AIM: Currently available medicines have little to offer in terms of supporting the regeneration of injured hepatic cells. Previous experimental studies have shown that resveratrol and metformin, less specific activators of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), can effectively attenuate acute liver injury. The aim of this experimental study was to elucidate whether modulation of AMPK and SIRT1 activity can modify drug/paracetamol (APAP)-induced hepatocyte damage in vitro. METHODS: Primary rat hepatocytes were pretreated with mutual combinations of specific synthetic activators and inhibitors of SIRT1 and AMPK and followed by a toxic dose of APAP. At the end of cultivation, medium samples were collected for biochemical analysis of alanine-aminotransferase and nitrite levels. Hepatocyte viability, thiobarbituric reactive substances, SIRT1 and AMPK activity and protein expression were also assessed. RESULTS: The harmful effect of APAP was associated with decreased AMPK and SIRT1 activity and protein expression alongside enhanced oxidative stress in hepatocytes. The addition of AMPK activator (AICAR) or SIRT1 activator (CAY10591) significantly attenuated the deleterious effects of AMPK inhibitor (Compound C) on the hepatotoxicity of APAP. Furthermore, CAY10591 but not AICAR markedly decreased the deleterious effect of APAP in combination with SIRT1 inhibitor (EX-527). CONCLUSION: Our findings demonstrate that decreased AMPK activity is associated with the hepatotoxic effect of APAP which can be significantly attenuated by the administration of a SIRT1 activator. These findings suggest that differentiated modulation of AMPK and SIRT1 activity could therefore provide an interesting and novel therapeutic opportunity in the future to combat hepatocyte injury.

• Keywords
• 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), CAY10591, adenosine monophosphate protein kinase (AMPK), enzyme activation, hepatocyte protection, sirtuin 1 (SIRT1),
• MeSH
• Cyclopentanes pharmacology   MeSH
• Hepatocytes * metabolism   MeSH
• Rats MeSH
• Chemical and Drug Induced Liver Injury * etiology   genetics   metabolism   pathology   MeSH
• Acetaminophen toxicity   MeSH
• AMP-Activated Protein Kinases * chemistry   metabolism   pharmacology   MeSH
• Sirtuin 1 * metabolism   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• CAY10591 MeSH Browser
• Cyclopentanes MeSH
• Acetaminophen MeSH
• AMP-Activated Protein Kinases * MeSH
• Sirt1 protein, rat MeSH Browser
• Sirtuin 1 * MeSH

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.

• MeSH
• Chemical and Drug Induced Liver Injury drug therapy   enzymology   MeSH
• Humans MeSH
• Polyphenols pharmacology   MeSH
• Sirtuin 1 antagonists & inhibitors   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Polyphenols MeSH
• Sirtuin 1 MeSH