HDAC9在肝脏脂代谢和非酒精性脂肪肝病中的作用和机制研究

Nonalcoholic fatty liver disease (NAFLD) refers to the presence of hepatic steatosis, as demonstrated by imaging or histology, in the absence of significant alcohol consumption or other known secondary causes. However, the precise pathogenesis of NAFLD is not fully understood. It has been reported HDACs, SIRT1 and HDAC3, play a critical role in occurrence of NAFLD. The preliminary results of our study showed that a significantly increased HDAC9 expression level in liver biopsies of NAFLD patients. Overexpressed HDAC9 in hepatic cells increased hepatic lipid accumulation and the activities of hepatic enzymes involved in fatty acid synthesis. These results indicated that HDAC9 protein may play an important role in regulating occurrence of NAFLD and hepatic lipid metabolism. In this project, we will use ob/ob mouse and HDAC9 overexpressed and knockout mouse as model systems to investigate the physiological role of HDAC9 in regulating hepatic lipid metabolism. We will further analyze the effects of HDAC9 on the metabonomics flux of lipid metabolism, expression and activity of key genes, and find interacting protein of HDAC9 in overexpression or knockdown of HDAC9 in hepatocytes. We will combine in vivo and in vitro results to reveal the physiological function and molecular mechanism of HDAC9 on hepatic lipid metabolism and NAFLD, then, verify the correlation between HDAC9 and NAFLD in clinical specimens, thus provide new insight of regulatory network of NAFLD and new target for prevention and treatment of NAFLD and metabolic syndrome.

非酒精性脂肪肝病（NAFLD）是指无过量饮酒史而出现肝细胞脂肪变性和脂质贮积等特征的临床病理综合征，但其发病机制尚未完全阐明。研究表明组蛋白去乙酰化酶SIRT1和HDAC3参与NAFLD发生，我们前期结果显示NAFLD患者肝脏中组蛋白去乙酰化酶9（HDAC9）的表达水平明显上升，体外过表达HDAC9导致脂滴明显增大，并促进脂肪酸合成关键酶的活性增加，提示HDAC9在NAFLD以及肝脏脂代谢调控中发挥重要的作用。本项目拟使用脂肪肝病动物模型ob/ob小鼠，HDAC9肝脏过表达以及敲除小鼠，通过分析各项生理学指标，确定HDAC9在肝脏脂代谢中的作用。进一步在肝细胞中分析HDAC9对各种脂代谢物质流以及关键基因表达及活性的影响，同时寻找与HDAC9相互作用蛋白，结合体内外实验确定HDAC9调节肝脏脂代谢的分子机制，最后在临床标本中验证HDAC9和NAFLD相关性，为NAFLD的治疗提供新靶点。

非酒精性脂肪肝病（NAFLD）是指无过量饮酒史而出现肝细胞脂肪变性和脂质贮积等特征的临床病理综合征，但其发病机制尚未完全阐明。研究表明HDACs 在 NAFLD 的发生中扮演重要角色。我们前期结果显示组蛋白去乙酰化酶9（HDAC9）参与了肝脏糖异生过程，同时我们发现NAFLD患者肝脏中HDAC9的表达水平也明显上升，提示HDAC9可能也参与了肝脏的脂质代谢。由此我们开展了HDAC9在NAFLD及肝脏脂代谢调控中的作用研究。首先分析了脂肪肝病动物模型ob/ob小鼠和HFD小鼠中HDAC9的表达水平，显示均明显上升。利用HDAC9肝脏敲除小鼠，通过分析各项生理学指标及组织学研究，确定HDAC9敲除后高脂饮食引起的肝脏脂质堆积明显减少，血清甘油三脂、总胆固醇、低密度脂蛋白胆固醇水平均显著下降，说明HDAC9确实参与了肝脏的脂质代谢。同时在ob/ob小鼠中敲降HDAC9显著改善肝脏脂质堆积，此外还能改善糖耐量，胰岛素敏感性等代谢紊乱问题。进一步在肝细胞中通过分析HDAC9对肝脏TAG的合成、分解，脂肪酸的合成、摄入、氧化和 VLDL 的分泌等脂代谢过程中关键分子的调控，确定HDAC9敲降后脂肪酸合成关键酶ACC1的磷酸化水平显著升高，而其上游的关键调节分子AMPK的磷酸化也明显升高。因此，我们推测HDAC9通过调控能量代谢感受分子AMPK的活性从而影响脂肪酸合成代谢，进而在肝脏脂质代谢乃至NAFLD的发生中发挥重要作用，为NAFLD的治疗提供可能的靶点。

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