MCLR-elicited hepatic fibrosis and carcinogenic gene expression changes persist in rats with diet-induced nonalcoholic steatohepatitis through a 4-week recovery period

Arman, Tarana; Baron, J Allen; Lynch, Katherine D.; White, Laura; Aldan, Johnny; Clarke, John

doi:10.1016/j.tox.2021.153021

Cited by 11 publications

(7 citation statements)

References 117 publications

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“…Earlier studies also indicated that MC-LR increased cell steatosis in hepatocytes and liver tissues [ 43 , 44 ]. Mechanistically, MC-LR inhibited fatty acid oxidation and increased hepatic inflammation [ 45 ], and induced nonalcoholic steatohepatitis (NASH), when rats were fed with a high-fat or high-cholesterol diet [ 46 ]. Moreover, functional autophagy (lipophagy) clears the accumulation of lipid droplets and reduces lipotoxicity in the liver by enhancing lipid metabolism [ 56 , 63 , 64 ], and our data suggest that cyanotoxins activate AKT/mTOR signaling partially, suppress autophagy by increasing the expression of p62, and increase cell steatosis in HCC cells.…”

Section: Discussionmentioning

confidence: 99%

“…Animal studies suggested that MC-LR induced cell steatosis in hepatocytes/liver tissues [ 43 , 44 ] by inhibiting fatty acid oxidation and by increasing hepatic inflammation [ 45 ]. Furthermore, MC-LR induced nonalcoholic steatohepatitis (NASH) in rats when rats were fed a high-fat or high-cholesterol diet [ 46 ]. Intraperitoneal (i.p.)…”

Section: Introductionmentioning

confidence: 99%

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Cyanotoxins Increase Cytotoxicity and Promote Nonalcoholic Fatty Liver Disease Progression by Enhancing Cell Steatosis

Niture

Gadi

et al. 2023

Toxins

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Freshwater prokaryotic cyanobacteria within harmful algal blooms produce cyanotoxins which are considered major pollutants in the aquatic system. Direct exposure to cyanotoxins through inhalation, skin contact, or ingestion of contaminated drinking water can target the liver and may cause hepatotoxicity. In the current study, we investigated the effect of low concentrations of cyanotoxins on cytotoxicity, inflammation, modulation of unfolded protein response (UPR), steatosis, and fibrosis signaling in human hepatocytes and liver cell models. Exposure to low concentrations of microcystin-LR (MC-LR), microcystin-RR (MC-RR), nodularin (NOD), and cylindrospermopsin (CYN) in human bipotent progenitor cell line HepaRG and hepatocellular carcinoma (HCC) cell lines HepG2 and SK-Hep1 resulted in increased cell toxicity. MC-LR, NOD, and CYN differentially regulated inflammatory signaling, activated UPR signaling and lipogenic gene expression, and induced cellular steatosis and fibrotic signaling in HCC cells. MC-LR, NOD, and CYN also regulated AKT/mTOR signaling and inhibited autophagy. Chronic exposure to MC-LR, NOD, and CYN upregulated the expression of lipogenic and fibrosis biomarkers. Moreover, RNA sequencing (RNA seq) data suggested that exposure of human hepatocytes, HepaRG, and HCC HepG2 cells to MC-LR and CYN modulated expression levels of several genes that regulate non-alcoholic fatty liver disease (NAFLD). Our data suggest that low concentrations of cyanotoxins can cause hepatotoxicity and cell steatosis and promote NAFLD progression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cyanotoxins Increase Cytotoxicity and Promote Nonalcoholic Fatty Liver Disease Progression by Enhancing Cell Steatosis

Niture

Gadi

et al. 2023

Toxins

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“…In studies performed by Arman et al, rats with diet-induced NASH that were exposed to sub-chronic levels of MC-LR showed increased fibrosis and inflammation compared to the control group [ 70 ]. These rats were then put on a 4-week recovery period after MC-LR exposure, and they observed that mice with pre-existing NASH continued to show dysregulation of the genes related to cellular differentiation and hepatocellular carcinoma [ 74 ]. This indicates that exposure to HAB toxins in pre-existing liver disease not only impairs hepatic recovery but that carcinogenic effects may also persist even after withdrawal from the exposure.…”

