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首页> 外文期刊>Frontiers in Cellular Neuroscience >Intermittent Fasting Alleviates the Increase of Lipoprotein Lipase Expression in Brain of a Mouse Model of Alzheimer's Disease: Possibly Mediated by β-hydroxybutyrate
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Intermittent Fasting Alleviates the Increase of Lipoprotein Lipase Expression in Brain of a Mouse Model of Alzheimer's Disease: Possibly Mediated by β-hydroxybutyrate

机译：间歇性禁食可减轻阿尔茨海默氏病小鼠模型脑中脂蛋白脂肪酶表达的增加：可能由β-羟基丁酸酯介导

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Intermittent fasting has been demonstrated to protect against Alzheimer's disease (AD), however, the mechanism is unclear. Histone acetylation and lipoprotein lipase (LPL) are involved in AD progression. Importantly, LPL has been documented to be regulated by histone deacetylases (HDACs) inhibitors (increase histone acetylation level) in adipocyte and mesenchymal stem cells, or by fasting in adipose and muscle tissues. In brain, however, whether histone acetylation or fasting regulates LPL expression is unknown. This study was designed to demonstrate intermittent fasting may protect against AD through increasing β-hydroxybutyrate, a HDACs inhibitor, to regulate LPL. We also investigated microRNA-29a expression associating with regulation of LPL and histone acetylation. The results showed LPL mRNA expression was increased and microRNA-29a expression was decreased in the cerebral cortex of AD model mice (APP/PS1), which were alleviated by intermittent fasting. No significant differences were found in the total expression of LPL protein (brain-derived and located in capillary endothelial cells from peripheral tissues) in the cerebral cortex of APP/PS1 mice. Further study indicated that LPL located in capillary endothelial cells was decreased in the cerebral cortex of APP/PS1 mice, which was alleviated by intermittent fasting. LPL and microRNA-29a expression were separately increased and down-regulated in 2 μM Aβ_(25?35)-exposed SH-SY5Y cells, but respectively decreased and up-regulated in 10 μM Aβ_(25?35)-exposed cells, which were all reversed by β-hydroxybutyrate. The increase of HDAC2/3 expression and the decrease of acetylated H3K9 and H4K12 levels were alleviated in APP/PS1 mice by intermittent fasting treatment, as well in 2 or 10 μM Aβ_(25?35)-exposed cells by β-hydroxybutyrate treatment. These findings above suggested the results from APP/PS1 mice were consistent with those from cells treated with 2 μM Aβ_(25?35). Interestingly, LPL expression was reduced (0.2-folds) and microRNA-29a expression was up-regulated (1.7-folds) in HDAC2-silenced cells, but respectively increased (1.3-folds) and down-regulated (0.8-folds) in HDAC3-silenced cells. Furthermore, LPL expression was decreased in cells treated with microRNA-29a mimic and increased with inhibitor treatment. In conclusion, intermittent fasting inhibits the increase of brain-derived LPL expression in APP/PS1 mice partly through β-hydroxybutyrate-mediated down-regulation of microRNA-29a expression. HDAC2/3 may be implicated in the effect of β-hydroxybutyrate on microRNA-29a expression.
机译：间歇性禁食已被证明可以预防阿尔茨海默氏病（AD），但是其机制尚不清楚。组蛋白乙酰化和脂蛋白脂肪酶（LPL）参与AD进展。重要的是，LPL已被脂肪细胞和间充质干细胞中的组蛋白脱乙酰基酶（HDACs）抑制剂（提高组蛋白乙酰化水平）或禁食在脂肪和肌肉组织中调节。然而，在大脑中，是否组蛋白乙酰化或禁食调节LPL表达尚不清楚。这项研究旨在证明间歇性禁食可以通过增加HDACs抑制剂β-羟基丁酸酯来调节LPL，从而预防AD。我们还调查了与LPL和组蛋白乙酰化调控相关的microRNA-29a表达。结果表明，AD小鼠（APP / PS1）的大脑皮层中LPL mRNA表达增加，而microRNA-29a表达降低，这被间歇性禁食所缓解。在APP / PS1小鼠的大脑皮层中，LPL蛋白的总表达（脑源性和位于外周组织的毛细血管内皮细胞中）没有发现显着差异。进一步的研究表明，APP / PS1小鼠的大脑皮层中毛细血管内皮细胞中的LPL减少，间歇性禁食可以缓解这种情况。在暴露于2μMAβ_（25？35）的SH-SY5Y细胞中，LPL和microRNA-29a的表达分别增加和下调，而暴露于10μMAβ_（25？35）的细胞中LPL和microRNA-29a的表达分别降低和上调。被β-羟基丁酸酯逆转。通过间歇禁食处理，在APP / PS1小鼠中以及通过β-羟基丁酸酯处理暴露于2或10μMAβ_（25？35）的细胞中，HDAC2 / 3表达的增加以及乙酰化的H3K9和H4K12水平的降低得到缓解。以上这些发现表明，APP / PS1小鼠的结果与2μMAβ_（25？35）处理的细胞的结果一致。有趣的是，在HDAC2沉默的细胞中，LPL表达降低（0.2倍），而microRNA-29a表达上调（1.7倍），但在HDAC3中分别增加（1.3倍）和下调（0.8倍）沉默的细胞。此外，在用microRNA-29a模拟物处理的细胞中LPL表达降低，并在抑制剂处理中增加。总之，间歇性禁食可部分通过β-羟基丁酸酯介导的microRNA-29a表达下调来抑制APP / PS1小鼠脑源性LPL表达的增加。 HDAC2 / 3可能与β-羟基丁酸酯对microRNA-29a表达的影响有关。

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