Coordinated signaling of activating transcription factor 6α and inositol-requiring enzyme 1α regulates hepatic stellate cell-mediated fibrogenesis in mice

Xue, Fei; Lu, Jianwen; Buchl, Samuel C.; Sun, Liankang; Shah, Vijay H.; Malhi, Harmeet; Maiers, Jessica L.

doi:10.1152/ajpgi.00453.2020

Cited by 8 publications

(8 citation statements)

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“…ATF6α as well as IRE1α boost fibrogenic transcription in HSCs, respectively, ATF6α impels fibrosis in vivo. Contrary to expectations, fragment of both pathways sensitized liver to fibrosis, recommending fine-tuned UPR signaling is vital to adjust hematopoietic stem cells stimulation and fibrosis [163] . Signaling from the homologous receptor EGFR contributes to the stimulation of HSCs by cytokines of the epidermal growth factor family.…”

Section: Other Pathwaysmentioning

confidence: 63%

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

Zheng

Yang

Luo

et al. 2022

Preprint

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Liver fibrosis (LF) is a trauma repair process carried out by the liver in response to various acute and chronic liver injuries, featured by excessive proliferation as well as abnormal dismissal of extracellular matrix as the main pathological features, and its continuous development will deteriorate into cirrhosis, liver cancer as well as other illnesses. The occurrence of LF is closely related to Hepatic stellate cells (HSCs) stimulation, and intervention in HSCs proliferation is expected to reverse LF. Plant-based small molecule drugs have anti-LF effects, and their mechanisms of action are related to anti-inflammation, anti-oxidative stress, as well as inhibition of abnormal accumulation of extracellular matrix. Consequently, new agents for HSCs will be required to furnish a possible curative response. Small-molecule natural products might be attractive for LF therapy. That is because they not only have the effect against HSCs, but also have excellent qualities such as low toxic side effects and easy availability from the perspective of safety and cost. In this review, we provide an updated review of the signal transduction pathways involved in HSCs and small-molecule natural products targeting HSCs reported in the past 3 years at home and abroad, with the aim of providing new ideas for the development of plant-based small molecule drugs targeting HSCs to reverse LF.

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Section: Other Pathwaysmentioning

confidence: 63%

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

Zheng

Yang

Luo

et al. 2022

Preprint

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“…ER stress and UPR signaling further potentiate liver damage through promoting hepatocyte apoptosis downstream of ATF4/CHOP signaling, inducing release of pathogenic extracellular vesicles through IRE1/XBP1, regulating steatosis, activating inflammatory pathways, and promoting fibrogenesis (Ji et al, 2005;Oyadomari et al, 2008;Cazanave et al, 2010;Pfaffenbach et al, 2010;Cazanave et al, 2011;Li et al, 2011;Malhi et al, 2013;Xiao et al, 2013;Toriguchi et al, 2014;Kakazu et al, 2016;Rahman et al, 2016;Shan et al, 2017;Dasgupta et al, 2020;Duwaerts et al, 2021). ATF6α is involved in lipid synthesis regulation, with ATF6α loss in hepatocytes limiting steatosis, but may also promote fibrogenesis in response to liver injury (Rutkowski et al, 2008;Yamamoto et al, 2010;Chen et al, 2016a;Xue et al, 2021). contributing to NAFLD development and progression.…”

Section: Er Quality Control Pathways and Chronic Liver Diseasementioning

confidence: 99%

“…Indeed, activated HSCs exhibit increased UPR signaling. Both IRE1α and ATF6α, upstream regulators of ERAD and autophagy, are crucial for hepatic fibrogenesis in vivo, though these studies have focused on transcriptional regulation of HSC activation and fibrogenesis downstream of the UPR, and not on ER quality control pathways (Xue et al, 2021;(Hernandez-Gea et al, 2013;Heindryckx et al, 2016;Liu et al, 2019). PERK, also known for a role in autophagy, promotes fibrogenesis (Koo et al, 2016;Zheng et al, 2019;B'Chir et al, 2013;Kang et al, 2017).…”

Section: Er Quality Control Pathways In Fibrogenesismentioning

confidence: 99%

“…These findings highlight the importance of proteasomal degradation in HSCs and fibrogenesis, but no studies have directly studied the impact of ERAD on fibrogenesis. ER stress and IRE1α signaling are elevated in activated HSCs, while disruption of IRE1α or ATF6α signaling in HSCs limits their activation and fibrosis in mice (Xue et al, 2021;Hernandez-Gea et al, 2013;Heindryckx et al, 2016;Liu et al, 2019). As IRE1α is a critical regulator of ERAD, and either proteasome inhibition or IRE1α inhibition limits HSC activation and fibrogenesis, the potential contributions of ERAD to these processes merit further study.…”

Section: Targeting Protein Degradation In Liver Fibrosismentioning

confidence: 99%

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ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets

Duwaerts

Maiers

2022

Front. Mol. Biosci.

