Sirtuin 1 Stimulation Attenuates Ischemic Liver Injury and Enhances Mitochondrial Recovery and Autophagy

Abstract

Objective Hepatic ischemia-reperfusion (I/R) is a major clinical problem with limited treatment options. The pathophysiology of hepatic I/R is characterized by mitochondrial dysfunction and cellular energy deficits. Sirtuin 1 (Sirt1) is an energy-sensing enzyme known to modulate mitochondrial biogenesis. We hypothesized that pharmacologic activation of Sirt1 is protective after hepatic I/R injury. Design Animal study. Setting University-based experimental laboratory. Subjects Wild-type C57BL/6 mice. Interventions C57BL/6 mice were subjected to 60-min partial hepatic I/R and post-treated with Sirt1 activator, SRT1720 (20 mg/kg), or vehicle. Blood and liver were collected at 24 h after I/R for analyses of hepatic injury, ATP levels, mitochondrial mass, autophagy, inflammation, and oxidative stress. H4IIE hepatoma cells and rat primary hepatocytes were incubated with oxyrase to induce hypoxia followed by reoxygenation (H/R) in the presence or absence of SRT1720 for assessment of mitochondrial mass, mitochondrial membrane potential, and autophagy. Measurements and Main Results SRT1720 restored the reduction in mitochondrial mass, enhanced autophagy, and preserved ATP levels in the liver after I/R, which was associated with a decrease in I/R-induced hepatic injury, apoptosis, and necrosis. I/R-induced inflammation was also significantly reduced by SRT1720 as measured by systemic and hepatic cytokine and chemokine levels as well as a decrease in neutrophil infiltration to the liver. Further, oxidative stress was markedly attenuated in the SRT1720-treated mice, compared to the vehicle. SRT1720 treatment increased ATP levels and survival of cultured hepatocytes after H/R. SRT1720 not only increased the mitochondrial mass but also increased mitochondrial membrane potential per cell in cultured hepatocytes after H/R. Moreover, SRT1720 prevented the H/R-induced mitochondrial depolarization and resulted in an enhancement of autophagy in cultured hepatocytes after H/R. Conclusions Pharmacologic stimulation of Sirt1 attenuates liver injury after hepatic I/R by restoring mitochondrial mass and membrane potential, which is associated with the enhancement of autophagy.

Resolvin D1 attenuates liver ischaemia/reperfusion injury through modulating thioredoxin 2‐mediated mitochondrial quality control

“…These NRFs activate TFAM, which drives mitochondrial gene transcription and genome replication (Ventura‐Clapier et al ., ). In rat primary hepatocytes subjected to H/R, TFAM protein levels decreased along with mitochondrial mass and membrane potential decrease (Khader et al ., ). Interestingly, in our study, the levels of PGC1α, NRF1 and TFAM protein expression and mtDNA copy number were reduced by IR, and RvD1 attenuated these changes, suggesting that RvD1 activates mitochondrial biogenesis.…”

Sirtuin-1 expression and activity is diminished in aged liver grafts

“…Second, we assessed mitochondrial function indirectly by measuring ATP and ADP levels in the tissue. While this is a standard approach in ischemia-reperfusion models 14,17 , alternative techniques to directly measure mitochondrial function such as high resolution respirometry may provide more precision. Finally, due to the limited availability of old rats, we included 2 strains (Lewis and ACI), with the ACI strain serving as the untreated control.…”

SRT1720, a sirtuin 1 activator, attenuates organ injury and inflammation in sepsis

“…31 Furthermore, we previously have demonstrated that SRT1720 treatment inhibits oxidative stress, reduces apoptosis, and restores mitochondrial integrity in the liver of mice after hepatic ischemia-reperfusion injury. 15 Upregulation of Sirt1 has also been shown to inhibit apoptosis and protect against oxidative stress, ameliorating hepatic steatosis and acute liver injury. 44 Therefore, SRT1720 may act through Sirt1 to attenuate the ROS production and maintain mitochondrial homeostasis, leading to downregulation of the of NLRP3 activation in the liver of septic mice.…”

“…11 Activation of Sirt1has been demonstrated to improve metabolism in murine models of cardiac, renal, intestinal, and hepatic ischemia-reperfusion injury. 12-15 In addition to its role in metabolic modulation, Sirt1 has also played a direct role in regulating inflammation, 16 such as by modulating the activity of nuclear factor kappa B (NF-κB), a critical transcription factor in the regulation of proinflammatory cytokine production. 17 …”