Cdc2-like kinase 2 suppresses hepatic fatty acid oxidation and ketogenesis through disruption of the PGC-1α and MED1 complex.
Cdc2-like kinase 2 suppresses hepatic fatty acid oxidation and ketogenesis through disruption of the PGC-1α and MED1 complex.
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DOI：
10.2337/db13-1304
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发表时间：
2014-05
期刊：
影响因子：
7.7
通讯作者：
Puigserver P
中科院分区：
文献类型：
--
作者：
Tabata M;Rodgers JT;Hall JA;Lee Y;Jedrychowski MP;Gygi SP;Puigserver P
肝脏生酮在禁食沿着膳食脂质超负荷的脂肪酸代谢中起着重要作用，但调节这一过程的机制仍知之甚少。在这里，我们表明，Cdc 2样激酶2（Clk 2）抑制脂肪酸氧化和酮体的生产在饮食诱导的肥胖。在瘦小鼠中，肝脏Clk 2蛋白在禁食期间非常低，在进食期间强烈增加;然而，在饮食诱导的肥胖小鼠中，Clk 2蛋白在进食和禁食状态下都保持升高。肝脏特异性Clk 2基因敲除小鼠喂食高脂饮食后，表现出血液酮体的空腹水平增加，呼吸交换率降低，脂肪酸氧化和生酮途径的基因表达增加。Clk 2的这种作用是细胞自主的，因为在肝细胞中操纵Clk 2控制基因和脂肪酸利用率。过氧化物酶体增殖物激活受体γ共激活因子（PGC-1α）的Clk 2磷酸化破坏了其与介体亚基1的相互作用，从而抑制了PGC-1α对过氧化物酶体增殖物激活受体α靶基因在脂肪酸氧化和生酮中的激活。这些数据证明了Clk 2在体内调节脂肪酸代谢中的重要性，并表明抑制肝脏Clk 2可以提供治疗脂肪肝疾病的新疗法。
Hepatic ketogenesis plays an important role in catabolism of fatty acids during fasting along with dietary lipid overload, but the mechanisms regulating this process remain poorly understood. Here, we show that Cdc2-like kinase 2 (Clk2) suppresses fatty acid oxidation and ketone body production during diet-induced obesity. In lean mice, hepatic Clk2 protein is very low during fasting and strongly increased during feeding; however, in diet-induced obese mice, Clk2 protein remains elevated through both fed and fasted states. Liver-specific Clk2 knockout mice fed a high-fat diet exhibit increased fasting levels of blood ketone bodies, reduced respiratory exchange ratio, and increased gene expression of fatty acid oxidation and ketogenic pathways. This effect of Clk2 is cell-autonomous, because manipulation of Clk2 in hepatocytes controls genes and rates of fatty acid utilization. Clk2 phosphorylation of peroxisome proliferator–activated receptor γ coactivator (PGC-1α) disrupts its interaction with Mediator subunit 1, which leads to a suppression of PGC-1α activation of peroxisome proliferator–activated receptor α target genes in fatty acid oxidation and ketogenesis. These data demonstrate the importance of Clk2 in the regulation of fatty acid metabolism in vivo and suggest that inhibition of hepatic Clk2 could provide new therapies in the treatment of fatty liver disease.
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影响因子：
16
作者：
Ngo, JCK;Chakrabarti, S;Ghosh, G
通讯作者：
Ghosh, G
影响因子：
29
作者：
Blättler SM;Cunningham JT;Verdeguer F;Chim H;Haas W;Liu H;Romanino K;Rüegg MA;Gygi SP;Shi Y;Puigserver P
通讯作者：
Puigserver P
影响因子：
3.7
作者：
Duncan, PI;Stojdl, DF;Bell, JC
通讯作者：
Bell, JC
影响因子：
5.3
作者：
Blaettler, Sharon M.;Verdeguer, Francisco;Puigserver, Pere
通讯作者：
Puigserver, Pere
影响因子：
64.8
作者：
Ge, K;Guermah, M;Roeder, RG
通讯作者：
Roeder, RG