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
page: 10
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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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