Advanced glycation end product (AGE)-induced hepatic stellate cell activation via autophagy contributes to hepatitis C-related fibrosis

He, Yingli; Zhu, Jingru; Huang, Yaqi; Gao, Heng; Zhao, Yingren

doi:10.1007/s00592-015-0763-7

Cited by 17 publications

(17 citation statements)

References 28 publications

(38 reference statements)

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“…Furthermore, AGEs enhanced BMDM cells polarization into M1 macrophage with producing IL-6 and TNF-a proinflammatory cytokines and upregulating the expressions of CD11c and CD86 through activating RAGE/NF-κB pathway in mice33. In addition, AGEs has been shown to induce autophagy in some cells, such as hepatic stellate cells34, cardimyocytes35, vascular smooth muscle cells36, and endothelial cells37. Our results for the first time show that AGEs could stimulate M1 polarized macrophage by inducing autophagy.…”

Section: Discussionmentioning

confidence: 57%

AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes

Guo

Cai

et al. 2016

Sci Rep

100

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Autophagy is essential in physiological and pathological processes, however, the role of autophagy in cutaneous wound healing and the underlying molecular mechanism remain elusive. We hypothesized that autophagy plays an important role in regulating wound healing. Here, we show that enhanced autophagy negatively impacts on normal cutaneous healing process and is related to chronic wounds as demonstrated by the increased LC3 in diabetic mice skin or patients’ chronic wounds. In addition, inhibition of autophagy by 3-MA restores delayed healing in C57BL/6 or db/db mice, demonstrating that autophagy is involved in regulating wound healing. Furthermore, we identify that macrophage is a major cell type underwent autophagy in wounds and increased autophagy induces macrophages polarization into M1 with elevated CD11c population and gene expressions of proinflammatory cytokines. To explore the mechanism underlying autophagy-impaired wound healing, we tested the role of IRF8, a regulator of autophagy, in autophagy-modulated macrophages polarization. IRF8 activation is up-regulating autophagy and M1 polarization of macrophages after AGEs (advanced glycation endproducts) treatment, blocking the IRF8 with shIRF8 inhibits autophagic activity and M1 polarization. In summary, this study elucidates that AGEs induces autophagy and modulates macrophage polarization to M1 via IRF8 activation in impairment of cutaneous wound healing.

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Section: Discussionmentioning

confidence: 57%

AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes

Guo

Cai

et al. 2016

Sci Rep

100

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“…The unfolded protein response (UPR) is a highly conserved ER stress effector pathway transmitting signal through either of protein kinase R-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1)/X-box transcriptional factor (XBP1) pathways that link ER stress, UPR, and fibrogenic HSC activation in distinct ways: the TGFβ pathway is stimulated in the PERK-mediated, but not IRE1/XBP1-mediated, UPR during HSC activation [284–286]. Advanced glycation end product (AGE)-induced HSC activation requires autophagy in HCV-related fibrosis [287]. Transient receptor potential vanilloid 4 inhibits apoptosis in rat HSC line, HSC-T6, through induction of autophagy [288].…”

Section: Mechanisms Of Hsc Activationmentioning

confidence: 99%

Hepatic stellate cells as key target in liver fibrosis

Higashi

Friedman

Hoshida

2017

Advanced Drug Delivery Reviews

1,042

894

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Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.

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“…When the liver is injured by viral infection or hepatic toxins, HSCs receive signals secreted by damaged hepatocytes and immune cells, causing them to transdifferentiate into activated myofibroblast‐like cells. Release of lipid droplets containing retinylesters and triglyceride is a defining feature of HSC activation . In HSCs, metabolism of lipid droplets by autophagy provides cellular energy to fuel cellular activation, collagen synthesis, and secretion .…”

Section: Discussionmentioning

confidence: 99%

“…Release of lipid droplets containing retinylesters and triglyceride is a defining feature of HSC activation. [25][26][27] In HSCs, metabolism of lipid droplets by autophagy provides cellular energy to fuel cellular activation, collagen synthesis, and secretion. 28 Here, our data from primary HSCs showed that NO inhibits autophagy.…”

Section: Discussionmentioning

confidence: 99%

Role and regulation of autophagy and apoptosis by nitric oxide in hepatic stellate cells during acute liver failure

Jin

Gao

Wang

et al. 2017

Liver International

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Advanced glycation end product (AGE)-induced hepatic stellate cell activation via autophagy contributes to hepatitis C-related fibrosis

Abstract: AGEs were found to induce autophagy and activation of HSCs, which subsequently contributes to the fibrosis in CHC patients. Blocking AGE-RAGE signaling may be a promising way to alleviate fibrosis.

Cited by 17 publications

References 28 publications

AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes

AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes

Hepatic stellate cells as key target in liver fibrosis

Role and regulation of autophagy and apoptosis by nitric oxide in hepatic stellate cells during acute liver failure

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