Liver-directed microRNA-7a depletion induces nonalcoholic fatty liver disease by stabilizing YY1-mediated lipogenic pathways in zebrafish
Liver-directed microRNA-7a depletion induces nonalcoholic fatty liver disease by stabilizing YY1-mediated lipogenic pathways in zebrafish
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DOI：
10.1016/j.bbalip.2018.04.009
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发表时间：
2018-08-01
影响因子：
4.8
通讯作者：
Her, Guor Mour
中科院分区：
文献类型：
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作者：
Lai, Chi-Yu;Lin, Chiu-Ya;Her, Guor Mour
非酒精性脂肪性肝病(NAFLD)与microRNAs(MiRs)的功能和表达水平变化有关。MIR-7已被证明在许多细胞过程中发挥重要作用；然而，其在肝脏脂肪生成中的功能仍不清楚。我们应用微RNA-海绵(miR-SP)技术，建立了转基因miR-7a-SP模型(hC7aSP和bC7aSP)，干扰了肝脏miR-7a的活性，并诱导了斑马鱼NAFLD和非酒精性脂肪性肝炎(NASH)的早期发病。我们发现了一个新的miR-7a靶点YY1，并证明了新的miR-7a通过调节生脂信号通路的表达来控制YY1的稳定，从而调节斑马鱼肝脏的脂代谢。相应地，肝脏特异性miR-7a缺失在功能上促进了hC7ASP肝脏中的脂质积累。NASH hC7aSP增加炎症基因(IL-1b、IL-6、TNF-α、干扰素-γ、NFKB2和核因子-kB)和内质网应激标志物(ATF6、ern2、IRE1、perk、hspa5和ddit3)的表达。分子分析表明，miR-7a-SP通过降低hC7aSP中CHOP-10的表达，进而诱导C/EBP-α和PPAR-γ的反式激活，稳定YY1的表达，促进肝脏甘油三酯的蓄积。PPAR-γ拮抗剂和miR-7a模拟治疗可改善hC7aSP NASH表型。结论：我们的结果提示miR-7a-SP通过直接增加YY1的稳定性而发挥脂质增强剂的作用，阻断CHOP 10依赖的成脂途径的抑制，导致脂质积累增加。MiR-7a的表达改善了hC7aSP的肝脏脂肪变性和脂肪性肝炎，这为人类NASH的预防和早期治疗提供了一种新的策略。
Nonalcoholic fatty liver disease (NAFLD) has been associated with the function and changes in expression levels of microRNAs (miRs). MiR-7 has been proven to play an important role in many cellular processes; however, its functions in the context of liver lipogenesis remain unknown. We applied the microRNA-sponge (miR-SP) technology and generated transgenic miR-7a-SP models (hC7aSP and bC7aSP), which disrupted the activities of hepatic miR-7a and induced the early onset of NAFLD and nonalcoholic steatohepatitis (NASH) in zebrafish. We identified a novel miR-7a target, YY1, and demonstrated novel miR-7a functions to regulate zebrafish hepatic lipid metabolism by controlling YY1 stabilization through the regulation of the expression of lipogenic signaling pathways. Correspondingly, liver specific miR-7a depletion functionally promoted lipid accumulation in hC7ASP livers. NASH hC7aSP increased the expression of inflammatory genes (il-1b, il-6, tnf-alpha, ifn-gamma, nfkb2, and NF-kB) and endoplasmic reticulum stress markers (atf6, ern2, ire1, perk, hspa5 and ddit3). Molecular analysis revealed that miR-7a-SP can stabilize YY1 expression and contribute to the accumulation of hepatic triglycerides by reducing the CHOP-10 expression in the hC7aSP and then inducing the transactivation of C/EBP-alpha and PPAR-gamma expression. PPAR-gamma antagonists and miR-7a mimic treatment ameliorate hC7aSP NASH phenotypes. Conclusion: Our results suggest that miR-7a-SP acts as a lipid enhancer by directly increasing YY1 stability to disrupt CHOP 10-dependent suppression of lipogenic pathways, resulting in increased lipid accumulation. MiR-7a expression improves liver steatosis and steatohepatitis in hC7aSPs, which suggests a novel strategy for the prevention and early treatment of NASH in humans.