Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver
Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver
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DOI：
10.2337/diabetes.54.5.1331
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发表时间：
2005-05-01
期刊：
影响因子：
7.7
通讯作者：
Viollet, B
中科院分区：
文献类型：
--
作者：
Foretz, M;Ancellin, N;Viollet, B
AMP活化蛋白激酶（AMPK）是治疗糖尿病的主要靶点。我们通过腺病毒介导的编码AMPK α 2组成型活性形式（AMPK α 2-CA）的基因转移，研究了AMPK在肝脏中特异性短期过表达的影响。肝脏AMPK α 2-CA表达显著降低血糖水平和促血管生成基因表达。AMPK α 2-CA在链脲佐菌素诱导的和ob/ob糖尿病小鼠肝脏中的表达消除了高血糖，并降低了致突变基因的表达。在正常小鼠肝脏中，AMPK α 2-CA显著降低了再喂养诱导的编码参与糖酵解和脂肪生成的蛋白质及其上游调节因子SREBP-1（固醇调节元件结合蛋白-1）和ChREBP（碳水化合物反应元件结合蛋白）的基因的转录激活。这导致肝糖原合成和循环脂质水平降低。令人惊讶的是，尽管抑制了肝脏脂肪生成，但AMPK α 2-CA的表达由于脂肪组织释放的脂质的积累而导致脂肪肝。由于AMPK α 2-CA表达导致葡萄糖相对缺乏，导致肝脂肪酸氧化和酮体产生增加，作为外周组织的替代能量来源。因此，肝脏中的短期AMPK激活降低血糖水平，并导致从葡萄糖转换为脂肪酸利用以供应能量需求。
AMP-activated protein kinase (AMPK) is a major therapeutic target for the treatment of diabetes. We investigated the effect of a short-term overexpression of AMPK specifically in the liver by adenovirus-mediated transfer of a gene encoding a constitutively active form of AMPK alpha 2 (AMPK alpha 2-CA). Hepatic AMPK alpha 2-CA expression significantly decreased blood glucose levels and gluconeogenic gene expression. Hepatic expression of AMPK alpha 2-CA in streptozotocin-induced and ob/ob diabetic mice abolished hyperglycemia and decreased gluconeogenic gene expression. In normal mouse liver, AMPK alpha 2-CA considerably decreased the refeeding-induced transcriptional activation of genes encoding proteins involved in glycolysis and lipogenesis and their upstream regulators, SREBP-1 (sterol regulatory element-binding protein-1) and ChREBP (carbohydrate response element-binding protein). This resulted in decreases in hepatic glycogen synthesis and circulating lipid levels. Surprisingly, despite the inhibition of hepatic lipogenesis, expression of AMPK alpha 2-CA led to fatty liver due to the accumulation of lipids released from adipose tissue. The relative scarcity of glucose due to AMPK alpha 2-CA expression led to an increase in hepatic fatty acid oxidation and ketone bodies production as an alternative source of energy for peripheral tissues. Thus, short-term AMPK activation in the liver reduces blood glucose levels and results in a switch from glucose to fatty acid utilization to supply energy needs.