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Review
. 2018 Nov 13:2018:2976957.
doi: 10.1155/2018/2976957. eCollection 2018.

SIRT3 a Major Player in Attenuation of Hepatic Ischemia-Reperfusion Injury by Reducing ROS via Its Downstream Mediators: SOD2, CYP-D, and HIF-1 α

Gaurav Katwal  1 , Dilip Baral  1 , Xiaoli Fan  1 , He Weiyang  1 , Xinjiang Zhang  1 , Li Ling  1 , Yan Xiong  1 , Qifa Ye  1   2 , Yanfeng Wang  1
Affiliations
Review

SIRT3 a Major Player in Attenuation of Hepatic Ischemia-Reperfusion Injury by Reducing ROS via Its Downstream Mediators: SOD2, CYP-D, and HIF-1 α

Gaurav Katwal et al. Oxid Med Cell Longev. .

Abstract

Reactive oxygen species (ROS) production in hepatic ischemia-reperfusion injury (IRI) is a complex process where multiple cellular and molecular pathways are involved. Few of those molecular pathways are under the direct influence of SIRT3 and its downstream mediators. SIRT3 plays a major role in the mechanism of IRI, and its activation has been shown to attenuate the deleterious effect of ROS during IRI via SOD2-, CYP-D-, and HIF-1α-mediated pathways. The objective of this review is to analyze the current knowledge on SIRT3 and its downstream mediators: SOD2, CYP-D, and HIF-1α, and their role in IRI. For the references of this review article, we have searched the bibliographic databases of PubMed, Web of Science databases, MEDLINE, and EMBASE with the headings "SIRT3," "SOD2," "CYP-D," "HIF-1α," and "liver IRI." Priority was given to recent experimental articles that provide information on ROS modulation by these proteins. All the recent advancement demonstrates that activation of SIRT3 can suppress ROS production during IRI through various pathways and few of those are via SOD2, CYP-D, and HIF-1α. This effect can improve the quality of the remnant liver following resection as well as a transplanted liver. More research is warranted to disclose its role in IRI attenuation via this pathway.

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Figures

Figure 1
Figure 1
Increased activity of Sirt3 promotes deacetylation of SOD2. Increased activity of Sirt3 promotes deacetylation of SOD2; this reduces the cellular oxidative stress via ROS scavenging. Sirt3 also stabilizes HIF1α, which activates Sirt3 gene promoter that leads to increased synthesis of Sirt3 mRNA transcripts, and deactivates CYPD and subsequently decreases mPTP opening. All these processes orchestrate to reduce hepatocyte damage. Dihydromyricetin (DHM), ischemic preconditioning (IPC), and Resveratrol (RSV).
Figure 2
Figure 2
Illustration of adopted and simplified mPTP complex [53]. Increased mitochondrial oxidative stress primes CypD to bind with ANT (thiol oxidation-dependent), and VDAC-ANT complex causes mPTP opening. Increased activities of Sirt3 inhibit CypD-ANT bond and subsequently suppress mPTP opening. For detailed mPTP complex structure please refer to Rizwan, M. et al. [53]
Figure 3
Figure 3
Illustration of HIF-1α stabilization via different pathways that finally leads to a decrease in inflammation, necrosis/apoptosis, and IRI of hepatocytes. HIF-1α stabilization also leads to an increase in aerobic glycolysis, angiogenesis, and metastasis, a sequel of tumorigenesis. Please find detail explanation in HIF-1α Stabilization via SIRT3 Modulates IRI. Heme oxygenase-1 (HO-1), Institute Georges Lopez preservation solution (IGL-1), mangafodipir (MnDPDP), and nitric oxide (NO).
Figure 4
Figure 4
Illustration of surgical and pharmacological Ischemic preconditioning (IPC) via multiple pathways that modulates inflammation and reduces oxidative stress by decreasing mitochondrial ROS. Please find detail explanation in Ischemic Preconditioning (IPC). Adenosine A1 receptors (A1R), deferoxamine (DFX), heme oxygenase-1 (HO-1), intermittent clamping (IC), and induced nitric oxide synthetase (iNOS).
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