Microcystin-leucine-arginine induces liver fibrosis by activating the Hedgehog pathway in hepatic stellate cells

Gu, Song; Yan, Minghao; Wang, Cong; Meng, Xiannan; Zou, Xiang; Qiu, Yudong; Han, Xiaodong

doi:10.1016/j.bbrc.2020.09.075

Cited by 15 publications

(12 citation statements)

References 30 publications

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“…In addition, environmental pollutant cadmium was found to cause pulmonary fibrosis, 41 and Gu et al found that acute exposure to MC-LR can cause liver fibrosis. 42 However, this study did not show that chronic exposure to MC-LR could result in pulmonary fibrosis. Taken together, these findings suggest that MC-LR can enter lung tissues and disrupt the lung barrier structure, seriously causing lung injury.…”

Section: Discussioncontrasting

confidence: 59%

“…It was further found that MC-LR caused inflammatory cell aggregation, bronchial epithelial cell shedding, and structure destruction in the lungs of mice exposed to MC-LR for 12 months, and these pathological injuries were associated with the exposure time and concentrations. In addition, environmental pollutant cadmium was found to cause pulmonary fibrosis, and Gu et al found that acute exposure to MC-LR can cause liver fibrosis . However, this study did not show that chronic exposure to MC-LR could result in pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

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Chronic Exposure to Environmentally Relevant Concentrations of Microcystin-Leucine Arginine Causes Lung Barrier Damage through PP2A Activity Inhibition and Claudin1 Ubiquitination

Liu

Zeng

Wang

et al. 2022

J. Agric. Food Chem.

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Microcystin-leucine arginine (MC-LR), ubiquitous in water and food, is a threat to public health. In the present study, after C57BL/6J mice were fed with environmental concentrations of MC-LR (0, 1, 30, 60, 90, and 120 μg/L) for 6, 9, and 12 months, it was found that MC-LR could enter into mouse lung tissues and cause microstructural damage, as shown by western blotting and HE staining. Electron microscopy examination showed that MC-LR could damage the lung barrier by disruption of the tight junctions, which was confirmed by the decreased expression of tight junction markers, including Occludin, Claudin1, and ZO-1. In addition, MC-LR also increased the ubiquitination of Claudin1, indicating that MC-LR could disrupt tight junctions by promoting the degradation of Claudin1. Furthermore, MC-LR increased the levels of TNF-α and IL-6 in mouse lung tissues, leading to pneumonia. Importantly, pretreatment with PP2A activator D-erythro-sphingosine (DES) was found to significantly alleviate MC-LR-induced decrease of Occludin and Claudin1 by inhibiting the P-AKT/Snail pathway in vitro. Together, this study revealed that chronic exposure to MC-LR causes lung barrier damage, which involves PP2A activity inhibition and enhancement of Claudin1 ubiquitination. This study broadens the awareness of the toxic effects of MC-LR on the respiratory system, which has deep implications for public health.

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Section: Discussioncontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Chronic Exposure to Environmentally Relevant Concentrations of Microcystin-Leucine Arginine Causes Lung Barrier Damage through PP2A Activity Inhibition and Claudin1 Ubiquitination

Liu

Zeng

Wang

et al. 2022

J. Agric. Food Chem.

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“…In preclinical models, acute exposure to microcystins produced centrilobular inflammation, disruption of hepatic plates, apoptosis, and necrosis, which is consistent with observations from the aforementioned dialysis patients from Brazil exposed to microcystin through contaminated dialysate [ 70 , 127 , 143 ]. Centrilobular fibrosis as a result of microcystin toxicity has been observed in preclinical models as well as in human populations [ 52 , 144 ]. Microcystin-elicited liver damage in preclinical models caused dysfunction in glucose, triglyceride, lipid, and cholesterol metabolic pathways [ 108 , 145 , 146 ].…”

Section: Microcystin Pathophysiologymentioning

confidence: 99%

Microcystin Toxicokinetics, Molecular Toxicology, and Pathophysiology in Preclinical Rodent Models and Humans

