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

• Published in: Ecotoxicology and environmental safety 2022-03, Vol.233, p.113306-113306, Article 113306
• Main Authors: Zhu, Yi, Zhao, Yuanyuan, Chai, Xin-Xin, Zhou, Jiang, Shi, Meng-Jie, Zhao, Yurong, Tian, Youjia, Wang, Xu-Meng, Ying, Tian-Xing, Feng, Qiao, Sheng, Jinghao, Luo, Chi
• Format: Article
• Language: English
• Subjects: Animals; Cadmium; Cadmium - metabolism; Fatty acid desaturation; Fatty Acids - metabolism; Hepatocytes - metabolism; Inflammation; Lipotoxicity; Liver; Mice; Mice, Inbred C57BL; NASH; Non-alcoholic Fatty Liver Disease - chemically induced
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2022.113306

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. [Display omitted] •Low-dose cadmium (Cd) facilitates non-alcoholic steatohepatitis (NASH).•Cd suppresses fatty acid desaturation, leading to buildup of saturated lipids.•Lipotoxicity by saturated lipids synergizes Cd to cause extensive liver damages.•Extensive hepatic cell deaths feedforward to persistent inflammatory responses.•Hepatic lipotoxicity and inflammation culminate in Cd-induced NASH.