SREBP-1c overactivates ROS-mediated hepatic NF-κB inflammatory pathway in dairy cows with fatty liver.

Abstract

Dairy cows with fatty liver are characterized by hepatic lipid accumulation and a severe inflammatory response. Sterol receptor element binding protein-1c (SREBP-1c) and nuclear factor κB (NF-κB) are components of the main pathways for controlling triglyceride (TG) accumulation and inflammatory levels, respectively. A previous study demonstrated that hepatic inflammatory levels are positively correlated with hepatic TG content. We therefore speculated that SREBP-1c might play an important role in the overactivation of the hepatic NF-κB inflammatory pathway in cows with fatty liver. Compared with healthy cows, cows with fatty liver exhibited severe hepatic injury and high blood concentrations of the inflammatory cytokines TNF-α, IL-6 and IL-1β. Hepatic SREBP-1c-mediated lipid synthesis and the NF-κB inflammatory pathway were both overinduced in cows with fatty liver. In vitro, treatment with non-esterified fatty acids (NEFA) further increased SREBP-1c expression and NF-κB pathway activation, which then promoted TG and inflammatory cytokine synthesis. SREBP-1c overexpression overactivated the NF-κB inflammatory pathway in hepatocytes by increasing ROS content and not through TLR4. Furthermore, SREBP-1c silencing decreased ROS content and further attenuated the activation of the NEFA-induced NF-κB pathway, thereby decreasing TNF-α, IL-6 and IL-1β synthesis. SREBP-1c-overexpressing mice exhibited hepatic steatosis and an overinduced hepatic NF-κB pathway. Taken together, these results indicate that SREBP-1c enhances the NEFA-induced overactivation of the NF-κB inflammatory pathway by increasing ROS in cow hepatocytes, thereby further increasing hepatic inflammatory injury in cows with fatty liver.

• Authors: Xinwei Li, Weikun Huang, Jingmin Gu, Xiliang Du, Lin Lei, Xue Yuan, Guoquan Sun, Zhe Wang, Xiaobing Li, Guowen Liu
• Journal: Cellular signalling (Cell Signal) Vol. 27 Issue 10 Pg. 2099-109 (Oct 2015) ISSN: 1873-3913 [Electronic] England
• PMID: 26189441 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier Inc.

Chemical References

• Reactive Oxygen Species
• Sterol Regulatory Element Binding Protein 1
• Toll-Like Receptor 4
• Transcription Factor RelA

Topics

• Animals
• Cattle
• Cattle Diseases (immunology, metabolism)
• Cells, Cultured
• Fatty Liver (immunology, metabolism, veterinary)
• Female
• Hepatocytes (immunology, metabolism)
• Liver (immunology, metabolism, pathology)
• Male
• Mice
• Reactive Oxygen Species (metabolism)
• Sterol Regulatory Element Binding Protein 1 (physiology)
• Toll-Like Receptor 4 (metabolism)
• Transcription Factor RelA (metabolism)