Hepatic Sirt6 activation abrogates acute liver failure

Area of Science:

• Hepatology
• Molecular Biology
• Biochemistry

Background:

• Acute liver failure (ALF) is a critical condition with limited treatment options.
• Acetaminophen (APAP) overdose is a leading cause of drug-induced ALF, but its mechanisms are not fully understood.
• Sirtuin 6 (Sirt6), a deacetylase, is involved in DNA repair, genomic stability, oxidative stress, and inflammation.

Purpose of the Study:

• To investigate the role of Sirtuin 6 (Sirt6) in acetaminophen-induced acute liver failure (ALF).
• To evaluate the therapeutic potential of Sirt6 activation for ALF.

Main Methods:

• Assessed Sirt6 expression in human ALF patients and APAP-treated mice.
• Utilized inducible Sirt6 transgenic (Sirt6-Tg, Sirt6-HepTg) and knockout (Sirt6-KO) mice.
• Administered APAP overdose and analyzed liver damage, apoptosis, necrosis, oxidative stress, inflammation, JNK, and PARP1.
• Tested Sirt6 activator MDL-800 and acetylcysteine.
• