Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis.
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ABSTRACT:
SUBMITTER: Inokuchi S
PROVIDER: S-EPMC2818947 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background & aimsTransforming growth factor (TGF)-β-activated kinase 1 (TAK1) is activated in different cytokine signaling pathways. Deletion of Tak1 from hepatocytes results in spontaneous development of hepatocellular carcinoma (HCC), liver inflammation, and fibrosis. TGF-β activates TAK1 and Smad signaling, which regulate cell death, proliferation, and carcinogenesis. However, it is not clear whether TGF-β signaling in hepatocytes, via TGF-β receptor-2 (Tgfbr2), promotes HCC and liver fibrosis.MethodsWe generated mice with hepatocyte-specific deletion of Tak1 (Tak1ΔHep), as well as Tak1/Tgfbr2DHep and Tak1/Smad4ΔHep mice. Tak1flox/flox, Tgfbr2ΔHep, and Smad4ΔHep mice were used as controls, respectively. We assessed development of liver injury, inflammation, fibrosis, and HCC. Primary hepatocytes isolated from these mice were used to assess TGF-β-mediated signaling.ResultsLevels of TGF-β, TGF-βR2, and phospho-Smad2/3 were increased in HCCs from Tak1ΔHep mice, which developed liver fibrosis and inflammation by 1 month and HCC by 9 months. However, Tak1/Tgfbr2ΔHep mice did not have this phenotype, and their hepatocytes did not undergo spontaneous cell death or compensatory proliferation. Hepatocytes from Tak1ΔHep mice incubated with TGF-β did not activate p38, c-Jun N-terminal kinase, or nuclear factor-κB; conversely, TGF-β-mediated cell death and phosphorylation of Smad2/3 were increased, compared with control hepatocytes. Blocking the Smad pathway inhibited TGF-β-mediated death of Tak1-/- hepatocytes. Accordingly, disruption of Smad4 reduced the spontaneous liver injury, inflammation, fibrosis, and HCC that develops in Tak1ΔHep mice. Levels of the anti-apoptotic protein Bcl-xL, β-catenin, connective tissue growth factor, and vascular endothelial growth factor were increased in HCC from Tak1ΔHep mice, but not in HCCs from Tak1/Tgfbr2ΔHep mice. Injection of N-nitrosodiethylamine induced HCC formation in wild-type mice, but less in Tgfbr2ΔHep mice.ConclusionsTGF-β promotes development of HCC in Tak1ΔHep mice by inducing hepatocyte apoptosis and compensatory proliferation during early phases of tumorigenesis, and inducing expression of anti-apoptotic, pro-oncogenic, and angiogenic factors during tumor progression.
| S-EPMC3752402 | biostudies-literature
Project description:Chronic inflammation is considered as an important pathophysiologic mechanism of hepatic cirrhosis, which induces hepatocyte injury and activates hepatic stellate cells (HSCs), thus resulting in hepatic fibrosis. Previous studies have reported that cyclooxygenase-2 (COX-2) inhibitor can effectively treat liver fibrosis, while somatostatin (SST) analogues inhibit the activation of HSCs. The present study aimed to investigate the effects of a COX-2 inhibitor, celecoxib, combined with a SST analogue, octreotide, for protection of hepatocytes and prevention of fibrosis in a rat model of hepatic fibrosis. Therefore, a hepatic fibrosis rat model was established following peritoneal injection of thioacetamide (TAA), and the rats were then treated with a combination of celecoxib and octreotide (TAA + C). Immunohistochemistry and western blotting assays were used to assess the expression levels of proteins associated with inflammation, epithelial-mesenchymal transition (EMT), proliferation, apoptosis and autophagy. H&E staining, transmission electron microscopy and scanning electron microscopy were used to evaluate the destruction of hepatocytes. Masson's Trichrome and Sirius Red were used to measure the degree of liver fibrosis. The results demonstrated that, compared with those of the control group, the degree of liver fibrosis and the expression of the intrahepatic inflammation factors were aggravated in the TAA group. Furthermore, the apoptosis rate, EMT and autophagy of hepatocytes were also increased in the TAA group. However, treatment with TAA + C restored the aforementioned increased levels compared with the TAA group. In conclusion, treatment of rats with the combination of celecoxib and octreotide could attenuate the progress of hepatic fibrosis via protection of hepatocytes by reducing apoptosis, EMT and autophagy in hepatocytes.
