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This article is directed at highlighting the involvement of the endogenous stress sensor SIRT1 (silent information regulator T1) as a possible factor involved in hepatoprotection. The selective SIRT1 modulators whether activators (STACs) or inhibitors are being tried experimentally and clinically. We discuss the modulation of SIRT1 on cytoprotection or even cytotoxicity in the liver chemically injured by hepatotoxic agents in rats, to shed light on the crosstalk between SIRT1 and its modulators. A combination of D-galactosamine and lipopolysaccharide (D-GalN/LPS) downregulated SIRT1 expression, while SIRT1 activators, SRT1720, resveratrol, and quercetin, upregulated SIRT1 and alleviated D-GalN/LPS-induced acute hepatotoxicity. Liver injury markers exhibited an inverse relationship with SIRT1 expression. However, under subchronic hepatotoxicity, quercetin decreased the significant increase in SIRT1 expression to lower levels which are still higher than normal ones and mitigated the liver-damaging effects of carbon tetrachloride. Each of these STACs was hepatoprotective and returned the conventional antioxidant enzymes to the baseline. Polyphenols tend to fine-tune SIRT1 expression towards normal in the liver of intoxicated rats in both acute and subchronic studies. Together, all these events give an impression that the cytoprotective effects of SIRT1 are exhibited within a definite range of expression. The catalytic activity of SIRT1 is important in the hepatoprotective effects of polyphenols where SIRT1 inhibitors block and the allosteric SIRT1 activators mimic the hepatoprotective effects of polyphenols. Our findings indicate that the pharmacologic modulation of SIRT1 could represent both an important move in alleviating hepatic insults and a future major step in the treatment of xenobiotic-induced hepatotoxicity.

The present review is intended to focus on naturally occurring cytoprotective agents such as resveratrol (trans-3,4’,5-trihydroxystilbene) and other related compounds, probably with similar molecular mechanisms of action and high capacity to find applications in medical fields. Several physiological aspects have been ascribed to resveratrol and similar compounds. Resveratrol, among others, has been recently described as a silent information regulator T1 (SIRT1) activator that increases AMP-activated protein kinase (AMPK) phosphorylation and reduces the oxidative damage biomarkers during aging in laboratory settings. The reports on resveratrol and other SIRT1 activators from various sources are encouraging. The pharmacological strategies for modulation of sirtuins by small molecules through allosteric mechanisms should gain a greater momentum including human research. Resveratrol and resveratrol-like molecules seem to fulfill the requirement of a new horizon in drug research since these molecules cover a growing research means as antioxidants with allosteric mechanism in epigenetic drug targets. However, one should keep in mind the challenges of extrapolation of basic research into clinical results. Overall, the issue of sirtuins in biology and disease provides an insight on therapeutic potentials of sirtuin-based therapeutics and demonstrates the high complexity of drug-targeting these modalities for human applications.

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D-Galactosamine/Lipopolysaccharide (D-GalN/LPS) is a well known model of hepatotoxicity that closely resembles acute liver failure (ALF) seen clinically. The role of sirtuin 1 in this model has not yet been documented. However, there have been a number of studies about the cytoprotective effects of resveratrol, a SIRT1 activator, in the liver. This study was aimed at elucidating the roles of SIRT1 protein expression or catalytic activity in D-GalN/LPS model of hepatotoxicity. ALF was induced in male Wistar rats by intraperitoneal injection of D-GalN and LPS. Some groups of animals were pretreated with resveratrol and/or EX-527 (SIRT1 inhibitor). The effects of these treatments were evaluated by biochemical and Western blot studies. D-GalN/LPS treatment was able to induce hepatotoxicity and significantly increase all markers of liver damage and lipid peroxidation. A dramatic decrease of SIRT1 levels in response to D-GalN/LPS treatment was also documented. Resveratrol pretreatment attenuated D-GalN/LPS-induced hepatotoxicity. EX-527 blocked the cytoprotective effects of resveratrol. However, both resveratrol and EX-527 pretreatments did not exhibit any significant effect on SIRT1 protein expression. Collectively, these results suggest that downregulation of SIRT1 expression is involved in the cytotoxic effects of D-GalN/LPS model and SIRT1 activity contributes to the cytoprotective effects of resveratrol in the liver.

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This mini-review highlights our and others’ experience about in vitro and in vivo models that are being used to follow up events of liver injuries under various hepatotoxic agents and potential hepatoprotective drugs. Due to limitations of the outcomes in each model, we focus primarily on two models. First, a developed perfusion method for isolated immobilized hepatocytes that improves the process of oxygenation and helps in end-product removal is of considerable value in improving cell maintenance. This cellular model is presented as a short-term research-scale laboratory bioreactor with various physiological, biochemical, molecular, toxicological and pharmacological applications. Second, the in vivo model of D-galactosamine and lipopolysaccharide (D-GalN/LPS) combination-induced liver damage is described with some details. Recently, we have revealed that resveratrol and other natural polyphenols attenuate D-GalN/LPS-induced hepatitis. Moreover, we reported that D-GalN/LPS down-regulates sirtuin 1 in rat liver. Therefore, we discuss here the role of sirtuin 1 modulation in hepatoprotection. A successful development of pharmacotherapy for liver diseases depends on the suitability of in vitro and in vivo hepatic injury systems. Several models are available to screen the hepatotoxic or hepatoprotective activity of any substance. It is important to combine different methods for confirmation of the findings.

Sirtuin 1 (SIRT1) is involved in important biological processes such as energy metabolism and regulatory functions of the cell cycle, apoptosis, and inflammation. Our previous studies have shown hepatoprotective effect of polyphenolic compound resveratrol, which is also an activator of SIRT1. Therefore, the aim of our present study was to clarify the role of SIRT1 in process of hepatoprotection in animal model of drug-induced liver damage. Male Wistar rats were used for both in vivo and in vitro studies. Hepatotoxicity was induced by single dose of acetaminophen (APAP). Some rats and hepatocytes were treated by resveratrol or synthetic selective activator of sirtuin 1 (CAY10591). The degree of hepatotoxicity, the activity and expression of the SIRT1 were determined by biochemical, histological and molecular-biological assessments of gained samples (plasma, liver tissue, culture media and hepatocytes). Resveratrol and CAY attenuated APAP-induced hepatotoxicity in vivo and in vitro. Moreover, both drugs enhanced APAP-reduced SIRT1 activity. Our results show that modulation of the SIRT1 activity plays a role in hepatoprotection. Synthetic activators of SIRT1 would help in understanding the role of SIRT1 and are therefore a major boost towards the search for specific treatment of liver disease.