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Chronic Microcystin-LR Exposure Induces Abnormal Lipid Metabolism via Endoplasmic Reticulum Stress in Male Zebrafish.

ABSTRACT: In order to explore effects of low levels of continuous microcystin-LR (MC-LR) (a cyanotoxin) exposure on hepatic lipid metabolism on the basis of the endoplasmic reticulum stress (ERS) pathway, we exposed adult male zebrafish to MC-LR (0, 1, 5, and 25 ?g/L) for 60 days, and hepatic histopathology as well as lipid metabolic parameters were determined with mRNA levels of ERS signal molecules and downstream factors, along with genes associated with lipid metabolism in zebrafish liver. The results revealed that prolonged exposure to MC-LR remarkably altered the levels of hepatic total cholesterol and triglyceride and led to hepatic steatosis, which was also confirmed by hepatic cytoplasmic vacuolization in Hematoxylin/eosin (H&E) stain and lipid droplet accumulation in Oil Red O stain. The severity of hepatic damage and lipidation was increased in a dose-related manner. MC-LR exposure significantly upregulated transcriptional levels of ERS markers including hspa5, mapk8, and chop, indicating the occurrence of ERS in the liver of zebrafish. Concurrently, MC-LR significantly improved mRNA expression of unfolded protein response (UPR) pathway-related genes including atf6, eif2ak3, ern1, and xbp1s, suggesting that all of the three UPR branches were activated by MC-LR. MC-LR also induced significant upregulation of downstream lipid metabolism-related factors and genes including srebf1, srebf2, fatty acid synthase (fasn), acetyl-CoA carboxylase (acaca), stearoyl-CoA desaturase (scd), HMG CoA reductase (hmgcra), and HMG CoA synthase (hmgcs1), and downregulation of genes associated with lipolysis such as triglyceride hydrolase gene (atgl), hormone-sensitive enzyme gene (hsla), and carnitine palmitoyltransferase gene (cpt1aa). Our present results indicated that the cause of hepatic lipid accumulation by MC-LR was mainly by upregulating lipogenic and cholesterol genes but downregulating the expression of lipolytic genes through the induction of srebf1 and srebf2, which were involved in the activation of ERS signal pathways.

SUBMITTER: Zhang D

PROVIDER: S-EPMC7076763 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Chronic Microcystin-LR Exposure Induces Abnormal Lipid Metabolism via Endoplasmic Reticulum Stress in Male Zebrafish.

Zhang Dandan D Lin Wang W Liu Yinjie Y Guo Honghui H Wang Lingkai L Yang Liping L Li Li L Li Dapeng D Tang Rong R

Toxins 20200207 2

In order to explore effects of low levels of continuous microcystin-LR (MC-LR) (a cyanotoxin) exposure on hepatic lipid metabolism on the basis of the endoplasmic reticulum stress (ERS) pathway, we exposed adult male zebrafish to MC-LR (0, 1, 5, and 25 μg/L) for 60 days, and hepatic histopathology as well as lipid metabolic parameters were determined with mRNA levels of ERS signal molecules and downstream factors, along with genes associated with lipid metabolism in zebrafish liver. The results ...[more]

PMID: 32046144

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Project description:Endoplasmic reticulum stress (ERS) is closely associated with the occurrence and development of many liver diseases. ERS models mostly include experimental animals such as rats and mice. However, pigs are more similar to humans with regards to digestion and metabolism, especially liver construction, yet few reports on ERS in pigs exist. In order to explore changes in the liver under ERS, we used tunicamycin (TM), which can cause liver jaundice and damage liver function, to establish acute ERS models in piglets using a low TM dosage (LD, 0.1 mg/kg body weight (bw)), high TM dosage (HD, 0.3 mg/kg bw), or vehicle for 48 h. We found that both LD- and HD-induced ERS, as verified by the ERS-linked proteins. Furthermore, the concentrations of the proinflammatory cytokines, namely, TNF-α and IL-6 were elevated in TM-treated piglet livers, and the plasma levels of IL-6 and CRP were also higher, indicating the occurrence of inflammation in TM-treated piglets. The complement system was activated in TM-treated piglets, as indicated by increased levels of complement factors and activation products C3, C5a, and AP50. In order to gain insights into the global changes in liver proteins under ERS, we performed an isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic analysis on the livers of HD- and vehicle-treated piglets. Proteomic analysis identified 311 differentially expressed proteins (DEPs) between the two groups, and a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that the DEPs were mainly enriched in signaling pathways such as metabolic pathways, protein processing in the endoplasmic reticulum, and complement and coagulation cascades. Many proteins involved in protein folding, lipid transport, and oxidation were upregulated. Proteins involved in lipid synthesis were downregulated to alleviate liver steatosis, and most complement factors were upregulated to protect the body, and Pearson correlation analysis found that most of the DEPs in the complement and coagulation pathway were significantly correlated with plasma CRP, IL6 and AP50. Our results revealed that TM can activate ERS, marked by liver injury and steatosis, inflammatory reactions, and complement activation in piglets.

Dataset Information

Chronic Microcystin-LR Exposure Induces Abnormal Lipid Metabolism via Endoplasmic Reticulum Stress in Male Zebrafish.

Publications

Chronic Microcystin-LR Exposure Induces Abnormal Lipid Metabolism via Endoplasmic Reticulum Stress in Male Zebrafish.

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