Role of Adenosine Monophosphate-Activated Protein Kinase-p70 Ribosomal S6 Kinase-1 Pathway in Repression of Liver X Receptor-Alpha-Dependent Lipogenic Gene Induction and Hepatic Steatosis by a Novel Class of Dithiolethiones
Role of Adenosine Monophosphate-Activated Protein Kinase-p70 Ribosomal S6 Kinase-1 Pathway in Repression of Liver X Receptor-Alpha-Dependent Lipogenic Gene Induction and Hepatic Steatosis by a Novel Class of Dithiolethiones
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DOI：
10.1002/hep.22887
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发表时间：
2009-06-01
期刊：
影响因子：
13.5
通讯作者：
Kim, Sang Geon
中科院分区：
文献类型：
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作者：
Hwahng, Seong Hwan;Ki, Sung Hwan;Kim, Sang Geon
二硫代硫酮是一类新型的腺苷单磷酸活化蛋白激酶（AMPK）激活剂，通过AMPK依赖性p70核糖体S6激酶-1（S6 K1）抑制来预防胰岛素抵抗。S6 K1对肝脏X受体-α（LXR α）介导的脂肪生成基因表达和脂肪变性（慢性肝病的一种原因）没有已知的影响。本研究研究了S6 K1在LYR α激活中的作用以及奥替普拉（原型）和其他二硫代硫醚对肝细胞和高脂饮食动物模型中LYR α依赖性脂肪生成的影响。奥替普拉阻止LXR α激动剂（T0901317）激活固醇调节元件结合蛋白-1c（SREBP-1c）的能力，抑制其自身的mRNA和蛋白质诱导。奥替普拉导致SREBP-1c活性受损，导致LXR α诱导的脂肪酸合成酶、LXR α、乙酰辅酶A羧化酶、硬脂酰辅酶A去饱和酶-1和三磷酸腺苷结合盒转运蛋白A1基因转录受到抑制。S6 K1激活拮抗奥替普拉对SREBP-1c激活的抑制作用，而显性阴性（DN）突变体S6 K1和雷帕霉素抑制T0901317诱导的SREBP-1c表达。奥替普拉损害LYRa DNA结合活性和LXR激动剂诱导的CYP 7A 1-LXRE-荧光素酶（CYP 7A 1）反式激活。此外，在体外S6 K1直接磷酸化LXR α的丝氨酸残基的基因反式激活，这是拮抗其DN突变体。S6 K1抑制拮抗AMPK抑制促进的CYP 7A 1诱导，而AMPK激活废除S6 K1依赖的CYP 7A 1诱导，支持S6 K1和AMPK在LXR活性中的相反作用。最后，发现oltipraz可抑制高脂饮食小鼠的肝脏甘油三酯蓄积和脂肪生成基因诱导。其他二硫代硫酮也抑制T0901317对SREBP-1c的诱导。结论：我们的研究结果显示AMPK-S6 K1途径在LXR活性中的作用以及一类新型二硫代硫醚对LXR α诱导的脂肪生成基因反式激活的S6 K1依赖性抑制，从而将S6 K1鉴定为干预肝脂肪变性的特别有吸引力的靶点。（《肝脏学》2009;49：1913-1925）
Dithiolethiones, a novel class of adenosine monophosphate-activated protein kinase (AMPK) activators, prevent insulin resistance through AMPK-dependent p70 ribosomal S6 kinase-1 (S6K1) inhibition. There is no known effect of S6K1 for liver X receptor-alpha (LXR alpha)-mediated lipogenic gene expression and steatosis, a cause of chronic liver disease. This study investigated the role of S6K1 in LYR alpha activation and the effects of oltipraz (prototype) and other dithiolethiones on LYR alpha-dependent lipogenesis in hepatocytes and high-fat diet animal model. Oltipraz prevented the ability of LXR alpha agonist (T0901317) to activate sterol regulatory element binding protein-1c (SREBP-1c), inhibiting its own mRNA and protein induction. Impaired SREBP-1c activity by oltipraz caused inhibition of LXR alpha-induced transcription of the fatty acid synthase, LXR alpha, acetyl-CoA carboxylase, stearoyl-CoA desaturase-1, and adenosine triphosphate-binding cassette transporter A1 genes. S6K1 activation antagonized the inhibitory effect of oltipraz on SREBP-1c activation, whereas dominant negative (DN) mutant S6K1 and rapamycin inhibited the T0901317-induced SREBP-1c expression. Oltipraz impaired LYRa DNA binding activity and LXR agonist-induced CYP7A1-LXRE-luciferase (CYP7A1) transactivation. Moreover, in vitro S6K1 directly phosphorylated LXR alpha at serine residues for gene transactivation, which was antagonized by its DN mutant. S6K1 inhibition antagonized CYP7A1 induction promoted by AMPK inhibition, whereas AMPK activation abrogated S6K1-dependent CYP7A1 induction, supporting the opposing role of S6K1 and AMPK in LXR activity. Finally, oltipraz was found to inhibit hepatic triglyceride accumulation and lipogenic gene induction in mice fed a high-fat diet. Other dithiolethiones also inhibited SREBP-1c induction by T0901317. Conclusion: Our findings showing the role of AMPK-S6K1 pathway in LXR activity and S6K1-dependent inhibition of LXR alpha-induced lipogenic gene transactivation by a novel class of dithiolethiones led to the identification of S6K1 as a particularly attractive target for intervention in hepatic steatosis. (HEPATOLOGY 2009;49:1913-1925.)