Pathophysiological role of hepatocyte nuclear factor 6 (HNF6) during cholestatic liver injury
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE80498 | GEO | 2016/10/06
SECONDARY ACCESSION(S): PRJNA319055
REPOSITORIES: GEO
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Project description:Background and aims: Signal transducer and activator of transcription 3 (Stat3) is the main mediator of interleukin-6 type cytokine signaling required for hepatocyte proliferation and hepatoprotection but its role in sclerosing cholangitis and other cholestatic liver diseases remains unresolved. Methods: We investigated the role of Stat3 in inflammation-induced cholestatic liver injury and used mice lacking the multidrug resistance gene 2 (mdr2-/-) as a model for SC. Results: We demonstrate that conditional inactivation of stat3 in hepatocytes and cholangiocytes (stat3 delta hc) of mdr2-/- mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2-/- mice lacking IL-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both, hepatocytes and cholangiocytes. Loss of Stat3 in cholangiocytes led to increased expression of TNFα which might reduce the barrier function of bile ducts. Loss of Stat3 in hepatocytes led to upregulation of bile acid biosynthesis genes and downregulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3deltahc mice were more sensitive to cholic acid-induced liver damage than control mice. Conclusions: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes. Affymetrix microarray analyses was performed to identify metabolic and molecular pathways in stat3Dhc mdr2-/- mice that lead to cholestasis and bile acid-induced liver injury. To avoid false positive results that are due to differential cellular composition, we defined the onset of fibrosis and expression of fibrogenic factors in stat3Dhc mdr2-/- mice.
2010-10-20 | E-GEOD-18759 | biostudies-arrayexpress
Project description:Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type (WT) and PAI-1-deficient (PAI-1-/-) mice after BDL. PAI-1-/- mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1-/- mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than WT mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases. Total RNA isolated using TRI Reagent (Sigma, St. Louis, MO) was purified with an RNeasy mini kit (Qiagen, Valencia, CA). Twenty micrograms cRNA was hybridized to a mouse GeneChip (U74Av2, Affymetrix, Santa Clara, CA) at the Siteman Cancer Center GeneChip facility as described by the manufacturer. Analyses used one mouse per chip. Gene expression changes were analyzed using Affymetrix MicroArray Suite 4.0 and GeneChip 3.1 Expression Analysis and Statistical Algorithms (Affymetrix). The complete methodology and full data sets for all 6 analyzed chips are available at http://bioinformatics.wustl.edu.beckerproxy.wustl.edu This study compares the injury and repair processed in wild-type mice after BDL.
2011-06-09 | E-GEOD-29776 | biostudies-arrayexpress
Project description:Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type (WT) and PAI-1-deficient (PAI-1-/-) mice after BDL. PAI-1-/- mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1-/- mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than WT mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases.
2011-06-09 | GSE29776 | GEO
Project description:The liver is the central organ critically regulating the balance of the metabolically potent yet toxic bile acids in the body. While genomic association studies have pointed to hepatic Sel1L – a critical component of mammalian Hrd1 ER-associated degradation (ERAD) machinery – as an influencer of serum bile acid levels, physiological relevance and mechanistic insights of ERAD in bile homeostasis remain unexplored. Using hepatocyte-specific Sel1L-deficient mouse models, we report that hepatic Sel1L-Hrd1 ERAD critically manages bile homeostasis in the body. Mice with hepatocyte-specific Sel1L developed intrahepatic cholestasis, with significant overload of bile acids in the liver and circulation under basal condition, and were hypersensitive to dietary bile acid challenge. By contrast, biliary bile acid and phosphatidylcholine levels were reduced, pointing to an export defect from hepatocytes. Unbiased proteomics analysis followed by biochemical assays revealed significant accumulation of the bile-stabilizing phosphatidylcholine exporter ATP-binding cassette 4 (Abcb4) in the ER of Sel1L-deficient livers, a gene associated with Progressive Familial Intrahepatic Cholestasis type III. Indeed, Abcb4 was a substrate of Sel1L-Hrd1 ERAD. Hence, hepatic Sel1L-Hrd1 ERAD maintains bile equilibrium via quality control of Abcb4 maturation in the ER.
2023-03-11 | PXD035243 | Pride
Project description:Growth hormone (GH) resistance has been associated with liver cirrhosis in humans but its contribution to the disease remains controversial. In order to elucidate whether GH resistance plays a causal role in the establishment and development of liver fibrosis, or rather represents a major consequence thereof, we challenged mice lacking the Growth hormone receptor gene (Ghr-/-, a model for GH resistance) by crossing them with Mdr2 knockout mice (Mdr2-/-), a mouse model of inflammatory cholestasis and liver fibrosis. Ghr-/-;Mdr2-/- mice showed elevated serum markers associated with liver damage and cholestasis, extensive bile duct proliferation and increased collagen deposition relative to Mdr2 -/- mice, thus suggesting a more severe liver fibrosis phenotype. Additionally, Ghr-/-;Mdr2-/- mice had a pronounced down-regulation of hepato-protective genes Hnf6, Egfr and Igf-1, and significantly increased levels of ROS and apoptosis in hepatocytes, compared to control mice. Moreover, single knockout mice (Ghr-/-) fed with a diet containing 1% cholic acid displayed an increase in hepatocyte ROS production, hepatocyte apoptosis and bile infarcts compared to their wildtype littermates, indicating that loss of Ghr renders hepatocytes more susceptible to toxic bile acid accumulation. Surprisingly, and despite their severe fibrotic phenotype, Ghr-/-;Mdr2-/- mice displayed a significant decrease in tumour incidence compared to Mdr2-/- mice, indicating that loss of Ghr signaling may slow the progression from fibrosis/cirrhosis to cancer in the liver.
