Critical role of CREBH‐mediated induction of transforming growth factor β2 by hepatitis C virus infection in fibrogenic responses in hepatic stellate cells

Chida, Takeshi; Ito, Masahiko; Nakashima, Kenichiro; Kanegae, Yumi; Aoshima, Takuya; Takabayashi, Shuji; Kawata, Kazuhito; Nakagawa, Yoshimi; Yamamoto, Masahiro; Shimano, Hitoshi; Matsuura, Tomokazu; Kobayashi, Yoshimasa; Suda, Takafumi; Suzuki, Tetsuro

doi:10.1002/hep.29319

Cited by 29 publications

(26 citation statements)

References 34 publications

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“…Human HCC cells; HuH-7, HepG2, PLC/PRF5, FLC7 (Homma et al, 1990) and ORL8c (Kato et al, 2009), human hepatic stellate TWNT4 JP7 cell (Shibata et al, 2003; Chida et al, 2017), mouse hepatoma Hepa1c1c7 cell and human non-hepatic cells; A549 (lung carcinoma), HEK293 (embryonic kidney), HEK293T (embryonic kidney), Caco2 (colorectal adenocarcinoma), C33A (cervical carcinoma), and HeLa (cervical adenocarcinoma) were maintained in Dulbecco’s modified Eagle medium supplemented with 10% fetal bovine serum. Cells were transiently transfected with plasmid DNAs using transfection reagents as follows; Lipofectamine LTX (Thermo Fisher Scientific, Waltham, MA, United States) used for HuH-7, FLC7, A549, Caco2, HeLa, Hepa1c1c7, and TWNT4 JP7, Lipofectamine 3000 (Thermo Fisher Scientific) for HepG2, PLC/PRF/5, ORL8c, and C33A, and linear polyethyleneimine, MW 25,000 (Thermo Fisher Scientific) for HEK293 and HEK293T.…”

Section: Methodsmentioning

confidence: 99%

Cell Type Diversity in Hepatitis B Virus RNA Splicing and Its Regulation

et al. 2019

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Although RNA splicing of hepatitis B virus (HBV) is a commonly observed in livers of hepatitis B patients as well as in the cultured cells replicating the viral genome, its biological significance in the HBV life cycle and the detailed regulatory mechanisms are still largely unclear. In this study, we found cell-type dependency of HBV splicing of the 3.5 kb pregenomic RNA, which is efficiently spliced in human hepatoma cells but not in cells derived from human hepatic stellate, mouse hepatoma and human non-hepatic cells. It may be likely that RNA splicing is one of the determinants of host range restriction of HBV. Given the finding indicating the difference in cell-type dependency of the splicing efficiency between HBV and simian virus 40, we carried out intron-swapping experiments. The results suggest the presence of putative exonic splicing enhancer that possibly works in the cell-type dependent fashion. Together with further mutational analyses, a novel 50-nt intronic splicing silencer, whose secondary structure is well conserved among the HBV strains, was identified. It appears that this intronic silencer functions effectively independent of cell backgrounds.

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Section: Methodsmentioning

confidence: 99%

Cell Type Diversity in Hepatitis B Virus RNA Splicing and Its Regulation

et al. 2019

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“…The authors thus suggest TGF-β2 as a promising biomarker for liver fibrosis in HCV [19]. Mechanistically, the increased expression of TGF-β2 in HCV-induced liver fibrosis is mediated via a cAMP-responsive element-binding protein (CREBH) site in the promoter of the TGF-β2 gene in hepatocytes that is activated from HCV infection [20].…”

Section: Tgf-β Familymentioning

confidence: 99%

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis: Updated

et al. 2015

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Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment is mainly the removal of the causative factor. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-β has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-β and its upstream and downstream regulatory mechanisms will help to design better TGF-β based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-β signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-β on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-β. Finally, we discuss new approaches to target the TGF-β pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.

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“…Recent studies indicate intestinal Creb3L3 also regulates lipid metabolism, but particularly cholesterol metabolism (Kikuchi et al, 2016; Zeituni et al, 2016). In response to hepatitis C virus infections, Creb3L3 enhances TGF-β2 transcription, which increases fibrogenic responses in hepatic stellate cells (Chida et al, 2017). These results point to Creb3L3 regulating lipid metabolism and mediating responses to infection that in turn can result in inflammation.…”

Section: Creb3 Proteins Regulate Biological Processes Requiring Protementioning

confidence: 99%

The Role of Mammalian Creb3-Like Transcription Factors in Response to Nutrients

Khan

Margulies

2019

Front. Genet.

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Our ability to overcome the challenges behind metabolic disorders will require a detailed understanding of the regulation of responses to nutrition. The Creb3 transcription factor family appears to have a unique regulatory role that links cellular secretory capacity with development, nutritional state, infection, and other stresses. This role in regulating individual secretory capacity genes could place this family of transcription factors at an important regulatory intersection mediating an animal’s responses to nutrients and other environmental challenges. Interestingly, in both humans and mice, individuals with mutations in Creb3L3/CrebH, one of the Creb3 family members, exhibit hypertriglyceridemia (HTG) thus linking this transcription factor to lipid metabolism. We are beginning to understand how Creb3L3 and related family members are regulated and to dissect the potential redundancy and cross talk between distinct family members, thereby mediating both healthy and pathological responses to the environment. Here, we review the current knowledge on the regulation of Creb3 family transcription factor activity, their target genes, and their role in metabolic disease.

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Critical role of CREBH‐mediated induction of transforming growth factor β2 by hepatitis C virus infection in fibrogenic responses in hepatic stellate cells

Cited by 29 publications

References 34 publications

Cell Type Diversity in Hepatitis B Virus RNA Splicing and Its Regulation

Cell Type Diversity in Hepatitis B Virus RNA Splicing and Its Regulation

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis: Updated

The Role of Mammalian Creb3-Like Transcription Factors in Response to Nutrients

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