Arman

Clarke

2021

Toxins

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Microcystins are ubiquitous toxins produced by photoautotrophic cyanobacteria. Human exposures to microcystins occur through the consumption of contaminated drinking water, fish and shellfish, vegetables, and algal dietary supplements and through recreational activities. Microcystin-leucine-arginine (MCLR) is the prototypical microcystin because it is reported to be the most common and toxic variant and is the only microcystin with an established tolerable daily intake of 0.04 µg/kg. Microcystin toxicokinetics is characterized by low intestinal absorption, rapid and specific distribution to the liver, moderate metabolism to glutathione and cysteinyl conjugates, and low urinary and fecal excretion. Molecular toxicology involves covalent binding to and inhibition of protein phosphatases, oxidative stress, cell death (autophagy, apoptosis, necrosis), and cytoskeleton disruption. These molecular and cellular effects are interconnected and are commonly observed together. The main target organs for microcystin toxicity are the intestine, liver, and kidney. Preclinical data indicate microcystins may also have nervous, pulmonary, cardiac, and reproductive system toxicities. Recent evidence suggests that exposure to other hepatotoxic insults could potentiate microcystin toxicity and increase the risk for chronic diseases. This review summarizes the current knowledge for microcystin toxicokinetics, molecular toxicology, and pathophysiology in preclinical rodent models and humans. More research is needed to better understand human toxicokinetics and how multifactorial exposures contribute to disease pathogenesis and progression.

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“…OPN controls cell survival, migration, proliferation and differentiation [46,47]. Studies showed that blocking Hg signaling in activated HSCs not only inhibited liver fibrosis, but also prevented accumulation of liver progenitor cells [48][49][50][51].…”

Section: Intracellular Pathways Involved In Hsc Activationmentioning

confidence: 99%

The Space of Disse: The Liver Hub in Health and Disease

Sanz‐Garcia

Fernández‐Iglesias

Gracia‐Sancho

et al. 2021

Livers

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Since it was first described by the German anatomist and histologist, Joseph Hugo Vincenz Disse, the structure and functions of the space of Disse, a thin perisinusoidal area between the endothelial cells and hepatocytes filled with blood plasma, have acquired great importance in liver disease. The space of Disse is home for the hepatic stellate cells (HSCs), the major fibrogenic players in the liver. Quiescent HSCs (qHSCs) store vitamin A, and upon activation they lose their retinol reservoir and become activated. Activated HSCs (aHSCs) are responsible for secretion of extracellular matrix (ECM) into the space of Disse. This early event in hepatic injury is accompanied by loss of the pores—known as fenestrations—of the endothelial cells, triggering loss of balance between the blood flow and the hepatocyte, and underlies the link between fibrosis and organ dysfunction. If the imbalance persists, the expansion of the fibrotic scar followed by the vascularized septae leads to cirrhosis and/or end-stage hepatocellular carcinoma (HCC). Thus, researchers have been focused on finding therapeutic targets that reduce fibrosis. The space of Disse provides the perfect microenvironment for the stem cells niche in the liver and the interchange of nutrients between cells. In the present review article, we focused on the space of Disse, its components and its leading role in liver disease development.

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Microcystin-leucine-arginine induces liver fibrosis by activating the Hedgehog pathway in hepatic stellate cells

Cited by 15 publications

References 30 publications

Chronic Exposure to Environmentally Relevant Concentrations of Microcystin-Leucine Arginine Causes Lung Barrier Damage through PP2A Activity Inhibition and Claudin1 Ubiquitination

Chronic Exposure to Environmentally Relevant Concentrations of Microcystin-Leucine Arginine Causes Lung Barrier Damage through PP2A Activity Inhibition and Claudin1 Ubiquitination

Microcystin Toxicokinetics, Molecular Toxicology, and Pathophysiology in Preclinical Rodent Models and Humans

The Space of Disse: The Liver Hub in Health and Disease

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