Shi Le, Zhao Daina, Hou Chen, Peng Yunhua, Liu Jing, Zhang Shuangxi, Liu Jiankang, Long Jiangang
Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Neurobiol Aging. 2017 Aug;56:115-126. doi: 10.1016/j.neurobiolaging.2017.04.014. Epub 2017 Apr 26.
Alzheimer's disease (AD) is considered a multifactorial disease that affects the central nervous system and periphery. A decline in brain glucose metabolism is an early feature of AD and is accompanied by a phenotypic shift from aerobic glycolysis to ketogenesis. The liver is responsible for the generation of the ketone body. However, the mechanism that underlies hepatic ketogenesis in AD remains unclear. Here, we investigated hepatic ketogenesis during the early stage of AD pathogenesis in amyloid precursor protein (APP) and presenilin (PSEN1dE9) (APP/PS1) mice. We observed that β-hydroxybutyric acid was increased in the brain of the postmortem mild cognitive impairment and AD subjects and in 3-month-old APP/PS1 AD mice. A rise in 3-hydroxy-3-methylglutary-CoA synthase 2 (HMGCS2), a key enzyme for catalyzing β-hydroxybutyric acid production, was observed in early AD mice. We further showed that proinflammatory cytokines were activated in the liver prior to their activation in the brain of 3-month-old APP/PS1 mice. Among the cytokines, interleukin-6 significantly activated HMGCS2 through the binding of nuclear factor κB (NF-κB) p65 to the HMGCS2 promoter. Additionally, interleukin-6 stimulated phosphorylation of p38 mitogen activated protein kinases, an upstream molecule for NF-κB p65 signaling. We have demonstrated that a hepatic inflammatory factor enhances ketogenesis through HMGCS2 signaling activation by p38/NF-κB p65. These results provide a novel peripheral metabolic mechanism for enhanced ketone production and suggest a plausible early AD phenotype to diagnose AD.
阿尔茨海默病（AD）被认为是一种影响中枢神经系统和外周的多因素疾病。脑葡萄糖代谢下降是AD的早期特征，并伴随着从有氧糖酵解到生酮作用的表型转变。肝脏负责酮体的生成。然而，AD中肝脏生酮作用的潜在机制仍不清楚。在此，我们研究了淀粉样前体蛋白（APP）和早老素（PSEN1dE9）（APP/PS1）小鼠AD发病早期的肝脏生酮作用。我们观察到，在死后轻度认知障碍和AD受试者以及3月龄APP/PS1 AD小鼠的大脑中，β-羟基丁酸增加。在早期AD小鼠中观察到3-羟基-3-甲基戊二酰辅酶A合酶2（HMGCS2）升高，HMGCS2是催化β-羟基丁酸生成的关键酶。我们进一步表明，在3月龄APP/PS1小鼠大脑中的促炎细胞因子被激活之前，其在肝脏中就已被激活。在这些细胞因子中，白细胞介素-6通过核因子κB（NF-κB）p65与HMGCS2启动子的结合显著激活HMGCS2。此外，白细胞介素-6刺激p38丝裂原活化蛋白激酶的磷酸化，p38丝裂原活化蛋白激酶是NF-κB p65信号传导的上游分子。我们已经证明，肝脏炎症因子通过p38/NF-κB p65信号激活增强HMGCS2信号来促进生酮作用。这些结果为酮生成增加提供了一种新的外周代谢机制，并提示了一种可能的早期AD表型用于诊断AD。
