Sepsis, with high mortality, is a complex clinical syndrome caused by systemic inflammatory response, resulting in immune suppression and eventually leading to shock and multiple organs dysfunction. The liver, as an important immune and metabolic organ, is often severely damaged during  sepsis. Liver injury caused by  sepsis is attributed to pathological mechanisms such as liver microcirculation disorder, oxidation and antioxidant system imbalance, intestinal bacterial migration, and uncontrolled inflammatory response. Liver dysfunction has a special prognostic correlation with  sepsis and is a strong independent predictor of sepsis-induced mortality. The current treatments for [2,4] sepsis-induced liver injury mainly include anti-infection, extracorporeal liver support, and other basic treatments, although these treatments are still less effective for some patients. Therefore, understanding the underlying mechanism of liver injury in sepsis can provide a direction for future precise treatment.
The fibroblast growth factor (FGF) superfamily consists of 22 members, of which FGF5 is a secreted signaling protein.
The FGFs participate in biological processes such as cardiovascular remodeling, [5-7] and pathological embryogenesis, [8-10] and exert complex effects on some diseases, including cancers. [11,12] However, in previous studies, [13,14] FGF5 seems to have received insufficient attention in areas other than hair growth. Recently, a few studies suggested that [15-17] FGF5 played a regulatory role in non-alcoholic fatty liver disease, but the specific mechanism is not fully understood. Therefore, given the possible role of [18,19] FGF5 in liver-related diseases, we conducted this study to investigate the effect of FGF5 on sepsis-induced liver injury and discussed its possible mechanism. We demonstrated that FGF5 overexpression protected the septic liver and confirmed that the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) signaling pathway was involved in the protective effect of FGF5. Methods
Male C57BL/6 mice aged eight weeks were obtained from the Animal Experimental Center of Three Gorges University (Yichang, China). The mice were housed under specific pathogen-free conditions and had free access to food and water. All animal experiments in this study were approved by the Animal Experimental Center of Wuhan Third Hospital (ethical number: SY2022–010) and were conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health.
Model of acute liver injury
A mouse model of acute liver injury was established by a single intraperitoneal injection of LPS. Mice were intraperitoneally injected with LPS with a dose of 10 mg/kg and sacrificed 12 h after injection.
The mice were divided into four groups as follows: normal group, fed normally and treated with an injection of saline; LPS group, received an intraperitoneal injection of LPS (L2880, Sigma-Aldrich, St. Louis, MO, USA); LPS + adenovirus (Ad)- [20,21] FGF5 group, injected with FGF5-overexpressed Ad (Gene Chem Co. Ltd., Shanghai, China) intravenously (injected via the tail vein with 1 × 10 9 plaque-forming units per mouse) one week before the 12 h LPS stimulation; and LPS + Ad-control group, injected with negative control adenovirus (Gene Chem Co. Ltd.) one week before the 12 h LPS stimulation. [22,23] Immunohistochemistry
Citrate antigen retrieval buffer (pH 6.0) (Pinuofei Biological Technology Co, Ltd., Wuhan, China) was used to retrieve the antigen of liver slices in the microwave. Then, the endogenous peroxidase in the tissue slices was blocked in a solution of 3% hydrogen peroxide. Next, the slices were incubated with 3% bovine serum albumin (Solarbio Life Science, Beijing, China) for 30 min, with an FGF5 antibody (1:200, Proteintech, Wuhan, China) overnight. Finally, the slices were stained with horseradish peroxidase-conjugated secondary antibody (Agilent Technologies, Santa Clara, CA, USA) for approximately 1 h at room temperature and with diaminobenzidine (Agilent Technologies) for 2–5 min at room temperature until a brown color developed. For cell samples, the cells were first grown on climbing slices and then subjected to immunohistochemical staining. The staining procedure was similar to that of the liver slices above.
Hematoxylin-eosin (HE) staining
Liver from the sacrificed mice in each group was freshly harvested and soaked in 4% paraformaldehyde for more than 24 h. The tissue samples were then dehydrated, embedded, sectioned, dewaxed, and stained with hematoxylin (nuclei staining) and eosin (cytoplasm staining), and the slides were finally observed under a microscope (Leica Microsystems, Weztlar, Hesse-Darmstadt, Germany).