Section: Microcystins and Liver Healthmentioning

confidence: 99%

As We Drink and Breathe: Adverse Health Effects of Microcystins and Other Harmful Algal Bloom Toxins in the Liver, Gut, Lungs and Beyond

Lad

Breidenbach

et al. 2022

Life

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Freshwater harmful algal blooms (HABs) are increasing in number and severity worldwide. These HABs are chiefly composed of one or more species of cyanobacteria, also known as blue-green algae, such as Microcystis and Anabaena. Numerous HAB cyanobacterial species produce toxins (e.g., microcystin and anatoxin—collectively referred to as HAB toxins) that disrupt ecosystems, impact water and air quality, and deter recreation because they are harmful to both human and animal health. Exposure to these toxins can occur through ingestion, inhalation, or skin contact. Acute health effects of HAB toxins have been well documented and include symptoms such as nausea, vomiting, abdominal pain and diarrhea, headache, fever, and skin rashes. While these adverse effects typically increase with amount, duration, and frequency of exposure, susceptibility to HAB toxins may also be increased by the presence of comorbidities. The emerging science on potential long-term or chronic effects of HAB toxins with a particular emphasis on microcystins, especially in vulnerable populations such as those with pre-existing liver or gastrointestinal disease, is summarized herein. This review suggests additional research is needed to define at-risk populations who may be helped by preventative measures. Furthermore, studies are required to develop a mechanistic understanding of chronic, low-dose exposure to HAB toxins so that appropriate preventative, diagnostic, and therapeutic strategies can be created in a targeted fashion.

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“…He et al identified that MC-LR could significantly inhibit fatty acid β-oxidation and promote hepatic inflammation, resulting in NASH [ 41 ]. Using a histological staining method, it was shown [ 42 ] that, besides the induction of NASH, MC-LR could aggravate NASH induced by a high-fat or high-cholesterol (HFHC) diet.…”

Section: Liver Fibrosis and Cirrhosis Induced By Microcystin-lrmentioning

confidence: 99%

Microcystin-LR in Primary Liver Cancers: An Overview

Jiang

Zhang

2022

Toxins

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The cyanobacterial blooms produced by eutrophic water bodies have become a serious environmental issue around the world. After cellular lysing or algaecide treatment, microcystins (MCs), which are regarded as the most frequently encountered cyanobacterial toxins in fresh water, are released into water. Among all the variants of MCs, MC-LR has been widely studied due to its severe hepatotoxicity. Since 1992, various studies have identified the important roles of MC-LR in the origin and progression of primary liver cancers (PLCs), although few reviews have focused on it. Therefore, this review aims to summarize the major achievements and shortcomings observed in the past few years. Based on the available literature, the mechanisms of how MC-LR induces or promotes PLCs are elucidated in this review. This review aims to enhance our understanding of the role that MC-LR plays in PLCs and provides a rational approach for future applications.

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MCLR-elicited hepatic fibrosis and carcinogenic gene expression changes persist in rats with diet-induced nonalcoholic steatohepatitis through a 4-week recovery period

Cited by 11 publications

References 117 publications

Cyanotoxins Increase Cytotoxicity and Promote Nonalcoholic Fatty Liver Disease Progression by Enhancing Cell Steatosis

Cyanotoxins Increase Cytotoxicity and Promote Nonalcoholic Fatty Liver Disease Progression by Enhancing Cell Steatosis

As We Drink and Breathe: Adverse Health Effects of Microcystins and Other Harmful Algal Bloom Toxins in the Liver, Gut, Lungs and Beyond

Microcystin-LR in Primary Liver Cancers: An Overview

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