Sirtuin 1 attenuates inflammation and hepatocellular damage in liver transplant ischemia/Reperfusion: From mouse to human

Abstract

Hepatic ischemia/reperfusion injury (IRI), an inevitable antigen-independent inflammation response in cadaveric liver transplantation, correlates with poor early graft function, rejection episodes, and contributes to donor organ shortage. Sirtuin 1 (SIRT1) is a histone deacetylase that may regulate inflammatory cell activity and manage liver function in IRI, though its functional role and clinical relevance remains to be elucidated. We investigated the efficacy of SIRT1 activation in a murine liver IRI model and verified the concept of putative SIRT1-mediated hepatoprotection in clinical liver transplantation. In the experimental arm, mice were subjected to 90 minutes of liver partial warm ischemia followed by 6 hours of reperfusion with or without adjunctive SIRT1 activation in vivo (resveratrol [Res]). In parallel, bone marrow–derived macrophage (BMDM) or spleen lymphocyte cultures were treated with Res. In the clinical arm, liver biopsies from 21 adult primary liver transplant patients (2 hours after reperfusion) were divided into “low” (n = 11) versus “high” (n = 10) SIRT1 expression groups, assessed by Western blots. Treatment with Res attenuated murine liver IRI while up-regulating SIRT1, suppressing leukocyte infiltration, and decreasing proinflammatory cytokine programs. SIRT1 silencing (small interfering RNA) in BMDM cultures enhanced inflammatory cytokine programs, whereas addition of Res decreased proinflammatory response in a SIRT1-dependent manner. In addition, Res decreased interferon γ production in liver-infiltrating and spleen lymphocyte cultures. Human liver transplants with high SIRT1 levels showed improved hepatocellular function and superior survival (P = 0.04), accompanied by lower proinflammatory cytokine profile. In conclusion, our translational study is the first to identify SIRT1 as a regulator of hepatocellular function in human liver transplant recipients under ischemia/reperfusion stress. By targeting innate and adaptive immune activation, manipulation of SIRT1 signaling should be considered as a novel means to combat inflammation in liver transplantation.

Heme oxygenase-1 regulates sirtuin-1–autophagy pathway in liver transplantation: From mouse to human

“…We have also recently reported on the anti-inflammatory and hepatoprotective role of SIRT1 activation in a warm liver IRI mouse model alongside negative correlation between SIRT1 and T-bet/IL-1β levels in twenty-one clinical OLT cases (23). The positive SIRT1 regulation by HO-1 seen in a mouse IRI model was then confirmed in twenty-one OLT patient cohort (41).…”

“…The mechanisms accounting for HO-1 mediated SIRT1 upregulation remain largely unknown. As oxidative stress suppresses hepatic SIRT1 (23, 49), anti-oxidant properties may be the key for HO-1 to regulate SIRT1 expression.…”

“…Primary Ab detecting HO-1 (Enzo Life Sciences, Farmingdale, NY), SIRT1, LC3B, β-actin (Cell Signaling Technology, Danvers, MA) were used. To compare target protein expression in multiple human OLT samples, densitometry quantification was conducted using a reference sample and normalization with β-actin as reported (23). …”

“…In addition to an anti-inflammatory role in pathogenesis of liver IRI (23), recent studies have demonstrated the significance of SIRT1-induced autophagy in hepatocyte resistance against IR-stress (24, 25). Molecular communication between SIRT1 and HO-1 in OLT has not been studied and the mechanism by which SIRT1 may regulate the HO-1 autophagy pathway remains to be elucidated.…”

“…Sirtuin 1 (SIRT1), an NAD + -dependent type III histone/protein deacetylase involved in cellular senescence, inflammation, and stress resistance, 20 plays a key role in autophagy induction. 21,22 In addition to an anti-inflammatory role in the pathogenesis of liver IRI, 23 recent studies have demonstrated the significance of SIRT1-induced autophagy in hepatocyte resistance against IR stress. 24,25 Molecular communication between SIRT1 and HO-1 in OLT has not been studied, and the mechanism by which SIRT1 may regulate the HO-1 autophagy pathway remains to be elucidated.…”