2020-06-20 | GSE58908 | GEO
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Project description:Hepatic fibrosis is a wound-healing response to chronic liver injury, which may result in cirrhosis and liver failure. The c-Jun N-terminal kinase-1 (JNK1) gene has been shown to be involved in liver fibrosis. Here, we aimed to investigate the molecular mechanism and identify the cell-type involved in mediating the JNK1-dependent effect on liver fibrogenesis Wild-type (WT), JNK1−/− and JNK1Δhepa (hepatocyte-specific deletion of JNK1) mice were subjected to bile duct ligation (BDL). Additionally, we performed bone marrow transplantations (BMT), isolated primary hepatic stellate cells (HSCs) and studied their activation in vitro. Serum markers of liver damage (liver transaminases, alkaline phosphatase and bilirubin) and liver histology revealed reduced injury in JNK1−/− compared to WT and JNK1Δhepa mice. Hepatocyte cell death and proliferation was reduced in JNK1−/− compared to WT and JNK1Δhepa. Parameters of liver fibrosis such as Sirius Red staining as well as Collagen IA1 and αSMA expression were down-regulated in JNK1−/− compared to WT and JNK1Δhepa livers, 4 weeks after BDL. To delineate the essential cell-type, we performed BMT of WT and JNK1-/- into JNK1-/- and WT mice, respectively. BMT experiments excluded bone marrow derived cells from having a major impact on the JNK1-dependent effect on fibrogenesis. Hence, we investigated primary HSCs from JNK1−/− livers showing reduced transdifferentiation compared with WT and JNK1Δhepa-derived HSCs. We conclude that JNK1 in HSCs plays a crucial role in hepatic fibrogenesis and thus represents a promising target for cell-directed treatment options for liver fibrosis. Control (JNK1f/f), JNK1 null (JNK1-/-) and hepatocyte-specific JNK1 null (JNK1Δhepa) mice were subjected to control, acute and chronic injury, i.e. sham or bile-duct ligation for 48h or 28 days resp., whereafter gene expression profiles were determined.
2013-11-27 | E-GEOD-40041 | biostudies-arrayexpress
Project description:Cholestasis is characterized by hepatic accumulation of cytotoxic bile acids (BAs), which often subsequentlyleads to liver injury, inflammation, fibrosis, and ultimately liver cirrhosis. Fibroblast growth factor 21 (FGF21) is a liver secreted hormone with pleiotropic effects on the homeostasis of glucose, lipid, and energy metabolism. However, whether hepatic FGF21 plays a role in cholestatic liver injury remains elusive. We found that serum and hepatic FGF21 levels were significantly increased in response to cholestatic liver injury. Hepatocyte-specific deletion of Fgf21 exacerbated hepatic accumulation of BAs, further accentuating liver injury. Consistently, administration of rFGF21 ameliorated cholestatic liver injury in α-naphthylisothiocyanate (ANIT)-treated and Mdr2 deficiency mice. Mechanically, FGF21 activated a hepatic FGFR4-JNK signaling pathway to decrease Cyp7a1 expression, thereby reducing hepatic BAs pool. Our study demonstrates that hepatic FGF21 functions as an adaptive stress-responsive signal to downregulate BA biosynthesis, thereby ameliorating cholestatic liver injury, and FGF21 analogs may represent a candidate therapy for cholestatic liver diseases.
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Project description:Hepatic fibrosis, the wound-healing response to repeated liver injury, ultimately leads to cirrhosis. There is an urgent need to develop effective antifibrotic therapies. Ghrelin (encoded by Ghrl) is an orexigenic hormone that has pleiotrophic functions including protection against cell death1. Here we investigate whether ghrelin modulates liver fibrosis and protects from acute liver injury. Recombinant ghrelin reduced the fibrogenic response to prolonged bile duct ligation in rats. This effect was associated with decreased liver injury and myofibroblast accumulation as well as attenuation of the altered gene expression profile. Ghrelin also reduced fibrogenic properties in cultured hepatic stellate cells. Moreover, Ghrl-/- mice developed exacerbated hepatic fibrosis and liver damage after chronic injury. Ghrelin also protected rat livers from acute liver injury and reduced the extent of oxidative stress and the inflammatory response. In patients with chronic liver diseases, ghrelin serum levels decreased in those with advanced fibrosis and hepatic expression of the ghrelin gene correlated with expression of fibrogenic genes. Finally, in patients with chronic hepatitis C, single nucleotide polymorphisms of the ghrelin gene (-994CT and â604GA) influenced the progression of liver fibrosis. We conclude that ghrelin exerts antifibrotic effects on the liver and may represent a novel antifibrotic therapy. Experiment Overall Design: Rats were divided into three groups: control rats receiving saline (sham operation), rats with bile duct ligation receiving saline and rats with bile duct ligation receiving recombinant ghrelin (10 micrograms/Kg/day by a subcutaneous osmotic mimi-pump). For the microarray analysis samples from 6 rats were analyzed except for the ghrelin-treated group (5 rats).
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