Oxidative stress and mitochondrial dysfunction mediated Cd-induced hepatic lipid accumulation in zebrafish Danio rerio

Aquat Toxicol. 2018 Jun;199:12-20. doi: 10.1016/j.aquatox.2018.03.017. Epub 2018 Mar 17.


The present study was performed to determine the effect of waterborne CdCl2 exposure influencing lipid deposition and metabolism, oxidative stress and mitochondrial dysfunction, and explore the underlying molecular mechanism of cadmium (Cd)-induced disorder of hepatic lipid metabolism in fish. To this end, adult zebrafish were exposed to three waterborne CdCl2 concentrations (0(control), 5 and 25 μg Cd/l, respectively) for 30 days. Lipid accumulation, the activities of enzymes related to lipid metabolism and oxidative stress, as well as the expression level of genes involved in lipid metabolism and mitophagy were determined in the liver of zebrafish. Waterborne CdCl2 exposure increased hepatic triglyceride (TG) and Cd accumulation, the activities of fatty acid synthase (FAS), 6-phosphogluconate dehydrogenase (6PGD), glucose 6-phosphate dehydrogenase (G6PD) and malic enzyme (ME), and the mRNA level of fatty acid synthase (fas), acetyl-CoA carboxylase alpha (acaca), glucose 6-phosphate dehydrogenase (g6pd) and malic enzyme (me), but reduced the mRNA level of carnitine palmitoyl transferase 1 (cpt1), hormone-sensitive lipase alpha (hsla), and adipose triacylglyceride lipase (atgl). The activities of superoxide dismutase (SOD), glutathoinine peroxidase (GPx) and cytochrome c oxidase (COX) and the ATP level were significantly reduced after CdCl2 exposure. CdCl2 exposure significantly increased the mRNA level of genes (microtubule-associated protein light chain 3 alpha (lc3a), PTEN-induced putative kinase 1 (pink1), NIP3-like protein X (nix) and PARKIN (parkin)) related to mitophagy. To elucidate the mechanism, reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the mitochondrial permeability transition (MPT) inhibitor cyclosporine A (CsA) were used to verify the role of ROS and mitochondrial dysfunction in Cd-induced disorder of lipid metabolism. NAC pretreatment reversed the Cd-induced up-regulation of TG accumulation and activities of lipogenic enzymes, and the Cd-induced down-regulation of mRNA levels of lipolytic genes. Meanwhile, NAC pretreatment also blocked the mitochondrial membrane potential (MMP) collapse and decreased the ATP level, suggesting that ROS played a crucial role in regulating the Cd-induced mitochondrial dysfunction. Taken together, our findings, for the first time, highlight the importance of the oxidative stress and mitochondrial dysfunction in Cd-induced disorder of hepatic lipid metabolism, which proposed a novel mechanism for elucidating metal element exposure inducing the disorder of lipid metabolism in vertebrates.

Keywords: Cadmium; Danio rerio; Lipid metabolism; Mitochondrial dysfunction; Oxidative stress.

MeSH terms

  • Acetylcysteine / chemistry
  • Acetylcysteine / pharmacology
  • Animals
  • Cadmium Chloride / metabolism
  • Cadmium Chloride / toxicity*
  • Fatty Acid Synthases / genetics
  • Fatty Acid Synthases / metabolism
  • Glucosephosphate Dehydrogenase / genetics
  • Glucosephosphate Dehydrogenase / metabolism
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / genetics
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Oxidative Stress / drug effects*
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Triglycerides / metabolism
  • Up-Regulation / drug effects
  • Water Pollutants, Chemical / toxicity*
  • Zebrafish / growth & development
  • Zebrafish / metabolism*
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism


  • RNA, Messenger
  • Reactive Oxygen Species
  • Triglycerides
  • Water Pollutants, Chemical
  • Zebrafish Proteins
  • Glucosephosphate Dehydrogenase
  • Superoxide Dismutase
  • Fatty Acid Synthases
  • Cadmium Chloride
  • Acetylcysteine