Pyruvate kinase L/R is a regulator of lipid metabolism and mitochondrial function
Pyruvate kinase L/R is a regulator of lipid metabolism and mitochondrial function
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DOI：
10.1016/j.ymben.2019.01.001
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发表时间：
2019-03-01
影响因子：
8.4
通讯作者：
Mardinoglu, Adil
中科院分区：
文献类型：
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作者：
Liu, Zhengtao;Zhang, Cheng;Mardinoglu, Adil
非酒精性脂肪性肝病(NAFLD)和肝细胞癌(HCC)的发病机制与肝脏特异性基因的表达改变有关，这些基因包括丙酮酸激酶、肝脏和红细胞(PKLR)、含3的Patatin样磷脂酶结构域(PNPLA3)和原蛋白转换酶枯草杆菌/可信9(PCSK9)。在这里，我们抑制和过表达了这三个基因在HepG2细胞中的表达，产生了干扰前后的RNA-SEQ数据，并利用整合网络(IN)分析揭示了这些基因调控下的整体生物学功能的变化。我们发现，这些基因的调节会影响细胞内的总甘油三酯水平和细胞的活力。接下来，我们为HepG2细胞生成了IN，并基于IN确定了报告转录因子，发现这些基因的调控影响了与脂代谢(类固醇生物合成、PPAR信号通路、脂肪酸合成和氧化)以及癌症发展(DNA复制、细胞周期和p53信号)相关的关键代谢通路，这些代谢通路参与了NAFLD和肝细胞癌的进展。最后，我们观察到抑制PKLR导致HepG2细胞葡萄糖摄取减少和线粒体活性降低。因此，我们的系统水平分析表明，PKLR可以作为开发NAFLD和肝癌有效治疗策略的靶点。
The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) has been associated with altered expression of liver-specific genes including pyruvate kinase liver and red blood cell (PKLR), patatin-like phospholipase domain containing 3 (PNPLA3) and proprotein convertase subtilisin/kexin type 9 (PCSK9). Here, we inhibited and overexpressed the expression of these three genes in HepG2 cells, generated RNA-seq data before and after perturbation and revealed the altered global biological functions with the modulation of these genes using integrated network (IN) analysis. We found that modulation of these genes effects the total triglycerides levels within the cells and viability of the cells. Next, we generated IN for HepG2 cells, identified reporter transcription factors based on IN and found that the modulation of these genes affects key metabolic pathways associated with lipid metabolism (steroid biosynthesis, PPAR signalling pathway, fatty acid synthesis and oxidation) and cancer development (DNA replication, cell cycle and p53 signalling) involved in the progression of NAFLD and HCC. Finally, we observed that inhibition of PKLR lead to decreased glucose uptake and decreased mitochondrial activity in HepG2 cells. Hence, our systems level analysis indicated that PKLR can be targeted for development efficient treatment strategy for NAFLD and HCC.