PNPLA7调控肝脏糖异生的机制及在HCV相关糖异生紊乱中的作用

Hepatic gluconeogenesis is an important part of glucose metabolism in liver.Clinical data suggests that chronic hepatitis C virus (HCV) is associated with abnormal hepatic homeostasis, however, the precise mechanisms are poorly understood. Previous study shows that hepatic gluconeogenesis can be enhanced by overexpression patatin-like phospholipase domain-containing 7 (PNPLA7) and inhibited by silencing PNPLA7 expression; PNPLA7 is upregulated by HCV infection, exaggerated gluconeogenesis induced by HCV is reduced by silencing PNPLA7. According to preliminary results, we will investigate that whether PNPLA7 regulates hepatic gluconeogenesis via activation of PKA or inhibition of AKT . We will analysis whether PNPLA7 can be upregulated by HCV proteins or HCV-induced oxidative stress and explore how HCV-induced PNPLA7 upregulation enhances hepatic gluconeogenesis. The research will reveal the molecular mechanism of PNPLA7 in regulation of hepatic gluconeogenesis, and provide a new target for the prevention and treatment of abnormal glucose homeostasis caused by HCV infection.

肝脏糖异生是肝糖代谢的重要组成部分，临床数据表明丙型肝炎病毒（HCV）感染及其所致的慢性肝病与糖异生紊乱有明显相关性，然而其分子机制尚不清晰。我们前期研究发现过表达含patatin样磷脂酶域蛋白7（PNPLA7）能够促进肝脏糖异生，而沉默该基因抑制肝脏糖异生；HCV感染上调PNPLA7的表达，沉默PNPLA7抑制HCV导致的肝脏糖异生增加。提示PNPLA7参与肝脏糖异生的调控，并与HCV诱导的肝脏糖异生紊乱相关。基于前期结果，本研究将探讨PNPLA7是否通过激活PKA，抑制AKT，促进PEPCK和G6PC蛋白转录，引起肝脏糖输出增加的机制；同时，通过研究HCV病毒蛋白及HCV感染后产生的活性氧对PNPLA7的影响明确HCV感染上调PNPLA7，进而导致肝糖输出过度的机制。上述研究将最终揭示PNPLA7促进肝脏糖异生的分子机制，并为HCV感染所致的糖异生紊乱的预防和治疗提供新的靶点。

背景：VLDL的调控对肝脏脂质代谢有非常重要的作用，VLDL的异常会导致脂肪肝及血脂紊乱的发生。多篇文献报道ApoE与肝脏VLDL的分泌密切相关。我们的前期研究结果显示病人脂肪肝中PNPLA7的表达显著增高，并且PNPLA7的表达与病人血清TAG水平呈明显正相关，但是PNPLA7调控肝脏VLDL的机制尚不明确。.主要内容和关键数据：用腺病毒沉默小鼠肝脏PNPLA7的表达，导致肝脏VLDL分泌显著减少，肝脏TAG堆积及apoE表达下降。在db/db小鼠中沉默PNPLA7也导致血清TAG减少，加重脂肪肝。我们进行了PNPLA7调控VLDL的机制研究，发现，PNPLA7与ApoE在内质网有相互作用，并且PNPLA7调控ApoE的泛素化降解。在原代肝细胞过表达ApoE回补沉默PNPLA7导致的VLVL-TAG分泌减少。.重要结论：PNPLA7通过与ApoE的相互作用，调控apoE的稳定性，从而参与调控肝脏VLDL的分泌。.除此之外，该项目还支撑了化合物Benzoic acid derivatives NC-2和金银花提取物对甲型流感的体内外活性，发现NC-2及金银花酸酮提取物对流感病毒有抑制作用，有较高的开发潜能。