A chronic high-cholesterol diet paradoxically suppresses hepatic CYP7A1 expression in FVB/NJ mice
A chronic high-cholesterol diet paradoxically suppresses hepatic CYP7A1 expression in FVB/NJ mice
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DOI：
10.1194/jlr.m012781
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发表时间：
2011-02-01
影响因子：
6.5
通讯作者：
Green, Richard M.
中科院分区：
文献类型：
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作者：
Henkel, Anne S.;Anderson, Kristy A.;Green, Richard M.
胆固醇7 α-羟化酶（CYP7A1）编码肝脏中胆固醇转化为胆汁酸的限速步骤。作为对急性胆固醇喂养的响应，小鼠通过刺激肝脏X受体（LXR）α上调CYP7A1。然而，长期高胆固醇饮食对小鼠肝脏CYP7A1表达的影响尚不清楚。我们证明，在FVB/NJ小鼠中长期喂食胆固醇（0.2%或1.25%w/w胆固醇，持续12周）导致肝脏CYP7A1表达抑制> 60%，与肝脏胆固醇含量增加> 2倍相关。相反，急性胆固醇喂养诱导肝脏CYP7A1表达上调> 3倍。我们发现，慢性而非急性胆固醇喂养会增加肝脏炎症细胞因子、肿瘤坏死因子（TNF）α和白细胞介素（IL）-1 β的表达，这些因子已知会抑制肝脏CYP7A1的表达。慢性胆固醇喂养还导致有丝分裂原活化蛋白（MAP）激酶、c-Jun N-末端激酶（JNK）和细胞外信号调节激酶（ERK）的活化。此外，我们在体外证明TNF α和IL-1 β对CYP7A1的抑制依赖于JNK和ERK信号传导。我们的结论是，慢性高胆固醇喂养抑制CYP7A1在小鼠中的表达。我们认为，慢性胆固醇喂养诱导炎症细胞因子激活和肝损伤，这导致抑制CYP7A1通过激活JNK和ERK信号通路。汉高，A.美国，K. a.安德森，A. M. Dewey，M. H. Kavesh，R. M.绿色。FVB/NJ小鼠长期高胆固醇饮食反常地抑制肝脏CYP7A1表达J. Lipid Res. 2011. 52：289 - 298。
Cholesterol 7 alpha-hydroxylase (CYP7A1) encodes for the rate-limiting step in the conversion of cholesterol to bile acids in the liver. In response to acute cholesterol feeding, mice upregulate CYP7A1 via stimulation of the liver X receptor (LXR) alpha. However, the effect of a chronic high-cholesterol diet on hepatic CYP7A1 expression in mice is unknown. We demonstrate that chronic cholesterol feeding (0.2% or 1.25% w/w cholesterol for 12 weeks) in FVB/NJ mice results in a > 60% suppression of hepatic CYP7A1 expression associated with a > 2-fold increase in hepatic cholesterol content. In contrast, acute cholesterol feeding induces a > 3-fold upregulation of hepatic CYP7A1 expression. We show that chronic, but not acute, cholesterol feeding increases the expression of hepatic inflammatory cytokines, tumor necrosis factor (TNF) alpha, and interleukin (IL)-1 beta, which are known to suppress hepatic CYP7A1 expression. Chronic cholesterol feeding also results in activation of the mitogen activated protein (MAP) kinases, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Furthermore, we demonstrate in vitro that suppression of CYP7A1 by TNF alpha and IL-1 beta is dependent on JNK and ERK signaling. We conclude that chronic high-cholesterol feeding suppresses CYP7A1 expression in mice. We propose that chronic cholesterol feeding induces inflammatory cytokine activation and liver damage, which leads to suppression of CYP7A1 via activation of JNK and ERK signaling pathways. Henkel, A. S., K. A. Anderson, A. M. Dewey, M. H. Kavesh, and R. M. Green. A chronic high-cholesterol diet paradoxically suppresses hepatic CYP7A1 expression in FVB/NJ mice. J. Lipid Res. 2011. 52: 289-298.