Thiamine pretreatment improves endotoxemia-related liver injury and cholestatic complications by regulating galactose metabolism and inhibiting macrophage activation.

Abstract

BACKGROUND:

As a major metabolic site, the liver is an important target organ of endotoxemia. High serum lipopolysaccharide (LPS) levels can cause hepatocyte necrosis and produce cholestasis, which results in severe liver injury. Contrastingly, thiamine (THA) has shown anti-inflammatory effects against severe infections and may be indicated for systemic endotoxemia treatment. Therefore, the present study was conducted to investigate the effective treatment of endotoxemia-induced liver injury with THA and the possible molecular mechanisms.

METHODOLOGY/PRINCIPAL FINDINGS:

in vivo, We established two models of endotoxemia-induced liver injury at the in vivo level using LPS and bile duct ligation (BDL) + LPS, administering prophylactic THA intraperitoneally to mice. In vitro, the effects of THA on RAW264.7 and THP-1 administration of LPS-induced inflammatory macrophage activation were observed. Metabolomic analysis screening and subsequent validation experiments were also performed. THA has different degrees of preventive therapeutic effects on different causes of endotoxemia-induced liver injury, as evidenced by a decreased alanine aminotransferase (ALT) and decreased inflammatory factors. This study aimed to clarify the specific mechanism. We subsequently found that THA reduced the inflammatory macrophages produced by RAW264.7 and THP-1 in response to LPS. Additionally, THA reduced galactose liver accumulation and improved glucose metabolism. Moreover, Galectin-3 (Gal-3), as a point of interaction between macrophage activation and galactose metabolism mechanisms, was observed to inhibit Gal-3 expression by THA at both in vivo and in vitro levels.

CONCLUSIONS:

This study revealed that THA may be a viable prophylactic treatment option for the prevention of liver injury occurring in endotoxemia, which is associated with its effects on the modulation of Gal-3 to improve the inflammatory response and the inhibition of galactose metabolism. Additional evidence is provided for its clinical application.

• Authors: Tongxi Li, Junjie Bai, Yichao Du, Peng Tan, Tianxiang Zheng, Yifan Chen, Yonglang Cheng, Tianying Cai, Meizhou Huang, Wenguang Fu, Jian Wen
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 108 Pg. 108892 (Jul 2022) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 35640376 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Lipopolysaccharides
• Galactose
• Thiamine

Topics

• Animals
• Chemical and Drug Induced Liver Injury, Chronic (metabolism)
• Cholestasis (complications)
• Endotoxemia (drug therapy)
• Galactose (metabolism)
• Lipopolysaccharides (pharmacology)
• Liver
• Macrophage Activation
• Mice
• Thiamine (metabolism, pharmacology, therapeutic use)