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The endoplasmic reticulum is a central player in liver pathophysiology. Chronic injury to the ER through increased lipid content, alcohol metabolism, or accumulation of misfolded proteins causes ER stress, dysregulated hepatocyte function, inflammation, and worsened disease pathogenesis. A key adaptation of the ER to resolve stress is the removal of excess or misfolded proteins. Degradation of intra-luminal or ER membrane proteins occurs through distinct mechanisms that include ER-associated Degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD), which includes macro-ER-phagy, micro-ER-phagy, and Atg8/LC-3-dependent vesicular delivery. All three of these processes are critical for removing misfolded or unfolded protein aggregates, and re-establishing ER homeostasis following expansion/stress, which is critical for liver function and adaptation to injury. Despite playing a key role in resolving ER stress, the contribution of these degradative processes to liver physiology and pathophysiology is understudied. Analysis of publicly available datasets from diseased livers revealed that numerous genes involved in ER-related degradative pathways are dysregulated; however, their roles and regulation in disease progression are not well defined. Here we discuss the dynamic regulation of ER-related protein disposal pathways in chronic liver disease and cell-type specific roles, as well as potentially targetable mechanisms for treatment of chronic liver disease.

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“…immunoHistoCHemistRy Immunohistochemistry (IHC) was performed as described. (16) In brief, paraffin-embedded tissues were deparaffinized, rehydrated, and stained with an antibody targeting α-smooth muscle actin (αSMA) (Table S1). Five images were taken per mouse (magnification ×10) and analyzed by ImageJ.…”

Section: Immunoblottingmentioning

confidence: 99%

Traf2 and NCK Interacting Kinase Is a Critical Regulator of Procollagen I Trafficking and Hepatic Fibrogenesis in Mice

et al. 2021

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Hepatic fibrosis is driven by deposition of matrix proteins following liver injury. Hepatic stellate cells (HSCs) drive fibrogenesis, producing matrix proteins, including procollagen I, which matures into collagen I following secretion. Disrupting intracellular procollagen processing and trafficking causes endoplasmic reticulum stress and stress-induced HSC apoptosis and thus is an attractive antifibrotic strategy. We designed an immunofluorescence-based small interfering RNA (siRNA) screen to identify procollagen I trafficking regulators, hypothesizing that these proteins could serve as antifibrotic targets. A targeted siRNA screen was performed using immunofluorescence to detect changes in intracellular procollagen I. Tumor necrosis factor receptor associated factor 2 and noncatalytic region of tyrosine kinase-interacting kinase (TNIK) was identified and interrogated in vitro and in vivo using the TNIK kinase inhibitor NCB-0846 or RNA interference-mediated knockdown. Our siRNA screen identified nine genes whose knockdown promoted procollagen I retention, including the serine/threonine kinase TNIK. Genetic deletion or pharmacologic inhibition of TNIK through the small molecule inhibitor NCB-0846 disrupted procollagen I trafficking and secretion without impacting procollagen I expression. To investigate the role of TNIK in liver fibrogenesis, we analyzed human and murine livers, finding elevated TNIK expression in human cirrhotic livers and increased TNIK expression and kinase activity in both fibrotic mouse livers and activated primary human HSCs. Finally, we tested whether inhibition of TNIK kinase activity could limit fibrogenesis in vivo. Mice receiving NCB-0846 displayed reduced CCl 4 -induced fibrogenesis compared to CCl 4 alone, although α-smooth muscle actin levels were unaltered. Conclusions: Our siRNA screen effectively identified TNIK as a key kinase involved in procollagen I trafficking in vitro and hepatic fibrogenesis in vivo. (Hepatology Communications 2022;6:593-609).

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Coordinated signaling of activating transcription factor 6α and inositol-requiring enzyme 1α regulates hepatic stellate cell-mediated fibrogenesis in mice

Cited by 8 publications

References 73 publications

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets

Traf2 and NCK Interacting Kinase Is a Critical Regulator of Procollagen I Trafficking and Hepatic Fibrogenesis in Mice

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