IDENTIFICATION OF KEY TARGET GENES AND PATHWAY ANALYSIS IN NONALCOHOLIC FATTY LIVER DISEASE VIA INTEGRATED BIOINFORMATICS ANALYSIS
Chen X.1, Zhang L.2, Wang Y.1, Li R.1, Yang M.1, Gao L.3*
*Corresponding Author: Lei Gao, MD, College of Basic Medicine, Changchun University of Chinese Medicine, 1035 Boshuo, Road, Jingyue District, Changchun City, Jilin Province, 130117, China; Tel:+ 86-431-8604 5309, Email: gaolei790708@163.com
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DISCUSSION

The characteristics of NAFLD include necrotizing inflammation and lipid accumulation in the liver, as well as continuous improvement of living standards leading to overnutrition. In addition, bad living habits lead to the incidence of NAFLD on a global scale (27). The specific mechanism of the transition from benign steatosis to steatohepatitis in NAFLD is not fully understood, and there are currently no pharmacological options for the treatment of NAFLD. Therefore, the treatment of NASH mainly depends on lifestyle changes, such as strengthening exercises, reducing weight, and a light diet (28). Although current studies have shown that weight loss improves the histological characteristics of NAFLD, most patients have not however achieved the goal of curing NAFLD. There are some potentially valuable molecules, nevertheless, which are currently being clinically evaluated (29). For example, PNPLA3 (30), TM6SF2 (31), MBOAT7 (32), and HSD17B13 (33), molecules that predispose an individual to the spectrum of NAFLD-related disease, have been found to play a role in macrophage phagocytosis, immune response, oxidative stress, and inflammation, insulin signaling, and lipid metabolism in NAFLD susceptibility and progression (34). But there is no unmet clinical need for drug discovery and development for patients with NAFLD. Increased levels of toxic lipids (free fatty acids or free cholesterol) can lead to liver cell damage and trigger inflammation is the pathogenesis of NAFLD as is currently understood. In addition, oxidative stress, proinflammatory chemokines and cytokines have been proven to lead to liver inflammation, which, in turn, leads to damage and fibrosis of the liver. Therefore, the identification of pro- Figure 4. Gene–drug connection network. Squares represent drug molecules, circles represent genes, and green and red dots represent the significantly downregulated DERs at both baseline and 1-year follow-up time points. inflammatory cytokines related to lipotoxicity may improve our understanding of the pathogenesis of NAFLD, helping to develop new pharmacological methods. In this study, a total of 220 overlapping DERs were identified between the baseline and 1-year follow-up time points. In addition, functional enrichment analysis of overlapping DERs, based on online DAVID analyses, revealed 22 significantly related GO biological processes and 9 KEGG pathways, with P < .05 as the cutoff criteria. We found that chemotaxis (P = 3.110E-04), unsaturated fatty acid biosynthetic process (P = 4.770E-04), and cell-cell signaling (P = 1.513E-03) were the three most significant pathways in GO biological processes. Meanwhile, fatty acid metabolism (P = 2.300E-04), PPAR signaling pathway (P = 1.090E-03), and Toll-like receptor signaling pathway (P = 1.479E-03) were the three most significant pathways in KEGG signaling pathways. Afterwards, a ceRNA regulatory network was constructed. The GO and pathway enrichment analyses indicated that the mRNAs of the ceRNA regulatory network were involved in various important biological functions and metabolic pathways associated with NAFLD, including lipid biosynthetic process, steroid metabolic process, steroid biosynthetic process, biosynthesis of unsaturated fatty acids, terpenoid backbone biosynthesis, heparan sulfate biosynthesis, Cytokine–cytokine receptor interaction, Insulin signaling pathway, and the pathways in cancer. To further understand the functional mechanism of the ceRNA network, a drug regulation gene network was constructed which included 154 gene–drug connection pairs. Subsequently, LEPR, CXCL10, and FOXO1 were investigated using the PharmGKB database. It was revealed that the therapeutic effect of antipsychotics, atorvastatin, valproic acid, risperidone, clozapine, olanzapine, simvastatin, and quetiapine were produced, thus possibly targeting to LEPR through the Cytokine–cytokine receptor interaction pathway. The therapeutic effect of Peginterferon alfa-2a and peginterferon alfa-2b were produced by targeting CXCL10 through the Cytokine–cytokine receptor interaction pathway. The therapeutic effect of Epirubicin, cyclophosphamide, and fluorouracil were produced by targeting FOXO1 through the Insulin signaling pathway or the pathways in cancer. LEPR is responsible for encoding the leptin receptor that binds to leptin in target tissues. Due to its role in regulating lipid metabolism and insulin resistance, it is considered to be a candidate gene for NAFLD and coronary atherosclerosis (35). Simultaneously, An et al. (36) found that LEPR Q223R polymorphism may lead to a significant risk of NAFLD and coronary atherosclerosis, which is consistent with the results of this study. The CXC motif chemokine ligand 10 (CXCL10) is a particularly important pro-inflammatory cytokine related to lipotoxicity, which can recruit inflammatory cells to the site of tissue injury (37, 38). Studies have shown that CXCL10 is upregulated in NAFLD patients (39), and revealed that CXCL10 may be a key molecule that contributes to the transition from benign steatosis to steatohepatitis, promoting liver cell damage and inflammation (40). Our study revealed that peginterferon alfa-2a and peginterferon alfa-2b can downregulate the expression of CXCL10, suggesting a potential role of CXCL10 in the development of intrahepatic inflammation through the Cytokine–cytokine receptor interaction pathway, and demonstrated that CXCL10 is an independent risk factor for patients with NAFLD. FOXO1 is an important transcriptional effector. It is widely expressed in various types of tissues and plays an important role in the signaling pathway of insulin and insulin-like growth factor 1 (41). In addition, the expression levels of most genes related to adipocyte differentiation are affected by the coordination of FOXO1 (42). Yue Li et al. (43) conducted a comprehensive analysis of the relevant information about the activity of FOXO1 in lipid metabolism, and found that FOXO1 has a significant inhibitory effect on the production of fibrotic effector cells, and pointed out that FOXO1 has the potential to become a target for the treatment of NAFLD, but the related mechanism needs to be further verified by experiments (44). L. Valenti et al. (45) found that FOXO1 may affect the susceptibility of NAFLD, and regulating the level of FOXO1 mRNA in order to regulate the relevant cytokines in insulin signaling to promote the progression of liver injury. This study found that epirubicin, cyclophosphamide, and fluorouracil can downregulate the expression of FOXO1, suggesting that these drugs may produce therapeutic effect by targeting FOXO1 through the insulin signaling pathway or the pathways in cancer. However, further study is necessary to validate this hypothesis.



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