Immunofluorescence assay for the staining for F4/80 and cleaved-caspase-3 was used to assess the infiltration of inflammatory cells in the mouse liver tissue and apoptosis level of hepatocytes, respectively. Specifically, the paraffin sections were dewaxed in water, and the tissue sections were placed in a repair box filled with citric acid antigen repair buffer (pH 6.0) (Pinuofei Biological Technology Co, Ltd.), and the antigen retrieval was performed in a microwave oven. The sections were then blocked in 3% bovine serum albumin for approximately 30 min. Next, the sections were incubated with the relevant primary antibodies (F4/80 [1:200, Proteintech] and cleaved-caspase-3 [1:200, Abcam, Cambridge, UK]) overnight at 4°C to allow the binding of antigen to antibody. At the next day, the sections were incubated with secondary antibodies (1:500, Jackson, Pennsylvania, USA) at room temperature for 1 h, and 4′,6-diamidino-2-phenylindole (DAPI, 1:100, Solarbio) was used to stain the nuclei. The images were obtained through an immunofluorescence microscope system (NIKON, Tokyo, Japan).
L-02 cells of the human fetal hepatocyte line were purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). Cells were maintained in high-glucose dulbecco's modified eagle medium (HyClone, Logan, Utah, USA) supplemented with 10% fetal bovine serum (BIOEXPLORER, Colorado, USA). Cells were incubated at 37°C with 5% CO
2. When the cell density reached about 70% in the six-well plate, the cells were transfected using Lipo8000™ Transfection Reagent (C0533FT, Beyotime Biotechnology, Shanghai, China) with either a plasmid (3 μg)-carrying human FGF5 gene (Gene Chem Co. Ltd.) or a control plasmid (3μg) (Gene Chem Co. Ltd.); 48 h after transfection, these cells were then stimulated using 100 ng/mL LPS for 24 h. In addition, a PI3K/AKT signaling inhibitor, LY294002 (20 μmol/L, MedChemExpress, NJ, USA) combined with LPS was administered simultaneously 48 h after cell transfection. Determination of biochemical indexes
Blood was obtained by retro-orbital bleeding from anesthetized mice. Serum samples were collected after centrifugation and sent to the Laboratory Department of Renmin Hospital of Wuhan University for automated biochemical analysis. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected to reflect liver function and liver injury.
Detection of reactive oxygen species (ROS) level
Intra-cellular ROS levels were detected using dihydroethidium reagent. Frozen liver slices and L-02 cells were successively stained with dihydroethidium (D7008, Sigma, for liver slices; S0063, Beyotime Institute of Biotechnology, for cells) and DAPI (C1002, Beyotime Biotechnology). Specifically, the liver slices were stained with dihydroethidium for 30 min and DAPI for 10 min; the cells were washed with serum-free culture medium and incubated with the 5 μmol/L dihydroethidium at 37°C for 30 min and the DAPI for 10 min. The images were obtained under a fluorescence microscope (NIKON).
Analysis of ribonucleic acid (RNA)-sequencing
Total RNA of L-02 cells from different groups was extracted using RNAiso Plus (TaKaRa, Kyoto, Japan) according to the manufacturer's instructions. After RNA was tested for purity, concentration, and integrity, only high-quality RNA sample was used to construct sequencing library; high-throughput RNA sequencing was performed by Majorbio (Shanghai, China). The data were analyzed on the online platform of Majorbio Cloud Platform (
). www.majorbio.com P value <0.05 and >1.5 times difference in gene expression was considered statistically significant between the two groups. Flow cytometry
The cultured cells were trypsinized and washed with phosphate-buffered saline, and then, the annexin binding buffer was added to resuspend the cells. After 15 min incubation with 5 μL Annexin V-Phycoerythrin (PE) (BD Biosciences, New York, NJ, USA) and 5 μL 7-amino-actinomycin D (BD Biosciences), the cells were analyzed by flow cytometry (NovoCyte, Palo Alto, CA, USA). The apoptotic rate was taken as the sum of early and late apoptosis.
