Non-esterified Fatty Acid Induce Dairy Cow Hepatocytes Apoptosis via the Mitochondria-Mediated ROS-JNK/ERK Signaling Pathway

Abstract

Elevated plasma non-esterified fatty acid (NEFA) levels and hepatocytes damage are characteristics of ketosis in dairy cows. Oxidative stress is associated with the pathogenesis of NEFA-induced liver damage. However, the exact mechanism by which oxidative stress mediates NEFA-induced hepatocytes apoptosis and liver injury remains poorly understood. The results of the present study demonstrated that NEFA contribute to reactive oxygen species (ROS) generation, resulting in an imbalance between oxidative and antioxidant species, transcriptional activation of p53, transcriptional inhibition of nuclear factor E2-related factor 2 (Nrf2), loss of mitochondria membrane potential (MMP) and release of apoptosis-inducing factor (AIF) and cytochrome c (cyt c) into the cytosol, leading to hepatocytes apoptosis. Besides, NEFA triggered apoptosis in dairy cow hepatocytes via the regulation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), Bcl-2-associated X protein (Bax), B-cell lymphoma gene 2 (Bcl-2), caspase 9 and poly (ADP-ribose) polymerase (PARP). Pretreatment with the inhibitor SP600125 or PD98059 or the antioxidant N-acetylcysteine (NAC) revealed that NEFA-ROS-JNK/ERK-mediated mitochondrial signaling pathway plays a crucial role in NEFA-induced hepatocytes apoptosis. Moreover, the results suggested that the transcription factors p53 and Nrf2 function downstream of this NEFA-ROS-JNK/ERK pathway and are involved in NEFA-induced hepatocytes apoptosis. In conclusion, these findings indicate that the NEFA-ROS-JNK/ERK-mediated mitochondrial pathway plays an important role in NEFA-induced dairy cow hepatocytes apoptosis and strongly suggests that the inhibitors SP600125 and PD98059 and the antioxidant NAC may be developed as therapeutics to prevent hyperlipidemia-induced apoptotic damage in ketotic dairy cows.

Involvement of Nrf2-HO-1/JNK-Erk Signaling Pathways in Aconitine-Induced Developmental Toxicity, Oxidative Stress, and ROS-Mitochondrial Apoptosis in Zebrafish Embryos

“…Excessive generation of ROS in cells leads to activation of MAPK pathways, including ERKs, JNKs, or p38 MAPKs ( Thongsom et al, 2017 ). ROS activated JNK phosphorylation in berberine- and free fatty acid-induced SW620 cells triggered bovine hepatocytes apoptosis and downregulated ERK phosphorylation in response to 4-OHE2–induced cell death ( Li et al, 2020b ). The changes in JNK and ERK that are induced by many stimuli are involved in the transcription or phosphorylation of Nrf2 ( Cheng et al, 2008 ; Sun et al, 2009 ).…”

Targeting autophagy enhances atezolizumab-induced mitochondria-related apoptosis in osteosarcoma

“…Meanwhile, the excessive release of cyto-c could bind to APAF-1 in cytoplasm and thus activate caspase-9, one of the initiators of apoptosis, and eventually activating caspase-3 causing mitochondria-related apoptosis in cells [31][32][33] . The activation of JNK pathway is closely related to the tumor cell apoptosis, especially to the mitochondria-related apoptosis 34,35 . And we propose that the immune-independent cytotoxicity of Fig.…”

Palmitate and pyruvate carbon flux in response to choline and methionine in bovine neonatal hepatocytes

“…Choline infusion increased serum choline in calves and attenuated the clinical and inflammatory response and oxidative stress of induced endotoxemia, potentially by modulating the balance between oxidative stress and antioxidant capacity 31,32 . Additionally, recent work suggests that the NEFA-ROS-JNK/ERK-mediated mitochondrial signaling pathway may lead to NEFA-induced hepatocyte apoptosis 33 . Although connections between this signaling pathway and choline have not been noted in dairy cattle previously, it warrants future exploration.…”