| S-EPMC8422404 | biostudies-literature
Project description:Cullin 3 (CUL3) is part of the ubiquitin proteasomal system and controls several cellular processes critical for normal organ function including the cell cycle, and Keap1/Nrf2 signaling. Kidney tubule-specific Cul3 disruption causes tubulointerstitial fibrosis, but little is known about the mechanisms. Therefore, we tested the hypothesis that dysregulation of the cell cycle and Keap1/Nrf2 pathway play a role in initiating the kidney injury upon Cul3 disruption. Cul3 deletion increased expression of cyclin E and p21, associated with uncontrolled proliferation, DNA damage, and apoptosis, all of which preceded proximal tubule injury. The cdk2-cyclin E inhibitor roscovitine did not prevent the effects of Cul3 deletion, but instead exacerbated the kidney injury. Injury occurred despite accumulation and activation of CUL3 substrate Keap1/Nrf2, proposed to be protective in kidney injury. Cul3 disruption led to progressive interstitial inflammation, functionally relevant renal fibrosis and death. Finally, we observed reduced CUL3 expression in several AKI and CKD mouse models and in fibrotic human kidney tissue. These data establish CUL3 knockout mice as a novel genetic CKD model in which dysregulation of the cell cycle may play a primary role in initiating tubule injury, and that CUL3 dysregulation could contribute to acute and fibrotic kidney disease.
| S-EPMC6418206 | biostudies-literature
Project description:Toll-like receptor 4 (TLR4) signaling plays a key role in liver inflammation and fibrosis. The therapeutic effects of eritoran, a TLR4 antagonist, in mice with chronic liver injury remained unclear. C57BL/6 mice were fed a fast-food diet (FFD) or treated with carbon tetrachloride (CCl4) to induce chronic liver injury. Eritoran (10 mg/kg) or a vehicle was randomly intraperitoneally administered to the FFD-fed mice and the CCl4-injured mice. Primary mouse liver cells were cultured with lipopolysaccharide (LPS) or eritoran. In both FFD and CCl4 mouse models, eritoran significantly reduced serum ALT levels and decreased hepatic inflammatory cell infiltration without altering hepatic steatosis. Additionally, eritoran attenuated liver fibrosis by decreasing hepatic stellate cells (HSCs) activation and the abundance of α-smooth muscle actin and transforming growth factor-β1. Hepatic TLR4 downstream signaling including MyD88 expression, NF-κB p65 nuclear translocation, p38 and JNK phosphorylation were successfully inhibited by eritoran. In the in vitro study, LPS-induced nuclear translocation of NF-κB in primary HSCs and Kupffer cells was significantly suppressed by eritoran. In conclusion, eritoran attenuated hepatic inflammation and fibrosis by inhibition of the TLR4 signaling pathway in mice with chronic liver injury. Eritoran may serve as a potential drug for chronic liver disease.
| S-EPMC8235164 | biostudies-literature
Project description:Pneumoconiosis, caused by inhalation of mineral dusts, is a major occupational disease worldwide. Currently, there are no effective drugs owing to a lack of potential therapeutic targets during either the inflammation or fibrosis molecular events in pneumoconiosis. Here, we performed microarrays to identify aberrantly expressed genes in the above molecular events in vitro and found a hub gene transforming growth factor-β-activated kinase 1 (TAK1), which was highly expressed and activated in pneumoconiosis patients as well as silica-exposed rats with experimental pneumoconiosis. Genetic modulation of TAK1 by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9, RNA interference and overexpression indicated the important role of TAK1 in both inflammation and fibrosis in experimental pneumoconiosis. To achieve pharmacological TAK1 inhibition, we virtually screened out a natural product resveratrol, which targeted TAK1 at both N161 and A107 residues, and significantly inhibited TAK1 activation to attenuate inflammation and fibrosis in vitro. Consistently, in vivo prevention and intervention studies showed that resveratrol could inhibit pulmonary inflammation and fibrosis in silica-exposed rats.
