�-Hydroxybutyrate Activates the NF-κB Signaling Pathway to Promote the Expression of Pro-Inflammatory Factors in Calf Hepatocytes

Abstract

Background/Aims: ß-hydroxybutyrate (BHBA) is the major component of ketone bodies in ketosis. Dairy cows with ketosis often undergo oxidative stress. BHBA is related to the inflammation involved in other diseases of dairy cattle. However, whether BHBA can induce inflammatory injury in dairy cow hepatocytes and the potential mechanism of this induction are not clear. The NF-κB pathway plays a vital role in the inflammatory response. Methods: Therefore, this study evaluated the oxidative stress, pro-inflammatory factors and NF-κB pathway in cultured calf hepatocytes treated with different concentrations of BHBA, pyrrolidine dithiocarbamate (PDTC, an NF-κB pathway inhibitor) and N-acetylcysteine (NAC, antioxidant). Results: The results showed that BHBA could significantly increase the levels of oxidation indicators (MDA, NO and iNOS), whereas the levels of antioxidation indicators (GSH-Px, CAT and SOD) were markedly decreased in hepatocytes. The IKKß activity and phospho-IκBa (p-IκBa) contents were increased in BHBA-treated hepatocytes. This increase was accompanied by the increased expression level and transcription activity of p65. The expression levels of NF-κB-regulated inflammatory cytokines, namely TNF-a, IL-6 and IL-1ß, were markedly increased after BHBA treatment, while significantly decreased after NAC treatment. However, the p-IκBa level and the expression and activity of p65 and its target genes were markedly decreased in the PDTC + BHBA group compared with the BHBA (1.8 mM) group. Moreover, immunocytofluorescence of p65 showed a similar trend. Conclusion: The present data indicate that higher concentrations of BHBA can induce cattle hepatocyte inflammatory injury through the NF-κB signaling pathway, which may be activated by oxidative stress.

β-Hydroxybutyrate Facilitates Fatty Acids Synthesis Mediated by Sterol Regulatory Element-Binding Protein1 in Bovine Mammary Epithelial Cells

“…However, excessive NEB-induced lipid mobilization leads to hyperketonemia, which displayed high blood concentrations of BHBA. Previous reports indicated that high serum BHBA had strong connection with milk production, poor reproduction and inflammation in dairy cows [8,22]. Thus, high concentrations of BHBA could influence milk fat synthesis in bovine mammary epithelial cells.…”

“…The variations might be due to significant differences in BHBA treatment concentrations or cell line. Shi et al reported that high levels of BHBA could induce oxidative stress in hepatocytes of cows [8]. Under physiological condition, BHBA is the main fat milk precursor and used for the milk fat synthesis.…”

“…Recent research suggested that BHBA functioned as a signal molecule activating some signal pathways involved in inflammation and thermogenesis [8,9]. In ruminants, BHBA is utilized as precursors of de novo synthesized fatty acids in bovine mammary gland [10].…”

Hyperketonemia and ketosis increase the risk of complications in type 1 diabetes

“…The inflammatory response is mediated by signaling molecules such as cytokines. It has been suggested that ketones are directly involved in promoting pro-inflammatory factors and eliciting systemic inflammation [39, 53]. The role of elevated ketones in macrophage and lymphocyte activation, cytokine release, and perturbation of the endothelial cells lining the capillaries has been reported in T1D patients [54].…”

Hyperketonemia (Acetoacetate) Upregulates NADPH Oxidase 4 and Elevates Oxidative Stress, ICAM-1, and Monocyte Adhesivity in Endothelial Cells

“…Ketosis mediated cerebrovascular endothelial dysfunction has been shown to be associated with intracranial microvascular complications [20]. Studies have also shown that ketones can promote pro-inflammatory factors and elicit systemic inflammation [20,21]. …”