Mechanism of KLF4 Protection against Acute Liver Injury via Inhibition of Apelin Signaling

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.

4-OI Attenuates Carbon Tetrachloride-Induced Hepatic Injury via Regulating Oxidative Stress and the Inflammatory Response

“…CCl4 can cause hepatic damage by increasing oxidative stress and the inflammatory response ( Mohi-Ud-Din et al, 2019 ). Many chemicals showed a hepatic protective effect in the CCl4-induced mice model by activating the anti-oxidative pathway and increasing antioxidant synthesis ( Ji et al, 2019 ; Yi R. et al, 2020 ; Lyu et al, 2020 ). A growing number of evidences have revealed that metabolic intermediates are involved in many physical and pathological processes, including the regulation of inflammatory response, oxidative stress, and cancers.…”

MicroRNA‐7 deficiency ameliorates d‐galactose‐induced aging in mice by regulating senescence of Kupffer cells

“…To further investigate the mechanisms through which miR‐7 regulates IL‐1β production in senescent Kupffer cells, we utilized TargetScan databases ( https://www.targetscan.org/ ) and combined them with existing studies, to identify five potential target genes ATG7 (Guo et al., 2022 ), SIRT1 (Maeso‐Díaz et al., 2018 ), KLF4 (Ji et al., 2019 ), YY1 (Tang et al., 2020 ), and FoxO6 (Kim et al., 2019 ) of miR‐7 that are associated with liver tissue aging (Figure 5a ). We then examined the expression of these potential target genes in Kupffer cells from D‐miR‐7 def mice and found that KLF4 showed the most significant enrichment among the five genes in Kupffer cells (Figure 5b ).…”

<p>Downregulation of miR-7-5p Inhibits the Tumorigenesis of Esophagus Cancer via Targeting KLF4</p>

“…Kruppel-like factor 4 (KLF4) is an important factor that mediates genes participated in cell growth, differentiation, and metastasis. 26,27 Additionally, overexpression of KLF4 has been studied in multiple malignant tumors and has been found to regulate various biological functions, including cell proliferation, survival and metastasis. 11,28,29 We have indicated that KLF4 was a downstream target of miR-7-5p.…”