| S-EPMC5504492 | biostudies-literature
Project description:Background & aimsRapid induction of β-PDGF receptor (β-PDGFR) is a core feature of hepatic stellate cell activation, but its cellular impact in vivo is not well characterized. We explored the contribution of β-PDGFR-mediated pathway activation to hepatic stellate cell responses in liver injury, fibrogenesis, and carcinogenesis in vivo using genetic models with divergent β-PDGFR activity, and assessed its prognostic implications in human cirrhosis.MethodsThe impact of either loss or constitutive activation of β-PDGFR in stellate cells on fibrosis was assessed following carbon tetrachloride (CCl4) or bile duct ligation. Hepatocarcinogenesis in fibrotic liver was tracked after a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed from isolated stellate cells that expressed or lacked β-PDGFR to determine deregulated pathways and evaluate their association with prognostic gene signatures in human cirrhosis.ResultsDepletion of β-PDGFR in hepatic stellate cells decreased injury and fibrosis in vivo, while its auto-activation accelerated fibrosis. However, there was no difference in development of DEN-induced pre-neoplastic foci. Genomic profiling revealed ERK, AKT, and NF-κB pathways and a subset of a previously identified 186-gene prognostic signature in hepatitis C virus (HCV)-related cirrhosis as downstream of β-PDGFR in stellate cells. In the human cohort, the β-PDGFR signature was not associated with HCC development, but was significantly associated with a poorer outcome in HCV cirrhosis.Conclusionsβ-PDGFR is a key mediator of hepatic injury and fibrogenesis in vivo and contributes to the poor prognosis of human cirrhosis, but not by increasing HCC development.
| S-EPMC4475471 | biostudies-literature
Project description:Ubiquitin-specific peptidase 10 (USP10) protein is a deubiquitination enzyme involved in many important biological processes. However, the function of USP10 in hepatic ischaemic/reperfusion (I/R) injury remains unknown. The aim of this study was to explore the role of USP10 in hepatic I/R injury. USP10 Heterozygote mice and primary hepatocytes were used to construct hepatic I/R models. The effect of USP10 on hepatic I/R injury was examined via pathological and molecular analyses. Our results indicated that USP10 was significantly downregulated in the livers of mice after hepatic I/R injury and in hepatocytes subjected to hypoxia/reoxygenation stimulation. USP10 Heterozygote mice exhibited exacerbated hepatic I/R injury, as evidenced by enhanced liver inflammation via the NF-κB signalling pathway and increased hepatocyte apoptosis. Additionally, USP10 overexpression inhibited hepatocyte inflammation and apoptosis in hepatic I/R injury in vitro and in vivo. Mechanistically, our study demonstrated that USP10 knockdown exerted its detrimental effects on hepatic I/R injury by inducing activation of the transforming growth factor β-activated kinase 1 (TAK1)-JNK/p38 signalling pathways. TAK1 was required for USP10 function in hepatic I/R injury as TAK1 inhibition abolished USP10 function in vitro. In conclusion, our study demonstrated that USP10 plays a protective role in hepatic I/R injury by inhibiting the activation of the TAK1-JNK/p38 signalling pathways. Modulation of USP10/TAK1 might be a promising strategy to prevent this pathological process.
