Hepatic growth hormone - JAK2 - STAT5 signalling: Metabolic function, non-alcoholic fatty liver disease and hepatocellular carcinoma progression

Kaltenecker, Doris; Themanns, Madeleine; Mueller, Kristina M.; Spirk, Katrin; Suske, Tobias; Merkel, Olaf; Kenner, Lukas; Luís, Ana Teresa; Kozlov, Andrey V.; Haybaeck, Johannes; Müller, Mathias; Han, Xiaonan; Moriggl, Richard

doi:10.1016/j.cyto.2018.10.010

Cited by 54 publications

(53 citation statements)

References 178 publications

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“…Our study corroborates with previous findings that inhibition of the JAK2 pathway using the highly selective JAK2 antagonist inhibits the activation and contractility of hepatic myofibroblasts. We also showed that the effects are mediated via the STAT5 signaling pathway, which corroborated with the previous findings (23).…”

Section: Discussionsupporting

confidence: 92%

TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo

et al. 2019

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Hepatic fibrosis, characterized by an excessive extracellular matrix (ECM) accumulation, leading to scar‐tissue formation is a growing health problem worldwide. Hepatocellular damage due to liver injury triggers inflammation and transdifferentiation of quiescent hepatic stellate cells (HSCs) into proliferative, contractile, and ECM‐producing myofibroblasts. Involvement of the Janus kinase (JAK)‐2 pathway in the pathogenesis of fibrosis has been reported earlier. However, in this study, we have investigated the effect of selective JAK2 antagonist TG101348 in fibroblasts and inflammatory macrophages and in vivo in an acute carbon tetrachloride–induced liver injury mouse model. In vitro, TG101348 significantly inhibited TGF‐β‐induced collagen I expression in murine 3T3 fibroblasts. In human HSCs (LX2 cells), TG101348 potently attenuated TGF‐β‐induced contractility and the protein and gene expression of major fibrotic parameters (collagen I, vimentin, and α‐smooth muscle actin). In LPS‐ and IFN‐γ‐stimulated inflammatory macrophages, TG101348 significantly reduced the NO release and strongly inhibited the expression of inflammatory markers (inducible nitric oxide synthase, C‐C motif chemokine ligand 2, IL‐1β, IL‐6, and C‐C chemokine receptor type 2). In vivo in an acute liver injury mouse model, TG101348 significantly attenuated collagen accumulation and HSC activation. Interestingly, TG101348 drastically inhibited macrophage infiltration and intrahepatic inflammation. Pharmacological inhibition of the JAK2 signaling pathway in activated HSCs and inflammatory macrophages using TG101348 suggests a potential therapeutic approach for the treatment of liver fibrosis.—Akcora, B. O., Dathathri, E., Ortiz‐Perez, A., Gabriël, A. V., Storm, G., Prakash, J., Bansal, R. TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo. FASEB J. 33, 9466–9475 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 92%

TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo

et al. 2019

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“…SOCS2 along with other members of SOCS family are regarded as importantly negative regulator of the JAK/STAT pathway 33 . Although STAT3 signaling might be more important than STAT5 in HCC progression and miR-196b could activate STAT3 by targeting SOCS2 in macrophages 34,35 , previous work showed that importance of JAK2/STAT5 signaling in liver metabolism, liver diseases, and HCC 36 . Hence, we…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-196a/-196b regulate the progression of hepatocellular carcinoma through modulating the JAK/STAT pathway via targeting SOCS2

