Cadmium exposure exacerbates severe hyperlipidemia and fatty liver changes in zebrafish via impairment of high-density lipoproteins functionality

Toxicol In Vitro. 2018 Mar;47:249-258. doi: 10.1016/j.tiv.2017.11.007. Epub 2017 Nov 29.

Abstract

Cadmium (Cd) is a heavy metal with several toxicities that have destructive effect on most organ systems. However, its toxic effects on human lipoproteins are largely remained unknown especially in hyperlipidemic zebrafish model. Treatment of human high-density lipoprotein (HDL) with cadmium chloride (CdCl2, final 12 and 24μM) caused spontaneous formation of multimeric apoA-I as well as increased production of glycated extent products. Cd-HDL3 accelerated uptake of oxidized LDL (oxLDL) into macrophages and induced severe senescence in human dermal fibroblast (HDF) cells. Microinjection of Cd-HDL3 into zebrafish embryos resulted in acute embryonic toxicity with high mortality. Exposure of zebrafish embryos to water containing CdCl2 (final 12 and 24μM) caused early embryonic death along with increased production of oxidized products and impairment of skeletal development. Consumption of CdCl2 (12 and 24μM) by zebrafish for 4weeks resulted in severe elevation of plasma total cholesterol (TC) and triglyceride (TG) levels as well as cholesteryl ester (CE) transfer activity. Furthermore, consumption of CdCl2 resulted in acceleration of fatty liver changes and increased production of reactive oxygen species (ROS). In conclusion, CdCl2 caused structural modification of HDL3 and impaired the beneficial functions of HDL3, including anti-oxidation, anti-atherosclerosis, and anti-senescence effects. Consumption of CdCl2 also resulted in exacerbated hyperlipidemia and fatty liver changes in zebrafish via enhancement of cholesteryl ester transfer protein (CETP) activity.

Keywords: Cadmium; Cholesteryl ester transfer protein; Embryo; Hyperlipidemia; Lipoprotein; Zebrafish.

MeSH terms

  • Animals
  • Apolipoprotein A-I / chemistry
  • Apolipoprotein A-I / metabolism
  • Cadmium / toxicity*
  • Cells, Cultured
  • Cholesterol Ester Transfer Proteins / agonists*
  • Cholesterol Ester Transfer Proteins / blood
  • Cholesterol Ester Transfer Proteins / metabolism
  • Diet, High-Fat / adverse effects
  • Embryonic Development / drug effects
  • Female
  • Glycosylation / drug effects
  • Humans
  • Hyperlipidemias / etiology*
  • Hyperlipidemias / metabolism
  • Hyperlipidemias / pathology
  • Hyperlipidemias / physiopathology
  • Lipoproteins, HDL / blood
  • Lipoproteins, HDL / chemistry
  • Lipoproteins, HDL / metabolism*
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Microinjections
  • Non-alcoholic Fatty Liver Disease / etiology*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Non-alcoholic Fatty Liver Disease / physiopathology
  • Phagocytosis / drug effects
  • Protein Multimerization / drug effects
  • Reactive Oxygen Species / agonists
  • Reactive Oxygen Species / metabolism
  • Skin / cytology
  • Skin / drug effects
  • Skin / metabolism
  • Water Pollutants / toxicity*
  • Zebrafish
  • Zebrafish Proteins / agonists
  • Zebrafish Proteins / blood
  • Zebrafish Proteins / metabolism

Substances

  • APOA1 protein, human
  • Apolipoprotein A-I
  • Cholesterol Ester Transfer Proteins
  • Lipoproteins, HDL
  • Reactive Oxygen Species
  • Water Pollutants
  • Zebrafish Proteins
  • Cadmium