Hepatocyte KLF6 expression affects FXR signalling and the clinical course of primary sclerosing cholangitis

Sydor, Svenja; Manka, Paul; Buren, Lea Van; Theurer, Sarah; Schwertheim, Suzan; Best, Jan; Heegsma, Janette; Saeed, Ali; Vetter, Diana; Schlattjan, Martin; Dittrich, Anna; Fiel, M. Isabel; Baba, Hideo A.; Dechêne, Alexander; Cubero, Francisco Javier; Gerken, Guido; Canbay, Ali; Moshage, Han; Friedman, Scott L.; Faber, Klaas Nico; Bechmann, Lars P.

doi:10.1111/liv.14542

Cited by 5 publications

(2 citation statements)

References 49 publications

(55 reference statements)

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“…On the contrary, when FXR is reduced, tumor growth may continue. Therefore, we found that the expression of FXR in tumor cells of hilar cholangiocarcinoma was significantly lower than that in normal tissues 14 . Second, it controls the excretion and reabsorption of bile acids by regulating the target gene of bile salt export pump (BSEP, regulation of bile acid secretion) and sodium taurocholate transporter (NTCP, regulation of bile acid reabsorption), so as to maintain the stability of bile acid concentration 15 , avoid excessive accumulation of bile acids in the bile duct, lead to the occurrence of stones and cholangitis, cause repeated destruction and proliferation of bile duct cells, the emergence of heterogenous cells, and promote the further development of tumors.…”

Section: Discussionmentioning

confidence: 77%

Effect of FXR agonist GW4064 in the treatment of hilar cholangiocarcinoma in rats

Wang

Zhang

Luo

et al. 2022

Sci Rep

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The study objective was to observe the treatment effect of the farnesoid X receptor (FXR) agonist GW4064 in a rat model of hilar cholangiocarcinoma to explore a new therapeutic target for gene therapy for hilar cholangiocarcinoma. Eighty male Wistar rats were randomly divided into four groups (treatment group, model group, control group and sham operation group, 20 rats in each group). The four groups were fed a standard diet. The treatment group and the model group were injected with a suspension of cholangiocarcinoma QBC939 cells into the hilar bile duct with a microsyringe, the control group was injected with normal saline, and the sham operation group was not injected with anything. A modified tail suspension test (TST) was used to evaluate the vitality of the rats. At 4 weeks, one rat in the treatment group and model group was euthanized, and the changes in the hilar bile duct were recorded. The procedure was repeated at 6 weeks. After 6 weeks, hilar cholangiocarcinoma occurred in the treatment group and model group. Then, the treatment group was injected with GW4064 intraperitoneally at a dose of 50 mg/kg/day. One week after injection, the rats in the four groups were euthanized. Pathological examination confirmed that tumours had formed, and hilar bile duct tissues were taken from the four groups. FXR, Bsep, Ntcp and NF-κB expression in the hilar bile duct was detected by real-time polymerase chain reaction (RT–PCR) and immunohistochemistry. After three weeks, the rats in the treatment group and model group ate less, and their weight was significantly reduced. Six weeks later, hilar cholangiocarcinoma was detected in the treatment group and model group. After treatment with GW4064, the ratios of FXR/GAPDH mRNA, Bsep/GAPDH mRNA, Ntcp/GAPDH mRNA and NF-κBp65/GAPDH mRNA were significantly different among the four groups. Under a light microscope, FXR protein reacted with anti-FXR antibody, Bsep protein reacted with anti-Bsep antibody, Ntcp protein reacted with anti-Ntcp antibody and NF-κBp65 protein reacted with anti-NF-κBp65 antibody, and they showed granular expression. Every pathological section included 4,800 cells, and there were different numbers of positive cells in each group. FXR expression in the hilar cholangiocarcinoma of rats was significantly lower than that in normal hilar bile duct tissues. GW4064 increased the expression of FXR in tumour tissues. These findings suggest that FXR may be a new therapeutic target and that GW4064 may be helpful in the treatment of hilar cholangiocarcinoma.

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Section: Discussionmentioning

confidence: 77%

Effect of FXR agonist GW4064 in the treatment of hilar cholangiocarcinoma in rats

Wang

Zhang

Luo

et al. 2022

Sci Rep

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“…A previous study demonstrated that higher hepatic KLF6 expression is associated with a better prognosis in primary sclerosing cholangitis, which is a chronic liver disease, and KLF6 regulates FXR signaling by binding to FXREs ( 42 ). KLF6 can also affect lipid metabolism and activate the mTOR signaling pathway, thereby promoting the progression of renal clear cell carcinoma ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

miRNA‑21 promotes the progression of acute liver failure via the KLF6/autophagy/IL‑23 signaling pathway

Bao,

Zheng,

Yan

et al. 2024

Mol Med Rep

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Acute liver failure (ALF) is a complex syndrome characterized by overactivation of innate immunity, and the recruitment and differentiation of immune cells at inflammatory sites. The present study aimed to explore the role of microRNA (miRNA/miR)-21 and its potential mechanisms underlying inflammatory responses in ALF. Baseline serum miR-21 was analyzed in patients with ALF and healthy controls. In addition, miR-21 antagomir was injected via the tail vein into C57BL/6 mice, and lipopolysaccharide/D-galactosamine (LPS/GalN) was injected into mice after 48 h. The expression levels of miR-21, Krüppel-like-factor-6 (KLF6), autophagy-related proteins and interleukin (IL)-23, and hepatic pathology were then assessed in the liver tissue. Furthermore, THP-1-derived macrophages were transfected with a miRNA negative control, miR-21 inhibitor, miR-21 mimics or KLF6 overexpression plasmid, followed by treatment with or without rapamycin, and the expression levels of miR-21, KLF6, autophagy-related proteins and IL-23 were evaluated. The results revealed that baseline serum miR-21 levels were significantly upregulated in patients with ALF. In addition, LPS/GalN-induced ALF was attenuated in the antagomir-21 mouse group. KLF6 was identified as a target of miR-21-5p with one putative seed match site identified by TargetScan. A subsequent luciferase activity assay demonstrated a direct interaction between miR-21-5p and the 3′-UTR of KLF6 mRNA. Further experiments suggested that miR-21 promoted the expression of IL-23 via inhibiting KLF6, which regulated autophagy. In conclusion, in the present study, baseline serum miR-21 levels were highly upregulated in patients with ALF, antagomir-21 attenuated LPS/GalN-induced ALF in a mouse model, and miR-21 could promote the expression of IL-23 via inhibiting KLF6.

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Dietary chromium chemical species mitigate inflammation and cholestasis in primary sclerosing cholangitis via regulating bile acid metabolism

Shen,

Jiang,

Hao

et al. 2024

Food Bioscience

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Hepatocyte KLF6 expression affects FXR signalling and the clinical course of primary sclerosing cholangitis

Cited by 5 publications

References 49 publications

Effect of FXR agonist GW4064 in the treatment of hilar cholangiocarcinoma in rats

Effect of FXR agonist GW4064 in the treatment of hilar cholangiocarcinoma in rats

miRNA‑21 promotes the progression of acute liver failure via the KLF6/autophagy/IL‑23 signaling pathway

Dietary chromium chemical species mitigate inflammation and cholestasis in primary sclerosing cholangitis via regulating bile acid metabolism

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