From sugar to fat: How the transcription factor XBP1 regulates hepatic lipogenesis.
From sugar to fat: How the transcription factor XBP1 regulates hepatic lipogenesis.
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DOI：
10.1111/j.1749-6632.2009.04956.x
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发表时间：
2009-09
影响因子：
5.2
通讯作者：
Lee AH
中科院分区：
文献类型：
--
作者：
Glimcher LH;Lee AH
脂肪生成主要发生在肝脏中，其中膳食碳水化合物控制糖酵解和脂肪生成途径中关键酶的表达。我们最近发现，转录因子XBP1，最为人所知的未折叠蛋白反应（UPR）的关键调节因子，是肝脏中从头脂肪酸合成所必需的，这一功能与其在UPR中的作用无关。XBP1蛋白表达在肝脏中由高碳水化合物饮食诱导，并直接控制参与脂肪酸合成的关键基因的诱导。使用诱导方法在成人肝脏中特异性缺失XBP1导致严重的低胆固醇血症和低胆固醇血症，这可能归因于肝脏中脂质产生的减少。值得注意的是，这种表型与脂肪肝（肝性脂肪变性）或蛋白质分泌的显著损害无关。XBP1加入了一个已经丰富的领域的转录调控蛋白在控制肝脏脂肪生成。其在脂肪生成中的功能似乎是高度显著的，如遗传突变株的表型所证明的。更全面地了解XBP1加速肝脏中脂肪酸从头合成同时保持正常肝脏脂质组成的机制与治疗与血脂异常相关的疾病如动脉粥样硬化和代谢综合征高度相关。由于肝脏中过量的脂肪积累可能是由增加的肝脂肪酸合成引起的，因此抑制XBP1活化的化合物也可能是用于治疗人酒精性肝病（ALD）和非酒精性脂肪性肝病（NAFLD）的有用治疗剂，这是美国发病率和死亡率越来越常见的原因。
Lipogenesis occurs primarily in the liver, where dietary carbohydrates control the expression of key enzymes in glycolytic and lipogenic pathways. We have recently discovered that the transcription factor XBP1, best known as a key regulator of the unfolded protein response (UPR), is required for de novo fatty acid synthesis in the liver, a function unrelated to its role in the UPR. XBP1 protein expression is induced in the liver by a high carbohydrate diet and directly controls the induction of critical genes involved in fatty acid synthesis. Specific deletion of XBP1 in adult liver using an inducible approach results in profound hypocholesterolemia and hypotriglyceridemia, which could be attributed to diminished production of lipids in the liver. Notably, this phenotype is not associated with fatty liver (hepatic steatosis) or significant compromise in protein secretion. XBP1 joins an already rich field of transcriptional regulatory proteins in the control of hepatic lipogenesis. Its function in lipogenesis appears to be highly significant as evidenced by the phenotype of the genetic mutant strain. A more complete understanding of the mechanisms by which XBP1 accelerates de novo fatty acid synthesis in the liver while preserving normal hepatic lipid composition is highly relevant to the treatment of diseases such as atherosclerosis and metabolic syndrome that are associated with dyslipidemia. Since excess fat accumulation in the liver could result from increased hepatic fatty acid synthesis, compounds that inhibit XBP1 activation may also be useful therapeutics for the treatment of human alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), increasingly common causes of morbidity and mortality in the United States.
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DOI：
10.1073/pnas.95.11.5987
发表时间：
1998-05-26
影响因子：
11.1
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DOI：
10.1073/pnas.96.22.12737
发表时间：
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影响因子：
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