Quantitative real-time polymerase chain reaction analysis (PCR)
RNAiso Plus (TaKaRa) was used to extract total RNA. Next, complementary DNA (cDNA) was synthesized by using Servicebio RT First Strand cDNA Synthesis Kit (Servicebio, Wuhan, China) according to the manufacturer's instructions. Real-time quantitative polymerase chain reaction was performed using Servicebio 2∗SYBR Green qPCR Master Mix kit (Low ROX) (Servicebio) and ABI ViiA7 Real-Time PCR system (Applied Biosystems, MA, USA).
Briefly, the proteins extracted from the livers and cells were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and then transferred to nitrocellulose filter membranes. After blocking in the protein-free rapid blocking buffer (Epizyme Biotech, Shanghai, China), the membranes were washed with tris-buffered saline + Tween 20 (TBST) for three times and incubated overnight with primary antibodies for FGF5 (1:500, Affinity Biosciences, Jiangsu, China), phosphorylated-PI3K (p-PI3K, 1:1000, Abcam), PI3K (p85, 1:1000, Abcam), phosphorylated-AKT (p-AKT; Ser473, 1:1000, Cell Signaling Technology, Danvers, MA, USA), AKT (1:1000, Cell Signaling Technology), B cell lymphoma-2 (BCL-2) (1:1000, Abcam), BCL2-associated X (BAX) (1:1000, Abcam), caspase-9 (1:1000, Abcam), cleaved-caspase-9 (1:1000, Abcam), caspase-3 (1:1000, Abcam), cleaved-caspase-3 (1:1000, Abcam), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (1:1000, Cell Signaling Technology). The next day, the membranes were incubated with horseradish peroxidase-conjugated secondary antibody for 1 h at room temperature. Finally, the visualization of membranes was realized by enhanced chemiluminescence reagent and in a ChemiDoc XRS
+ system (BIO-RAD, Hercules, CA, USA). The gray value of protein was quantified by Image J software (National Institutes of Health, Bethesda, MD, USA). Statistical analysis of data
All data in our study were analyzed through GraphPad Prism software (GraphPad Software, San Diego, California, USA). One-way analysis of variance (ANOVA) followed by Tukey
post hoc test was performed when comparing multiple groups; while the comparison of differences in two groups was done by unpaired Student's t-test. The criterion for statistical significance was P < 0.05. Results
FGF5 was down-regulated in liver cells exposed to LPS
We determined the levels of
FGF5 in normal livers and LPS-treated livers, and as shown in Figure 1A, 1C, and 1E, a significantly down-regulated level of FGF5 was revealed in livers exposed to LPS. Further, the same trend was also observed in L-02 cells treated with LPS in vitro [ Figure 1B, 1D, and 1F].
FGF5 is down-regulated in hepatocytes treated with LPS. (A) Representative images of liver immunohistochemical staining for FGF5. (B) Representative images of immunohistochemical staining for FGF5 in L-02 cells. (C, E) Expression of FGF5 in liver tissues detected by Western blot and its statistical analysis results displayed by a bar graph. (D, F) Expression of FGF5 in L-02 cells detected by Western blot and its statistical analysis results displayed by the bar graph.
n = 6, ∗ P < 0.05. CTL: Control group; FGF5: Fibroblast growth factor 5; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; LPS: Lipopolysaccharide. Overexpression of FGF5 ameliorated liver injuries
Next, FGF5 was overexpressed in livers of mice by injecting an adenovirus carrying the
FGF5 gene [ Figure 2A and 2B]. After LPS stimulation, the liver exhibited remarkable damage, characterized by the destruction of liver tissue structure [ Figure 2C], abnormal elevations of liver enzymes [ Figure 2D and 2E] and inflammatory cytokines [ Figure 2J and 2K], obvious infiltration of inflammatory cells [ Figure 2F and 2H], and increased ROS level [ Figure 2G and 2I]. Interestingly, with FGF5 overexpression, these LPS-induced pathological changes in the liver were ameliorated compared to the negative control group [ Figure 2C–K].
