Department of Biochemistry and Integrated Omics for Biomedical Science, World Class University Program, College of Life Science and Biotechnology, Yonsei Proteome Research Center, Yonsei University, Seoul, Korea.
PLoS One. 2012;7(7):e41755. doi: 10.1371/journal.pone.0041755. Epub 2012 Jul 27.
In Caenorhabditis elegans, slow fat consumption has been suggested to contribute to the extension of the survival rate during nutritionally adverse conditions. Here, we investigated the potential role of pyruvate dehydrogenase kinase (PDHK)-2, the C. elegans homolog of mammalian PDK, effects on fat metabolism under nutritional conditions. PDHK-2 was expressed at low levels under well-fed conditions but was highly induced during long-term starvation and in the dauer state. This increase in pdhk-2 expression was regulated by both DAF-16 and NHR-49. Dauer-specific induction of PDHK-2 was abolished upon entry into the post-dauer stage. Interestingly, in the long-term dauer state, stored fat levels were higher in daf-2(e1370);pdhk-2 double mutants than in daf-2(e1370), suggesting a positive relationship between PDHK-2 activity and fat consumption. PDHK-2 deficiency has been shown to lead to greater preservation of residual fats, which would be predicted to contribute to survival during the dauer state. A test of this prediction showed that the survival rates of daf-2(e1370);pdhk-2(tm3075) and daf-2(e1370);pdhk-2(tm3086) double mutants were higher than that of daf-2(e1370), suggesting that loss of either the ATP-binding domain (tm3075) or branched chain keto-acid dehydrogenase kinase domain (tm3086) of PDHK-2 leads to reduced fat consumption and thus favors increased dauer survival. This attenuated fat consumption in the long-term dauer state of C. elegans daf-2 (e1370);pdhk-2 mutants was associated with concomitant down-regulation of the lipases ATGL (adipose triglyceride lipase), HSL (hormone-sensitive lipase), and C07E3.9 (phospholipase). In contrast, PDHK-2 overexpression in wild-type starved worms induced lipase expression and promoted abnormal dauer formation. Thus, we propose that PDHK-2 serves as a molecular bridge, connecting fat metabolism and survival under nutritionally adverse conditions in C. elegans.
在秀丽隐杆线虫中，缓慢的脂肪消耗被认为有助于在营养条件不利的情况下延长存活率。在这里，我们研究了丙酮酸脱氢酶激酶 (PDHK)-2 的潜在作用，PDHK-2 是哺乳动物 PDK 的秀丽隐杆线虫同源物，它在营养条件下对脂肪代谢的影响。PDHK-2 在营养充足的条件下表达水平较低，但在长期饥饿和 dauer 状态下高度诱导。这种 pdhk-2 表达的增加受到 DAF-16 和 NHR-49 的调节。进入 dauer 后阶段后，dafk-2 的 dauer 特异性诱导被消除。有趣的是，在长期 dauer 状态下，daf-2(e1370);pdhk-2 双突变体中的储存脂肪水平高于 daf-2(e1370)，这表明 PDHK-2 活性和脂肪消耗之间存在正相关关系。PDHK-2 缺陷导致剩余脂肪的保存增加，这预计有助于 dauer 状态下的存活。对这一预测的检验表明，daf-2(e1370);pdhk-2(tm3075)和 daf-2(e1370);pdhk-2(tm3086)双突变体的存活率高于 daf-2(e1370)，这表明 PDHK-2 的 ATP 结合域 (tm3075)或支链酮酸脱氢酶激酶域 (tm3086)的缺失导致脂肪消耗减少，从而有利于 dauer 存活增加。在 C. elegans daf-2(e1370);pdhk-2 突变体的长期 dauer 状态下，这种脂肪消耗的减弱与脂肪酶 ATGL（脂肪甘油三酯脂肪酶）、HSL（激素敏感脂肪酶）和 C07E3.9（磷酸酶）的下调同时发生。相比之下，在饥饿的野生型线虫中过表达 PDHK-2 诱导脂肪酶表达并促进异常 dauer 形成。因此，我们提出 PDHK-2 作为一个分子桥，连接脂肪代谢和 C. elegans 在营养条件不利下的存活。
