Therapeutic effect of Sirtuin 3 on ameliorating nonalcoholic fatty liver disease: The role of the ERK-CREB pathway and Bnip3-mediated mitophagy

Abstract

Increased mitochondrial damage is related to the progression of a diet-induced nonalcoholic fatty liver disease. The aim of our study is to investigate the role of Sirtuin 3 (Sirt3) in treating nonalcoholic fatty liver disease with a focus on mitophagy and the ERK-CREB pathway. Our data indicated that Sirt3 was downregulated in liver tissue in response to chronic HFD treatment. Interestingly, re-introduction of Sirt3 protected hepatic function, attenuated liver fibrosis, alleviated the inflammatory response, and prevented hepatocyte apoptosis. Molecular investigations demonstrated that lipotoxicity was associated with an increase in mitochondrial apoptosis as evidenced by reduced mitochondrial potential, augmented ROS production, increased cyt-c leakage into the nucleus, and activated caspase-9 apoptotic signalling. Additionally, Sirt3 overexpression protected hepatocytes against mitochondrial apoptosis via promoting Bnip3-required mitophagy. Functional studies showed that Sirt3 reversed Bnip3 expression and mitophagy activity via the ERK-CREB signalling pathway. Blockade of the ERK-CREB axis repressed the promotive effects of Sirt3 on Bnip3 activation and mitophagy augmentation, finally negating the anti-apoptotic influences of Sirt3 on hepatocytes in the setting of high-fat-stress. Collectively, our data show that high-fat-mediated liver damage is associated with Sirt3 downregulation, which is followed by ERK-CREB pathway inactivation and Bnip3-mediated inhibition of mitophagy, causing hepatocytes to undergo mitochondria-dependent cell death. Based on this, strategies for enhancing Sirt3 activity and activating the ERK-CREB-Bnip3-mitophagy pathways could be used to treat nonalcoholic fatty liver disease.

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

“…The influence of mitochondrial stress on neuronal injury has been extensively explored. For example, in spinal cord injury, mitochondrial dysfunction is associated with neuronal apoptosis in a manner dependent on Akt‐GSK3β pathway . In hippocampal neuron development, mitochondrial dysfunction promotes chronic energy depletion due to iron deficiency.…”

“…For example, in spinal cord injury, mitochondrial dysfunction is associated with neuronal apoptosis in a manner dependent on Akt-GSK3β pathway. 67,68 In hippocampal neuron development, mitochondrial dysfunction promotes chronic energy depletion due to iron deficiency. Besides, attenuation of mitochondrial oxidative stress via antioxidant mitoQ improves RPS-mediated sensorineural hearing loss.…”

Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway

“…Moreover, mitochondrial apoptosis has been acknowledged as the primary reason for reperfusion-mediated renal tubular epithelial cell apoptosis [53]. In addition, mitochondrial DNA damage [54], mitochondrial biosynthesis disorder [55], and mitophagy delay [56] have been found to be implicated in mitochondrial dysfunction and renal damage exerted by I/R injury. In the present study, we also found that mitochondria were the potential target of the renal I/R injury.…”

Melatonin attenuates myocardial ischemia‐reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK‐OPA1 signaling pathways

“…State 3 respiration was initiated by adding ADP (150 nmol/L); state 4 was measured as the rate of oxygen consumption after ADP phosphorylation. The respiratory control ratio (state 3/state 4) and the ADP/O ratio (number of nmol ADP phosphorylated to atoms of oxygen consumed) were calculated as previously described …”