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  2. Cadmium exacerbates liver injury by remodeling ceramide metabolism: Multiomics and laboratory evidence

Cadmium exacerbates liver injury by remodeling ceramide metabolism: Multiomics and laboratory evidence

  • Sci Total Environ. 2024 Mar 1:923:171405. doi: 10.1016/j.scitotenv.2024.171405.
Danna Xie 1 Jun Yan 1 Honglong Zhang 1 Haijun Zhang 2 Guole Nie 1 Xingwang Zhu 1 Xun Li 3
Affiliations

Affiliations

  • 1 The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China.
  • 2 Department of Anesthesiology, the First Hospital of Lanzhou University, Lanzhou 730000, China.
  • 3 The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China; Department of General Surgery, the First Hospital of Lanzhou University, Lanzhou 730000, China; Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, China; Center for Cancer Prevention and Treatment, School of Medicine, Lanzhou University, Lanzhou 730000, China; Gansu Provincial Institute of Hepatobiliary and Pancreatic Surgery, Lanzhou 730000, China. Electronic address: lxdr21@126.com.
Abstract

Cadmium (Cd) is a toxic heavy metal that primarily targets the liver. Cd exposure disrupts specific lipid metabolic pathways; however, the underlying mechanisms remain unclear. This study aimed to investigate the lipidomic characteristics of rat livers after Cd exposure as well as the potential mechanisms of Cd-induced liver injury. Our analysis of established Cd-exposed rat and cell models showed that Cd exposure resulted in liver lipid deposition and hepatocyte damage. Lipidomic detection, transcriptome Sequencing, and experimental analyses revealed that Cd mainly affects the sphingolipid metabolic pathway and that the changes in ceramide metabolism are the most significant. In vitro experiments revealed that the inhibition of ceramide synthetase activity or activation of ceramide decomposing Enzymes ameliorated the proapoptotic and pro-oxidative stress effects of Cd, thereby alleviating liver injury. In contrast, the exogenous addition of ceramide aggravated liver injury. In summary, Cd increased ceramide levels by remodeling ceramide synthesis and catabolism, thereby promoting hepatocyte Apoptosis and oxidative stress and ultimately aggravating liver injury. Reducing ceramide levels can serve as a potential protective strategy to mitigate the liver toxicity of Cd. This study provides new evidence for understanding Cd-induced liver injury at the lipidomic level and insights into the health risks and toxicological mechanisms associated with Cd.

Keywords

Cadmium; Ceramide; Lipidomics; Liver injury; Transcriptomics.

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