| S-EPMC7550542 | biostudies-literature
Project description:Insulin controls glucose uptake into adipose and muscle cells by regulating the amount of GLUT4 in the plasma membrane. The effect of insulin is to promote the translocation of intracellular GLUT4 to the plasma membrane. The small Rab GTPase, Rab10, is required for insulin-stimulated GLUT4 translocation in cultured 3T3-L1 adipocytes. Here we demonstrate that both insulin-stimulated glucose uptake and GLUT4 translocation to the plasma membrane are reduced by about half in adipocytes from adipose-specific Rab10 knockout (KO) mice. These data demonstrate that the full effect of insulin on adipose glucose uptake is the integrated effect of Rab10-dependent and Rab10-independent pathways, establishing a divergence in insulin signal transduction to the regulation of GLUT4 trafficking. In adipose-specific Rab10 KO female mice, the partial inhibition of stimulated glucose uptake in adipocytes induces insulin resistance independent of diet challenge. During euglycemic-hyperinsulinemic clamp, there is no suppression of hepatic glucose production despite normal insulin suppression of plasma free fatty acids. The impact of incomplete disruption of stimulated adipocyte GLUT4 translocation on whole-body glucose homeostasis is driven by a near complete failure of insulin to suppress hepatic glucose production rather than a significant inhibition in muscle glucose uptake. These data underscore the physiological significance of the precise control of insulin-regulated trafficking in adipocytes.
| S-EPMC4878419 | biostudies-literature
Project description:Functions of transforming growth factor-? (TGF-?) in the liver vary depending on specific cell types and their temporal response to TGF-? during different stages of hepatocarcinogenesis (HCG). Through analysis of tumor tissues from hepatocellular carcinoma (HCC) patients, we were able to cluster hepatic epithelial cell-derived TGF-? gene signatures in association with distinct clinical prognoses. To delineate the role of hepatic epithelial TGF-? signaling in HCC development, we used an experimental system in which tumor-initiating hepatocytes (TICs) were isolated from TGF-? receptor II floxed mice (Tgfbr2fl/fl ) and transplanted into syngeneic C57BL/6J mice by splenic injection. Recipient mice were then administered Cre-expressing adenovirus (Ad-Cre) to inactivate Tgfbr2 in transplanted TICs. After latency, Tgfbr2-inactivated TICs formed larger and more tumor nodules in recipient livers compared to TICs without Tgfbr2 inactivation. In vitro analyses revealed that treatment of cultured TICs with TGF-? inhibited expression of progenitor cell factors (including SRY (sex determining region Y)-box 2 [Sox2]). RNA sequencing (RNA-seq) analysis identified H19 as one of the most up-regulated long noncoding RNA (lncRNA) in association with Tgfbr2 inactivation in TICs. Tgfbr2 inactivation by Ad-Cre led to a 5-fold increase of H19 expression in TICs. Accordingly, TGF-? treatment reduced H19 expression. We observed that forced overexpression of Sox2 in TICs increased transcription of H19, whereas knockdown of Sox2 decreased it. Furthermore, depletion of H19 reduced the progenitor property of TICs in vitro and decreased their tumorigenic potential in vivo. Finally, we observed a low level of H19 mRNA expression in human HCC tissues from patients with the epithelial TGF-? gene signature in association with favorable prognosis. Conclusion: Our findings describe a TGF-? and H19 signaling axis by Sox2 in TICs that importantly regulates HCG.
| S-EPMC6335184 | biostudies-literature
Project description:Autoimmune hepatitis (AIH) is a chronic liver disease due to autoimmune system attacks hepatocytes and causes inflammation and fibrosis. Intracellular signalling and miRNA may play an important role in regulation of liver injury. This study aimed to investigate the potential roles of microRNA 143 in a murine AIH model and a hepatocyte injury model. Murine AIH model was induced by hepatic antigen S100, and hepatocyte injury model was induced by LPS. Mice and AML12 cells were separated into six groups with or without the treatment of miRNA-143. Inflammation and fibrosis as well as gene expression were examined by different cellular and molecular techniques. The model was successfully established with the elevation of ALT and AST as well as inflammatory and fibrotic markers. Infection or transfection of mir-143 in mice or hepatocytes significantly attenuated the development of alleviation of hepatocyte injury. Moreover, the study demonstrated phosphorylation of TAK1-mediated miRNA-143 regulation of hepatic inflammation and fibrosis as well as hepatocyte injury. Our studies demonstrated a significant role of miRNA-143 in attenuation of liver injury in AIH mice and hepatocytes. miRNA-143 regulates inflammation and fibrosis through its regulation of TAK1 phosphorylation, which warrants TAK1 as a target for the development of new therapeutic strategy of autoimmune hepatitis.
| S-EPMC6991639 | biostudies-literature