Zhang Jingzhu, Liu Yufan, Wang Sihui, Que Ran, Zhao Weidong, An Li
Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, China.
China Medical University-The Queen's University of Belfast Joint College, China Medical University, Shenyang, China.
Front Aging Neurosci. 2020 May 12;12:132. doi: 10.3389/fnagi.2020.00132. eCollection 2020.
Progressive accumulation of amyloid-β (Aβ) plaques in the brain is a characteristic pathological change in Alzheimer's disease (AD). We previously found the expression of lipoprotein lipase (LPL) was increased in SH-SY5Y cells exposed to low-dose Aβ and decreased in cells with high-dose Aβ exposure, but the molecular mechanism is still unclear. Based on previous studies, the opposite regulation of histone deacetylase2 (HDAC2) and HDAC3 on LPL expression probably explain the above molecular mechanism, in which microRNA-29a and peroxisome proliferator-activated receptor γ (PPARγ) may be involved. This study further revealed the mechanism of HDAC2 and HDAC3 on conversely regulating LPL expression. The results showed that HDAC2 down-regulated microRNA-29a by decreasing histone acetylation (Ace-H3K9) level in its promoter region, subsequently increasing LPL expression directly or through PPARγ/LPL pathway; HDAC3 decreased LPL expression through inhibiting Ace-H3K9 levels in LPL and PPARγ promoter regions and up-regulating microRNA-29a. This study also found that with increasing concentrations of Aβ in cells, HDAC2 and HDAC3 expression were gradually increased, and Ace-H3K9 levels in LPL and PPARγ promoter region regulated by HDAC3 were decreased correspondingly, while Ace-H3K9 levels in microRNA-29a promoter region modulated by HDAC2 were not decreased gradually but presented a U-shaped trend. These may lead to the results that a U-shaped alteration in microRNA-29a expression, subsequently leading to an inverse U-shaped alteration in PPARγ or LPL expression. In conclusion, HDAC2 and HDAC3 at least partly mediate LPL expression variations in different concentrations of Aβ exposed SH-SY5Y cells, in which microRNA-29a and PPARγ are involved, and the histone acetylation level in microRNA-29a promoter region plays a key role.
淀粉样β蛋白（Aβ）斑块在大脑中的逐渐积累是阿尔茨海默病（AD）的特征性病理变化。我们之前发现，暴露于低剂量Aβ的SH-SY5Y细胞中脂蛋白脂肪酶（LPL）的表达增加，而暴露于高剂量Aβ的细胞中LPL表达降低，但其分子机制仍不清楚。基于之前的研究，组蛋白去乙酰化酶2（HDAC2）和HDAC3对LPL表达的相反调节可能解释了上述分子机制，其中可能涉及微小RNA-29a和过氧化物酶体增殖物激活受体γ（PPARγ）。本研究进一步揭示了HDAC2和HDAC3对LPL表达进行反向调节的机制。结果表明，HDAC2通过降低其启动子区域的组蛋白乙酰化（Ace-H3K9）水平下调微小RNA-29a，随后直接或通过PPARγ/LPL途径增加LPL表达；HDAC3通过抑制LPL和PPARγ启动子区域的Ace-H3K9水平并上调微小RNA-29a来降低LPL表达。本研究还发现，随着细胞中Aβ浓度的增加，HDAC2和HDAC3的表达逐渐增加，HDAC3调节的LPL和PPARγ启动子区域的Ace-H3K9水平相应降低，而HDAC2调节的微小RNA-29a启动子区域的Ace-H3K9水平并非逐渐降低，而是呈U形趋势。这些可能导致微小RNA-29a表达呈U形改变，随后导致PPARγ或LPL表达呈倒U形改变。总之，HDAC2和HDAC3至少部分介导了不同浓度Aβ暴露的SH-SY5Y细胞中LPL表达的变化，其中涉及微小RNA-29a和PPARγ，微小RNA-29a启动子区域的组蛋白乙酰化水平起关键作用。
