4.7 Article

Chronic exposure to low-dose cadmium facilitated nonalcoholic steatohepatitis in mice by suppressing fatty acid desaturation

期刊

出版社

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ecoenv.2022.113306

关键词

Cadmium; Fatty acid desaturation; Lipotoxicity; Inflammation; NASH

资金

  1. National Natural Science Foundation of China (NSF) [91957105, 81972611]
  2. NSF of Zhejiang Province [LR20H160004]
  3. Fundamental Research Funds for the Central Universities [2021QNA7009]

向作者/读者索取更多资源

In this study, we found that chronic low-dose exposure to cadmium promoted the development of nonalcoholic steatohepatitis (NASH) in mice. Mechanistically, chronic cadmium exposure reshaped the liver transcriptional landscape and altered fatty acid metabolic pathways, leading to reduced fatty acid desaturation, increased cell death, and inflammation.
Exposure to cadmium (Cd), a toxic metal, is epidemiologically linked to nonalcoholic steatohepatitis (NASH) in humans. However, the role of Cd in NASH remains to be fully elucidated. This study employed a novel murine NASH model to investigate the effects of chronic low-dose Cd on hepatic pathology and its underlying mechanisms. NASH is characterized by lipid accumulation, extensive cell death, and persistent inflammation in the liver. We found that treatment with Cd in drinking water (10 mg/L) for 6 or 12 weeks significantly boosted hepatic fat deposition, increased hepatocyte destruction, and amplified inflammatory responses in mice, confirming that low-dose Cd can facilitate NASH development in vivo. Mechanistically, chronic Cd exposure reshaped the hepatic transcriptional landscape, with PPAR-mediated fatty acid metabolic pathways being the most significantly altered. In particular, Cd repressed fatty acid desaturation, leading to the accumulation of saturated fatty acids whose lipotoxicity exacerbated cell death and, consequently, inflammatory activation. In summary, we validated the causal effects of chronic low-dose Cd on NASH in vivo and identified the fatty acid desaturation program as a novel target for Cd to instigate hepatopathological alterations.

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