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西安交大研究人员揭示阿尔茨海默病的肝脏脂肪代谢特征

已有 4696 次阅读 2015-11-24 17:43 |个人分类:论文分享|系统分类:论文交流| 西安交大, 线粒体, 炎症因子, 阿尔兹海默病, 脂肪代谢

西安交大研究人员揭示阿尔茨海默病的肝脏脂肪代谢特征 

随着老龄化社会的到来,阿尔茨海默病(Alzheimer’s diseaseAD)已成为威胁老龄人口健康的重大疾病及全球面临的公共卫生和经济负担。AD 不仅仅是一种中枢神经系统疾病,而是能够影响外周系统的多因素疾病。流行病学调查认为,AD患者罹患二型糖尿病(Type 2 diabetes mellitusT2DM)的风险增高,但相关机制尚不清楚。

西安交大刘健康研究团队采用APP/PS1转基因小鼠高脂饲喂模型,揭示了阿尔茨海默病的外周脂肪代谢和糖代谢特征。该研究发表在近期Journal Neurochemistry封面论文上(在线发表)。Tang_et_al-Journal_of_Neurochemistry.pdf

唐颖、彭韵桦等研究人员发现,AD转基因小鼠在高脂饲喂后,肥胖、高血糖、胰岛素抵抗等T2DM相关病理表现更为明显,但高脂饮食并未损伤认知能力,而且能够显著改善AD所致的骨质丢失2014-Pengyunhua-High-fat-diet-induced weight gain ameliorates bone without exace.pdf。同时,研究发现AD病理发生早期(小鼠认知行为学发生异常之前),肝脏既已发生显著的炎性因子增加,并通过SREBP途径抑制高脂饲喂所诱导的脂肪合成及脂肪肝形成,从而促使代谢底物更多的用于葡萄糖生成,形成高血糖,损伤机体胰岛素敏感性。该研究对于AD早期外周诊断标志物的筛选和AD相关病理症状的防治具有重要意义。


Schematic summary  In HFD-fed AD mice, early-stage inflammation blunts hepatic SREBP-1-mediated de novo lipogenesis, which contributes to the resistance to HFD-induced fatty liver. However, since lipogenesis is blocked, excessive substrate flux provided by HFD may be mainly used to produce glucose, leading to higher hyperglycemia and more severe hepatic insulin resistance in AD mice. Thus, the ability of insulin signaling to inhibit glucose production is further impaired. Dotted line: impaired pathway; Line with arrow head: promoting effect; Line with bar head: inhibitory effect.


Early inflammation-associated factors blunt sterolregulatory element-binding proteins-1-mediated lipogenesis in high-fat diet-fedAPPSWE/PSEN1dE9 mouse model of Alzheimer's disease

YingTang, Yunhua Peng, Jing Liu, Le Shi,Yongyao Wang, JiangangLong and Jiankang Liu

Abstract
Alzheimer’s disease (AD) patients have increased an incidence of Type 2 diabetes (T2D), however the underlying mechanisms are not well understood. Since AD is considered a multifactorial disease, that affects both the central nerves system and periphery, and the dysregulation of hepatic lipid and glucose metabolism play critical roles in T2D, we therefore aim to explore the influence of AD genotype on the liver during the progress of high-fat diet (HFD)-induced T2D. 14-week-old female APPSWE/PSEN1dE9 (AD) mice and age-, gender-matched wild type controls C57BL/6J (WT) mice were fed a HFD (45% kcal fat content) or a standard chow diet (Chow, 12% kcal fat content) for 22 weeks. The effects of diet and genotype were analyzed. Mouse primary hepatocytes were used to decipher the underlying mechanisms. HFD induced significantly higher body weight gain, more severe hyperglycemia, glucose intolerance as well as hepatic insulin resistance in AD mice than in WT mice. However, AD mice showed reduced HFD-induced hepatic steatosis, and SREBP-1-mediated lipogenic signaling was activated by HFD in WT mice but not in AD mice. Additionally, 14-week-old AD mice exhibited higher expression of NF-κB p65, p-JNK and p-p38MAPK, as well as higher hepatic and serum contents of IL-6 and TNFα. In mouse primary hepatocyte cultures, IL-6 and TNFα inhibited high glucose plus insulin-induced activation of SREBP-1-mediated lipogenic signaling and biosynthesis of NEFA and TG. Early inflammation-associated factors most likely diminish HFD-induced hepatic lipid deposition by inhibiting SREBP-1-mediated de novo lipogenesis, thus driving substrate flux to glucose production for hyperglycemia and hepatic insulin resistance in T2D development.

参考文献:

YingTang, Yunhua Peng, Jing Liu, Le Shi,Yongyao Wang, JiangangLong and Jiankang Liu . Early inflammation-associated factors blunt sterolregulatory element-binding proteins-1-mediated lipogenesis in high-fat diet-fedAPPSWE/PSEN1dE9 mouse model of Alzheimer's disease. J Neurochem. 2015 Nov18. doi: 10.1111/jnc.13437. [Epub ahead of print]

PengYnhua, Liu Jing, Tang Ying, Liu Jianshu, Han Tingting, Han Shujun, Li Hua, Hou Chen, Liu Jiankang, Long Jiangang. High-Fat-Diet-InducedWeight Gain Ameliorates Bone Loss without Exacerbating AβPP Processing andCognition in Female APP/PS1 Mice.Front Cell Neurosci. 2014 Aug 8;8:225.






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