Ren

et al. 2019

Cell Death Dis

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microRNAs (miRNAs) play essential roles in progression of hepatocellular carcinoma (HCC). However, the roles of miR-196a and miR-196b as well as mechanism in HCC progression remain poorly understood. The expressions of miR-196a, miR-196b and suppressor of cytokine signaling 2 (SOCS2) were measured in HCC tissues and cells by quantitative realtime polymerase chain reaction or immunohistochemistry. HCC progression was investigated by cell proliferation, glycolysis, cycle, clones, apoptosis, and necrosis. The interaction between SOCS2 and miR-196a or miR-196b was explored by luciferase activity and RNA immunoprecipitation analyses. The expressions of proteins in Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway were measured by western blot. A xenograft model was established to investigate the roles of miR-196a or miR-196b in vivo. We found that miR-196a and miR-196b were highly expressed in HCC tissues and cells. High expression of miR-196a or miR-196b was correlated with tumor size, tumor-node-metastasis stage, lymph node metastasis, albumin-bilirubin grade and poor 5-year survival. Knockdown of miR-196a or miR-196b suppressed cell proliferation, glycolysis, cell cycle process, colony formation but induced apoptosis or necrosis in HCC cells. SOCS2 was targeted by miR-196a and miR-196b and its interference ablated abrogation of miR-196a or miR-196b-mediated inhibitory effect on HCC progression. SOCS2 was negatively associated with activation of the JAK/STAT pathway. Besides, knockdown of miR-196a or miR-196b limited xenograft tumor growth by blocking the JAK/STAT pathway. We concluded that downregulation of miR-196a or miR-196b inhibited HCC progression through regulating the JAK/STAT pathway via targeting SOCS2, providing novel targets for prognosis and therapeutics of HCC.

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“…GH signaling also plays a significant role in regulating hepatic lipid metabolism. A reduction in GH signaling, through either GH deficiency or reduced GHR activity, leads to an upregulation of the fatty acid transporter Cd36, and several genes involved in lipogenesis ( Fasn, Scd1 ) resulting in hepatic accumulation of triglycerides and lipid, leading to the development of nonalcoholic fatty liver disease (NAFLD; reviewed in Kaltenecker et al, ). The data presented here suggest that the increase in expression of the mir‐465 family could contribute to the reduction in circulating IGF‐1 and to the onset of NAFLD with age.…”

Section: Discussionmentioning

confidence: 99%

The mir‐465 family is upregulated with age and attenuates growth hormone signaling in mouse liver

et al. 2019

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We analyzed the small RNA transcriptome from 5‐month‐old, 24‐month‐old, and 36‐month‐old mouse liver and found 56 miRNAs that changed their expression profile with age. Among these is a cluster of 18 miRNAs that are upregulated between 50‐ and 1,000‐fold at 24 and 36 months of age. This cluster is located in a 60‐kb region of the X‐chromosome that is devoid of other coding sequences and is part of a lamin‐associated domain. Potential targets of the miRNAs in the cluster suggest they may regulate several pathways altered in aging, including the PI3K‐Akt pathway. Total transcriptome analyses indicate that expression of several potential genes in the PI3K‐Akt pathway that may be targeted by the mir‐465 family (mmu‐mir‐465a, mmu‐mir‐465b, and mmu‐mir‐465c) is downregulated with age. Transfection of the liver cell line AML12 with mir‐465 family members leads to a reduction of three of these potential targets at the mRNA level: a 40% reduction of the growth hormone receptor (GHR), and a 25% reduction in Kitl and PPP2R3C. Further investigation of the GHR 3′UTR revealed that the mir‐465 family directly targets the GHR mRNA. Cells transfected with mir‐465 showed a reduction of JAK2 and STAT5 phosphorylation upon growth hormone (GH) stimulation, resulting in a reduction in insulin‐like growth factor 1 (IGF‐1) and IGF‐1‐binding protein 3 expression. With age, GH signaling falls and there is a reduction in circulating IGF‐1. Our data suggest that an increase in expression of the mir‐465 family with age may contribute to the reduction in the GH signaling.

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Hepatic growth hormone - JAK2 - STAT5 signalling: Metabolic function, non-alcoholic fatty liver disease and hepatocellular carcinoma progression

Cited by 54 publications

References 178 publications

TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo

TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo

MicroRNA-196a/-196b regulate the progression of hepatocellular carcinoma through modulating the JAK/STAT pathway via targeting SOCS2

The mir‐465 family is upregulated with age and attenuates growth hormone signaling in mouse liver

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