Overexpression of fibroblast growth factor 5 (FGF5) ameliorates liver injuries induced by LPS. (A, B) Representative blot images and corresponding statistical analysis graph reflecting the expressions of FGF5 in the liver (
n = 4, ∗ P < 0.05). (C) Representative HE staining of liver from different groups. (D, E) The levels of ALT and AST in normal, LPS, LPS + Ad- FGF5, and LPS + Ad-control groups. (F, H) Representative immunofluorescence images of F4/80 staining in livers and its statistical analysis ( n = 5, ∗ P < 0.05). (G, I) Representative ROS staining of livers from different groups and its statistical analysis is shown in a bar graph ( n = 5, ∗ P < 0.05). (J, K) Relative mRNA levels of TNF-α and IL-1β in livers ( n = 5, ∗ P < 0.05). ALT: Alanine aminotransferase; AST: Aspartate transaminase; DAPI: 4′,6-diamidino-2-phenylindole; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; HE: Hematoxylin-eosin; IL-1β: Interleukin-1β; LPS: Lipopolysaccharide; LPS + Ad-control group: LPS + adenovirus-control group; LPS + Ad- FGF5: LPS + adenovirus- FGF5 group; mRNA: Message RNA; ROS: Reactive oxygen species; TNF-α: Tumor necrosis factor-α. Overexpression of FGF5 relieved hepatocyte injuries
We performed an
in vitro experiment to confirm the protective effects of FGF5 overexpression on hepatocytes. We used plasmids carrying FGF5 gene to overexpress FGF5 in L-02 cells [ Figure 3A–C]. As expected and similar to our animal results, LPS-stimulated cells showed an elevated ROS level compared with those in the control group, whereas FGF5-overexpressed cells showed decreased ROS levels compared with the negative control group [ Figure 3D and 3E]. Further, flow cytometry [ Figure 3H and 3I] results indicated that FGF5 overexpression in hepatocytes reduced LPS-induced cell apoptosis; immunofluorescence assay showed that the expression of cleaved-caspase-3 [ Figure 3F and 3G] was also reduced after FGF5 overexpression. In conclusion, these results suggested that FGF5 overexpression reduced hepatocyte ROS levels and LPS-induced apoptosis.
Overexpression of fibroblast growth factor 5 (
FGF5) reduces LPS-induced hepatocyte injury in vitro. (A, B) Representative blot image and its corresponding statistical analysis graph reflecting the expression of FGF5 in L-02 cells ( n = 4, ∗ P < 0.05). (C) Merged fluorescent figures indicated the efficiency of plasmid transfection in L-02 cells. (D, E) Representative ROS staining of cells from different groups and its statistical analysis shown as a bar graph (×400, n = 5, ∗ P < 0.05). (F, G) Representative immunofluorescence image of cleaved-caspase-3 staining in livers and its statistical analysis ( n = 5, ∗ P < 0.05). (H, I) Results of apoptosis rate assessed by flow cytometry and statistical analysis (×400, n = 3, ∗ P < 0.05). Annexin V-PE: Annexin V-Phycoerythrin; C- cas3: Cleaved-caspase 3; CTL: Control group; DAPI: 4′,6-diamidino-2-phenylindole; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; LPS: Lipopolysaccharide; ROS: Reactive oxygen species; 7AAD: 7-Aminoactinomycin D. PI3K/AKT signaling might account for the protective effects of FGF5
To elucidate the possible mechanism of
FGF5 ameliorating LPS-induced liver cell damage, we performed RNA sequencing to determine the possible signaling pathway through which FGF5 may exert its action. A total of 453 differentially expressed genes were detected between the LPS + FGF5-plasmid and LPS + Control-plasmid groups, of which 204 genes were up-regulated and 249 genes were down-regulated in the LPS + FGF5-plasmid group. Subsequently, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment was performed on these differentially expressed genes, and it was found that the PI3K/AKT signaling pathway was most significantly enriched [ Figure 4A]. Therefore, the analysis of differentially expressed genes suggested that PI3K/AKT signaling was regulated by FGF5.
