Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c
Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c
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DOI：
10.1074/jbc.m111421200
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发表时间：
2002-03-15
影响因子：
4.8
通讯作者：
Brown, MS
中科院分区：
文献类型：
--
作者：
Liang, GS;Yang, J;Brown, MS
两种治疗方法，禁食/再喂养和给予肝脏X受体（LXR）激动剂，升高了肝脏中固醇调节元件结合蛋白1c （SREBP-1c）的mRNA，并增强了肝脏中的脂质合成。这些处理不影响SREBP-la的mRNA，这是来自同一基因的另一种转录物。通过同源重组，我们从小鼠基因组中剔除了编码SREBP-1c的外显子，留下了完整的SREBP-la转录本。在正常饮食下，SREBP-1c（-/-）小鼠肝脏中编码脂肪酸和甘油三酯合成酶的多种mrna减少，包括乙酰辅酶a羧化酶（ACC）和脂肪酸合成酶WAS。相反，SREBP-1c（-/-）肝脏显示肝脏SREBP-2 mRNA代偿性增加，同时胆固醇生物合成酶mRNA水平升高。在禁食/饲料动物中，ACC和FAS mrna升高，但与野生型肝脏的程度不同。再喂食诱导的SREBP-1c（-/-）小鼠的增加大于缺乏SREBP裂解激活蛋白（SCAP）的小鼠，其中所有核SREBP都缺失。因此，SREBP-2和/或SREBP-la可以部分替代SREBP-1c，使胰岛素介导的ACC和FAS mrna增加。相比之下，其他几种脂质酶（葡萄糖-6-磷酸脱氢酶、苹果酸酶、甘油-3-磷酸酰基转移酶和硬脂酰辅酶a去饱和酶-1）的mrna对再喂的正常诱导反应完全失败，表明对SREBP-1c的特异性依赖。此外，这些mrna以及其他多种脂质mrna对LXR激动剂T090137的反应明显减弱，表明SREBP-1c在LXR反应中起重要作用。
Two treatments, fasting/refeeding and administration of liver X receptor (LXR) agonists, elevate the mRNA for sterol regulatory element-binding protein-1c (SREBP-1c) and enhance lipid synthesis in liver. These treatments do not affect the mRNA for SREBP-la, an alternative transcript from the same gene. Through homologous recombination, we eliminated the exon encoding SREBP-1c from the mouse genome, leaving the SREBP-la transcript intact. On a normal diet, livers of SREBP-1c(-/-) mice manifested reductions in multiple mRNAs encoding enzymes of fatty acid and triglyceride synthesis, including acetylCoA carboxylase (ACC) and fatty acid synthase WAS). In contrast, SREBP-1c(-/-) livers showed a compensatory increase in hepatic SREBP-2 mRNA, accompanied by increased mRNA levels for cholesterol biosynthetic enzymes. In fasted/refed animals, ACC and FAS mRNAs rose, but not to the same extent as in wild-type livers. The refeeding-induced increase in SREBP-1c(-/-) mice was greater than in mice lacking SREBP cleavage-activating protein (SCAP), in which all nuclear SREBPs are absent. Thus, SREBP-2 and/or SREBP-la can substitute partially for SREBP-1c in permitting an insulin-mediated increase in ACC and FAS mRNAs. In contrast, mRNAs for several other lipogenic enzymes (glucose-6-phosphate dehydrogenase, malic enzyme, glycerol-3-phosphate acyltransferase, and stearoyl-CoA desaturase-1) showed a complete failure of the normal inductive response to refeeding, indicating specific reliance on SREBP-1c. Moreover, these mRNAs, as well as multiple other lipogenic mRNAs, showed a markedly blunted response to the LXR agonist T090137, indicating an essential role of SREBP-1c in the LXR response.