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 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 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.
Highlights
Due to combined effects of various factors such as water eutrophication and global warming, more and more freshwater lakes around the world are experiencing severe cyanobacterial blooms, such as Lake of the Woods in Canada [1]; Lake Erie in the USA [2]; Lake Zegerplas in the Netherlands [3]; Peel–Harvey estuaries in Western Australia [4]; and Lakes Poyang, Chaohu, and Dianchi, as well asErhai in China [5,6,7]
We investigated the effects of low levels of continuous MC-LR (0, 1, 5, and 25 μg/L) exposure on liver lipid metabolism in adult zebrafish, as well as the potential mechanism of the endoplasmic reticulum stress (ERS) in MC-LR-induced hepatic lipid metabolism disturbance
MC-LR exposure elevated the amount of lipid droplets in the liver of zebrafish (Figure 1B)
Summary
Due to combined effects of various factors such as water eutrophication and global warming, more and more freshwater lakes around the world are experiencing severe cyanobacterial blooms, such as Lake of the Woods in Canada [1]; Lake Erie in the USA [2]; Lake Zegerplas in the Netherlands [3]; Peel–Harvey estuaries in Western Australia [4]; and Lakes Poyang, Chaohu, and Dianchi, as well asErhai in China [5,6,7]. Due to combined effects of various factors such as water eutrophication and global warming, more and more freshwater lakes around the world are experiencing severe cyanobacterial blooms, such as Lake of the Woods in Canada [1]; Lake Erie in the USA [2]; Lake Zegerplas in the Netherlands [3]; Peel–Harvey estuaries in Western Australia [4]; and Lakes Poyang, Chaohu, and Dianchi, as well as. The frequent occurrence of cyanobacterial blooms deteriorates water quality and produces highly toxic microcystins (MCs). MC pollution has become a global public health concern as MCs have been reported to be involved in numerous cases of lethal poisonings in wild animals, livestock, and even humans [9,10,11]. It is important to realize that the World Health
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