The protective effect of fibroblast growth factor 5 (
FGF5) on LPS injury might be realized by regulating the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT ) pathway. (A) KEGGs enrichment analysis of the differentially expressed genes ( n = 3, P < 0.05, and >1.5 times difference in gene expression was considered statistically significant between the two groups). (B) The PI3K/AKT and apoptotic pathways in vivo: Representative blot images. (C–H): The corresponding statistical analysis graphs. ( n = 3, ∗ P < 0.05). AGE-RAGE: AGE-Receptor for AGE; BAX: B cell lymphoma-2 (BCL2)-associated X; cas-3: Caspase-3; cas-9: Caspase-9; DEGs: Different expression genes; ECM: Extra-cellular matrix; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; KEGG: Kyoto Encyclopedia of Genes and Genome; JAK-STAT: Janus kinase-signal transducers and activators of transcription; LPS: Lipopolysaccharide; LPS + Ad-control group: LPS + adenovirus-control group; LPS + Ad- FGF5: LPS + adenovirus- FGF5 group; nosig: No significance; p- AKT: Phosphorylated-protein kinase B; p- PI3K: Phosphorylated-phosphoinositide-3-kinase; Rap1: Ras-related Protein 1. FGF5 affected PI3K/AKT and apoptotic pathways in vivo
Given that the enrichment analysis indicated that the PI3K/AKT signaling pathway might be involved in the protective effect of FGF5, we adopted the Western blot method to detect the activation of this pathway. As shown in
Figure 4B–D, both p-PI3K and p-AKT were inhibited after LPS stimulation, whereas they were re-activated with FGF5 overexpression in the liver. Furthermore, reactivation of PI3K/AKT signaling was accompanied by decreased expression of pro-apoptotic proteins, including BAX, cleaved-caspase-9/caspase-9, and cleaved-caspase-3/caspase-3, and increased expression of anti-apoptotic proteins including BCL-2 [ Figure 4B, 4E–H]. These results confirmed that FGF5 indeed had a regulatory effect on the PI3K/AKT signaling pathway and might play an anti-apoptotic role by activating the PI3K/AKT signaling pathway in the liver. FGF5 affected PI3K/AKT and apoptotic pathways in vitro
We also verified the regulation of PI3K/AKT signaling by
FGF5 using in vitro hepatocyte experiments. As depicted in Figure 5, our in vitro experiment confirmed the activation effect of FGF5 on PI3K/AKT signaling and the inhibitory effect on apoptotic signals.
Fibroblast growth factor 5 (
FGF5) overexpression exerts effects on the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT ) and apoptotic pathways in vitro: (A) Representative blot images. (B–G) The corresponding statistical analysis graphs ( n = 4, ∗ P < 0.05). BAX: BCL2-associated X; cas-3: Caspase-3; cas-9: Caspase-9; CTL: Control group; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; LPS: Lipopolysaccharide; LPS + Ad-control group: LPS + adenovirus-control group; LPS + Ad- FGF5: LPS + adenovirus- FGF5 group; p- AKT: Phosphorylated-protein kinase B; p- PI3K: Phosphorylated- phosphoinositide-3-kinase. FGF5 protected hepatocytes against apoptosis via activating the PI3K/AKT pathway
To verify the anti-apoptotic effect of
FGF5 on liver cells through the activation of the PI3K/AKT signaling pathway, we applied PI3K/AKT signaling inhibitor, LY294002, to the liver cells based on FGF5 overexpression. The protein results [ Figure 6] showed that with the inhibition of PI3K/AKT signaling, the expression of pro-apoptotic proteins that had been down-regulated by FGF5 overexpression was increased and that of anti-apoptotic proteins that had been up-regulated by FGF5 overexpression was reduced; this meant that the anti-apoptotic effect of FGF5 was abrogated with the suppression of PI3K/AKT signaling. Therefore, FGF5 exerted an anti-apoptotic effect on hepatocytes by activating the PI3K/AKT signaling pathway, thus protecting hepatocytes from LPS-induced injury. Figure 6:
Fibroblast growth factor 5 (
FGF5) protects hepatocytes against apoptosis by activating the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT ) pathway. (A) Representative blot images. (B–G): The corresponding statistical analysis graphs ( n = 3, ∗ P < 0.05). BAX: BCL2-associated X; cas-3: Caspase-3; cas-9: Caspase-9; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; LPS: Lipopolysaccharide; p- AKT: Phosphorylated-protein kinase B; p- PI3K: Phosphorylated- phosphoinositide-3-kinase. Discussion
Currently, there is a lack of clear diagnostic criteria for
sepsis-related liver injury in clinical practice, and the incurrence mechanism is also unclear. As sepsis is usually accompanied by liver injury, it is of great significance to further study its pathogenesis and related treatment methods. In the current study, FGF5 showed a protective effect against liver injury, which was reflected by its ability to reduce liver inflammation levels and improve hepatocyte apoptosis. Further, elucidating the mechanism by which FGF5 exerted a protective effect in LPS-induced hepatic injury, the results of KEGG enrichment from RNA-sequence data showed that the PI3K/AKT signaling pathway was involved in the effect of FGF5 on LPS-treated hepatocytes. Moreover, FGF5 stimulated the activation of the PI3K/AKT signaling pathway, thereby relieving apoptosis and promoting hepatocyte survival, thus possibly serving as a mechanism to alleviate sepsis-induced liver injuries.
