alpha-deficient mice as compared with wild-type mice. Moreover, neither WY-14643 nor fenofibrate had any effect on SAA, apoA-I, or PON-1 expression in the absence of PPAR alpha.Conclusion-These results suggest that cytokines increase the expression of SAA through NF-kappa B transactivation, while simultaneously decreasing the expression of apoA-I and PON-1 by inhibiting PPAR alpha activation. Inflammation may convert HDL de novo into a more proatherogenic form by coordinate but inverse transcriptional regulation in the liver, rather than by physical displacement of apoA-I by SAA.