Apolipoprotein A-IV is regulated by nutritional and metabolic stress:: involvement of glucocorticoids, HNF-4α, and PGC-1α
Apolipoprotein A-IV is regulated by nutritional and metabolic stress:: involvement of glucocorticoids, HNF-4α, and PGC-1α
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DOI：
10.1194/jlr.m600303-jlr200
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发表时间：
2006-11-01
影响因子：
6.5
通讯作者：
Sinal, Christopher J.
中科院分区：
文献类型：
--
作者：
Hanniman, Elyhisha A.;Lambert, Gilles;Sinal, Christopher J.
载脂蛋白A-IV(apoA-IV)是一种46 kDa的糖蛋白，与富含甘油三酯的高密度脂蛋白有关。血液载脂蛋白A-IV水平通常与甘油三酯水平相关，糖尿病患者的载脂蛋白A-IV水平会增加。本研究探讨了小鼠肝脏和肠道中apoA-IV在体内表达的调节机制，以应对营养状态的变化。禁食显著增加肝脏和回肠载脂蛋白A-IV的mRNA和血浆蛋白浓度。这种诱导与血清糖皮质激素水平升高有关，并被肾上腺切除术取消。地塞米松治疗增加肾上腺切除小鼠载脂蛋白A-IV的表达。在两种糖尿病小鼠模型中，apoA-IV的表达也显著增加。对小鼠和人类apoA-IV/C-III启动子的报告基因分析表明，肝脏核因子-4α(HNF-4α)和过氧化物酶体增殖物激活受体γ共激活因子-1α(PGC-1α)具有保守的协同激活作用，但没有证据表明糖皮质激素受体具有直接调节作用。与这些体外数据一致的是，空腹诱导apoA-IV伴随着HNF-4α和PGC-1α表达的增加，并在肝脏特异性HNF-4α缺陷小鼠中被取消。总之，这些结果表明，除了糖皮质激素依赖的作用外，空腹和糖尿病患者apoA-IV表达的诱导可能还涉及PGC-1α介导的HNF-4α的共激活。
Apolipoprotein A-IV ( apoA-IV) is a 46 kDa glycoprotein that associates with triglyceride-rich and high density lipoproteins. Blood levels of apoA-IV generally correlate with triglyceride levels and are increased in diabetic patients. This study investigated the mechanisms regulating the in vivo expression of apoA-IV in the liver and intestine of mice in response to changes in nutritional status. Fasting markedly increased liver and ileal apoA-IV mRNA and plasma protein concentrations. This induction was associated with increased serum glucocorticoid levels and was abolished by adrenalectomy. Treatment with dexamethasone increased apoA-IV expression in adrenalectomized mice. Marked increases of apoA-IV expression were also observed in two murine models of diabetes. Reporter gene analysis of the murine and human apoA-IV/C-III promoters revealed a conserved cooperative activation by the hepatic nuclear factor-4 alpha (HNF-4 alpha) and the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) but no evidence of a direct regulatory role for the glucocorticoid receptor. Consistent with these in vitro data, induction of apoA-IV in response to fasting was accompanied by increases in HNF-4 alpha and PGC-1 alpha expression and was abolished in liver-specific HNF-4 alpha-deficient mice. Together, these results indicate that the induction of apoA-IV expression in fasting and diabetes likely involves PGC-1 alpha-mediated coactivation of HNF-4 alpha in addition to glucocorticoid-dependent actions.