Free fatty acids induce bile acids overproduction and oxidative damage of bovine hepatocytes via inhibiting FXR/SHP signaling

  • J Steroid Biochem Mol Biol. 2024 Jul 23:244:106589. doi: 10.1016/j.jsbmb.2024.106589.
Zhiyuan Fang  1 ,  Zhiru Zhou  1 ,  Lingxue Ju  1 ,  Qi Shao  1 ,  Yongwei Xu  2 ,  Yuxiang Song  1 ,  Wenwen Gao  1 ,  Lin Lei  1 ,  Guowen Liu  1 ,  Xiliang Du  3 ,  Xinwei Li  4
Affiliations
  • 1. State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China.
  • 2. Animal Husbandry and Veterinary Development Center, Xinjiang Uygur Autonomous Region, Xinyuan county 835800, China.
  • 3. State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China. Electronic address: [email protected].
  • 4. State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China. Electronic address: [email protected].
PMID: 39053701 DOI: 10.1016/j.jsbmb.2024.106589
Abstract

Hepatic oxidative injury induced by free fatty acids (FFA) and metabolic disorders of bile acids (BA) increase the risk of metabolic diseases in dairy cows during perinatal period. However, the effects of FFA on BA metabolism remained poorly understood. In present study, high concentrations of FFA caused cell impairment, oxidative stress and BA overproduction. FFA treatment increased the expression of BA synthesis-related genes [Cholesterol 7a-hydroxylase (CYP7A1), hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 7, sterol 12α-hydroxylase, sterol 27-hydroxylase and oxysterol 7α-hydroxylase], whereas reduced BA exportation gene (ATP binding cassette subfamily C member 1) and inhibited farnesoid X receptor/small heterodimer partner (FXR/SHP) pathway in bovine hepatocytes. Knockdown of nuclear receptor subfamily 1 group H member 4 (NR1H4) worsened FFA-caused oxidative damage and BA production, whereas overexpression NR1H4 ameliorated FFA-induced BA production and cell oxidative damage. Besides, reducing BA synthesis through knockdown of CYP7A1 can alleviate oxidative stress and hepatocytes impairment caused by FFA. In summary, these data demonstrated that regulation of FXR/SHP-mediated BA metabolism may be a promising target in improving hepatic oxidative injury of dairy cows during high levels of FFA challenges.

Keywords
Bile acids; Dairy cow; FXR; Oxidative stress; Periparturient period.
Products
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    98.49%, Mitochondrial Membrane Potential Fluorescent Dye
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