FGF family contains more than 20 molecules and is widely involved in various biological processes. A recent study has demonstrated that [24-26] FGF1 variant, a modified FGF1, is effective in preventing and reversing hepatic steatosis and steatohepatitis by activating adenosine 5′-monophosphate-activated protein kinase (AMPK), implicating the antioxidant function of FGF. Similarly,  FGF4 and  FGF21 have also been found to exert protective and antioxidant effects on the fatty liver by activating the AMPK-mediated signaling axis. Thus, [29-31] FGF family members show excellent antioxidant and anti-inflammatory abilities in some liver diseases. Additionally, FGFs also exert anti-apoptotic effects in other research fields. For instance, Okada [32-36] et al have uncovered therapeutic effects of  FGF2 on reducing neuronal apoptosis through activation of PI3K/AKT signaling.However, there are few studies on FGF5, and the current reports on FGF5 mainly focus on its regulation of hair growth. Interestingly, a few previous studies have shown a potential link between [15-17] FGF5 and inflammation-related diseases: FGF5 variance was reported to be associated with hypertension in humans, and [37-40] FGF5 deletion was related to severe hepatic steatosis. In a word, these studies support the protective role of [18,19] FGF5 in sepsis-related injury.
We constructed an adenovirus and a plasmid carrying the
FGF5 gene, which was then transferred into mice and L-02 cells. Excessive ROS production can lead to cell death, and reduced ROS often means lower levels of intra-cellular oxidative stress and better cellular status. Our results indicated a protective effect of FGF5 overexpression on LPS-induced injury in hepatocytes, which was reflected by decreased ROS levels and the subsequent increased survival rate. To further reveal the protective mechanism of  FGF5, RNA sequencing was carried out on a liver cell line after an in vitro experiment. KEGG enrichment analysis showed that the PI3K/AKT signaling pathway had the highest enrichment degree, suggesting that FGF5 might play a protective role on hepatocytes through the regulation of the PI3K/AKT signaling pathway.
PI3K/AKT signaling has widely been considered a regulator of cell survival and anti-apoptosis signaling.
Most studies have demonstrated the beneficial effects of PI3K/AKT on cell injury induced by various factors, [42,43] and some have proposed the regulatory role of FGFs on PI3K/AKT signaling. [44,45] In our current study, LPS induced both hepatocyte apoptosis and inhibited the PI3K/AKT pathway; FGF5 overexpression led to increased PI3K and AKT phosphorylation, which indicated that following LPS stimulation, the activation of the PI3K/AKT pathway was FGF5 dependent. Further, FGF5 overexpression also reduced the apoptosis level in hepatocytes. To further verify that [46-48] FGF5 did exert an anti-apoptotic effect on hepatocytes through the PI3K/AKT signaling pathway, LY294002, a PI3K/AKT signaling inhibitor, was applied to cells in vitro, which inhibited the anti-apoptotic effect of FGF5.
In conclusion, our current study demonstrated, for the first time, the anti-apoptotic effect of
FGF5 in hepatocytes and confirmed that the aforementioned protective effect of FGF5 on LPS-induced hepatic injury depended on the activation of the PI3K/AKT signaling pathway, thus providing new insights for the clinical treatment of the septic liver injury. Funding
This work was supported by the National Science and Technology Support Program (grant number: 2015BAI08B01).
Conflicts of interest
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