β-Hydroxybutyrate (BHB) is an important indicator for metabolic disorders in dairy cows, such as ketosis and fatty liver. Dairy cows with ketosis display oxidative stress that may be associated with high levels of BHB. The purpose of this study was to demonstrate a correlation between the high levels of BHB and oxidative stress in dairy cows with ketosis, and to investigate the molecular mechanisms underlying oxidative damage in bovine hepatocytes. The results showed that dairy cows with ketosis exhibited oxidative stress and liver damage, which was significantly correlated with plasma BHB. Similarly, high concentrations of BHB increased the oxidative stress of cow hepatocytes in vitro, resulting in the phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK), which led to increased expression, nuclear localization, and transcriptional activity of p53 and decreased Nrf2 in bovine hepatocytes. High concentrations of BHB significantly increased the expression of proapoptotic genes and significantly inhibited the expression of antiapoptotic genes. Finally, high concentrations of BHB promoted apoptosis in bovine hepatocytes. N-Acetyl-l-cysteine, glucose, and SB203580 (p38 inhibitor) significantly attenuated BHB-induced apoptotic damage in hepatocytes. These results indicate that BHB induces bovine hepatocyte apoptosis through the ROS-p38-p53/Nrf2 signaling pathway.
Dairy cows with ketosis are characterized by oxidative stress, hepatic damage, and hyperketonemia. Acetoacetate (AA) is the main component of ketone bodies in ketotic cows, and is associated with the above pathological process. However, the potential mechanism was not illuminated. Therefore, the aim of this study was to investigate the mechanism of AA-induced hepatic oxidative damage in ketotic cows. Compared with healthy cows, ketotic cows exhibited severe oxidative stress and hepatic damage. Moreover, the extent of hepatic damage and oxidative stress had a positive relationship with the AA levels. In vitro, AA treatment increased reactive oxygen species (ROS) content and further induced oxidative stress and apoptosis of bovine hepatocytes. In this process, AA treatment increased the phosphorylation levels of JNK and p38MAPK and decreased the phosphorylation level of ERK, which could increase p53 and inhibit nuclear factor E2-related factor 2 (Nrf2) expression, nuclear localization, and DNA-binding affinity, thereby inducing the overexpression of pro-apoptotic molecules Bax, Caspase 3, Caspase 9, PARP and inhibition of anti-apoptotic molecule Bcl-2. Antioxidant N-acetylcysteine (NAC) treatment or interference of MAPKs pathway could attenuate the hepatocytes apoptosis induced by AA. Collectively, these results indicate that AA triggers hepatocytes apoptosis via the ROS-mediated MAPKs pathway in ketotic cows.
The hepatic growth hormone (GH)-insulin-like growth factor (IGF)-I axis is essential for regulating intrahepatic lipid metabolism. Ketotic cows are characterized by high blood concentrations of fatty acids and β-hydroxybutyrate (BHB), which display lipotoxicity. The aim of this study was to investigate changes in the hepatic GH-IGF-I axis in ketotic cows and to determine the effects of fatty acids and BHB on the GH-IGF-I axis in calf hepatocytes. Liver and blood samples were collected from healthy (n = 15) and clinically ketotic (n = 15) cows. Hepatocytes were isolated from calves and treated with various concentrations of GH, fatty acids, and BHB. The results showed that clinically ketotic cows displayed a high blood concentration of GH, a low blood concentration of IGF-I, and decreased hepatic GHR1A expression as well as impaired hepatic Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling. In vitro, GH treatment induced activation of the JAK2-STAT5 pathway to increase the mRNA expression and secretion of IGF-I in calf hepatocytes. More importantly, treatment with fatty acids or BHB significantly inhibited GHR1A mRNA and JAK2 protein expression, as well as the STAT5 phosphorylation level and phospho-STAT5 nuclear translocation; these effects markedly reduced IGF1 mRNA expression and secretion in calf hepatocytes. In summary, these results indicate that high blood concentrations of fatty acids or BHB can impair the intrahepatic GH-mediated JAK2-STAT5 pathway and downregulate IGF-I expression and secretion in ketotic cows.
A high plasma concentration of non-esterified fatty acids (NEFAs) is an important pathogenic factor that leads to ketosis and fatty liver in dairy cows. NEFAs may be associated with oxidative stress in dairy cows with ketosis or fatty liver and the subsequent induction of hepatocyte damage. However, the molecular mechanism of NEFAs-induced oxidative stress and whether NEFAs cause apoptosis of hepatocytes are unclear. Therefore, the aim of this study was to investigate the molecular mechanism of NEFAs-induced oxidative liver damage in bovine hepatocytes. The results showed that NEFAs increased oxidative stress, resulting in p38 phosphorylation. High activated p38 increased the expression, nuclear localization and transcriptional activity of p53 and decreased the nuclear localization and transcriptional activity of Nrf2 in bovine hepatocytes treated with high concentrations of NEFAs. High concentrations of NEFAs also promoted the apoptosis of bovine hepatocytes. Both N-acetyl-L-cysteine (NAC) and glucose (GLU) could attenuate the NEFA-induced apoptotic damage. These results indicate that NEFAs activate the ROS-p38-p53/Nrf2 signaling pathway to induce apoptotic damage in bovine hepatocytes.
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