Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis

Gao, Hong; Jin, Zhongmou; Bandyopadhyay, Gautam; Wang, Gaowei; Zhang, Dinghong; Rocha, Karina Cunha e; Liu, Xiao; Zhao, Huayi; Kisseleva, Tatiana; Brenner, David A.; Karin, Michael; Ying, Wei

doi:10.1016/j.cmet.2022.07.006

Cited by 77 publications

(52 citation statements)

References 61 publications

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“…This study suggests that EVs play an important role in the tropism of specific cells and organs. Moreover, EVs have been reported to be associated with physiological functions, the development of various diseases, and control of the cellular microenvironment [ 8 , 9 , 11 ]. However, the target cell- or organ-tropism of EVs remains to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

“…The fibrotic microenvironment in the liver is controlled by the various liver-resident cells [ 12 , 13 ]. In particular, hepatocytes, which constitute a large population of liver cells, have been reported to interact with HSCs [ 11 , 14 , 15 ]. Furthermore, the lipotoxic treatment of hepatocytes affects HSC activation [ 9 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Increased Tropism of Extracellular Vesicles Derived from Palmitic Acid-Treated Hepatocytes to Activated Hepatic Stellate Cells

et al. 2022

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Myofibroblast-like activated hepatic stellate cells (aHSCs), which produce collagen, a major cause of liver fibrosis, are specific target cells for antifibrotic treatment. Recently, several reports have indicated that extracellular vesicles (EVs) play important roles in cell-to-cell communication through their tropism for specific cells or organs. Therefore, the present study aimed to identify aHSC-directed EVs by focusing on cell-to-cell interactions in the liver under pathological conditions. EVs were derived from the hepatocyte cell line AML12 treated with or without palmitic acid (PA) and evaluated for their physical properties and uptake by the aHSC cell line LX-2. AML12-derived EVs had a mean particle diameter of 110–130 nm, negative charge, and expressed the exosomal makers CD9 and CD63. PA-treated AML12 cells released larger EVs with higher protein levels than those without PA treatment. The intracellular uptake efficacy of EVs derived from PA-treated AML12 cells into activated LX-2 cells was significantly higher than those without PA treatment. Our study revealed that PA treatment induces hepatocytes to release EVs with aHSC-tropism. These findings may contribute to the development of an EV-based drug delivery system (DDS) for aHSC-targeted therapy and provide new insights into the role of steatotic hepatocyte-derived EVs in physiological or pathophysiological functions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased Tropism of Extracellular Vesicles Derived from Palmitic Acid-Treated Hepatocytes to Activated Hepatic Stellate Cells

et al. 2022

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“…[106] Tectorigenin alleviates fibrosis by inhibiting ferroptosis in TECs through the Smad3-NOX4 pathway. [46] Heart Oxidative damage MLK3-JNK/p53 pathway-mediated oxidative stress and ferroptosis cause myocardial fibrosis.…”

Section: Activation Of Inflammationmentioning

confidence: 99%

“…Excessive iron load directly stimulates ROS generation in HSCs, which in turn activates HSCs and promotes liver fibrosis. The aberrant distribution of iron is currently presumed to be an important link leading to hepatic steatosis and fibrosis [ 46 ]. In previous research, oxidative stress due to abnormal lipid deposition (lipotoxicity) was considered a critical upstream event in the pathogenesis of NASH.…”

Section: Ferroptosis and Fibrosismentioning

confidence: 99%

“…Likewise, tectorigenin showed promising efficacy against erastin/RSL3-induced ferroptosis and TGF- β 1-stimulated fibrosis in primary renal TECs. Ferroptosis inhibition with Fer-1 also alleviated TGF- β 1-mediated tissue fibrosis [ 46 ]. Ameliorating fibrosis progression by interfering with ferroptosis in TECs may be an approach worth considering.…”

Section: Ferroptosis and Fibrosismentioning

confidence: 99%

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Physiological Effects of Ferroptosis on Organ Fibrosis

Dong²,

et al. 2022

Oxidative Medicine and Cellular Longevity

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Ferroptosis is a new type of programmed cell death with unique morphological, biochemical, and genetic features. From the initial study of histomorphology to the exploration of subcellular organelles and even molecular mechanisms, a net connecting ferroptosis and fibrosis is being woven and formed. Inflammation may be the bridge between both processes. In this review, we will discuss the ferroptosis theory and process and the physiological functions of ferroptosis, followed by a description of the pathological effects and the underlying mechanisms of ferroptosis in the pathogenesis of tumorigenesis, ischemic damage, degenerative lesions, autoimmune diseases, and necroinflammation. We then focus on the role of ferroptosis in the fibrosis process in the liver, lung, kidney, heart, and other organs. Although the molecular mechanism of ferroptosis has been explored extensively in the past few years, many challenges remain to be resolved to translate this information into antifibrotic practice, which is becoming a promising new direction in the field of fibrotic disease prevention and treatment.

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Targeting Grancalcin Accelerates Wound Healing by Improving Angiogenesis in Diabetes

Xiang,

Jiang,

Chen

et al. 2024

Advanced Science

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Chronic diabetic wounds are a serious complication of diabetes and often result in limb amputations and confer high mortality rates. The proinflammatory secretome in the wound perpetuates defective neovascularization and contributes to dysregulated tissue repair. This study aims to design a gelatin methacrylamide (GelMA) hydrogel to sustained the release of grancalcin‐neutralizing antibody (GCA‐NAb) and evaluate it as a potential scaffold to promote diabetic wound healing. Results show that the expression of grancalcin(GCA), a protein secreted by bone marrow‐derived immune cells, is elevated in the wound sites of individuals and animals with diabetic ulcers. Genetic inhibition of grancalcin expression accelerates vascularization and healing in an animal model. Mechanistic studies show that grancalcin binds to transient receptor potential melastatin 8(TRPM8) and partially inactivates its downstream signaling pathways, thereby impairing angiogenesis in vitro and ex vivo. Systemic or topical administration of a GCA‐NAb accelerate wound repair in mice with diabetes. The data suggest that GCA is a potential therapeutic target for the treatment of diabetic ulcers.

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Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis

Cited by 77 publications

References 61 publications

Increased Tropism of Extracellular Vesicles Derived from Palmitic Acid-Treated Hepatocytes to Activated Hepatic Stellate Cells

Increased Tropism of Extracellular Vesicles Derived from Palmitic Acid-Treated Hepatocytes to Activated Hepatic Stellate Cells

Physiological Effects of Ferroptosis on Organ Fibrosis

Targeting Grancalcin Accelerates Wound Healing by Improving Angiogenesis in Diabetes

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