Abstract
Krüppel-like factor 4 (KLF4) is a key transcription factor that regulates genes involved in the proliferation or differentiation in different tissues. Apelin plays roles in cardiovascular functions, metabolic disease, and homeostatic disorder. However, the biological function of apelin in liver disease is still ongoing. In this study, we investigated the mechanism of KLF4-mediated protection against acute liver injury via the inhibition of the apelin signaling pathway. Mice were intraperitoneally injected with carbon tetrachloride (CCl4; 0.2 mL dissolved in 100 mL olive oil, 10 mL/kg) to establish an acute liver injury model. A KLF4 expression plasmid was injected through the tail vein 48 h before CCl4 treatment. In cultured LX-2 cells, pAd-KLF4 or siRNA KLF4 was overexpressed or knockdown, and the mRNA and protein levels of apelin were determined. The results showed that the apelin serum level in the CCl4-injected group was higher than that of control group, and the expression of apelin in the liver tissues was elevated while KLF4 expression was decreased in the CCl4-injected group compared to the KLF4-plasmid-injected group. HE staining revealed serious hepatocellular steatosis in the CCl4-injected mice, and KLF4 alleviated this steatosis in the mice injected with KLF4 plasmid. In vitro experiments showed that tumor necrosis factor-alpha (TNF-α) could downregulate the transcription and translation levels of apelin in LX-2 cells and also upregulate KLF4 mRNA and protein expression. RT-PCR and Western blotting showed that the overexpression of KLF4 markedly decreased basal apelin expression, but knockdown of KLF4 restored apelin expression in TNF-α-treated LX-2 cells. These in vivo and in vitro experiments suggest that KLF4 plays a key role in inhibiting hepatocellular steatosis in acute liver injury, and that its mechanism might be the inhibition of the apelin signaling pathway.
Highlights
The liver is a crucial organ with metabolic and detoxification functions
Studies have confirmed that Krüppel-like factor 4 (KLF4) can regulate pathological processes such as liver fibrosis and hepatocellular carcinoma cells (HCC) formation [7], and a recent study reported that KLF4 promoted HepG2 cell scattering induced by hepatocyte growth factor [8]
Immunohistochemical staining indicated that the expression of apelin protein increased, while KLF4 protein expression decreased, in the hepatocytes of mice treated with CCl4 (Figure 1(d))
Summary
The liver is a crucial organ with metabolic and detoxification functions. Acute liver injury can arise from multiple factors, including viral infection, trauma, or chemical reagents, such as alcohol, drugs, and toxic substance [1, 2]. Krüppel-like factor 4 (KLF4) is a multifunctional, zincfinger transcription factor that regulates genes involved in the cell cycle, proliferation, differentiation, apoptosis, and responses to external stress. It is a tumor suppressor and an oncogene in different tumor tissues where it regulates the expression of various genes [5, 6]. Studies have confirmed that KLF4 can regulate pathological processes such as liver fibrosis and HCC formation [7], and a recent study reported that KLF4 promoted HepG2 cell scattering induced by hepatocyte growth factor [8]. The function of KLF4 in acute liver injury remains unclear
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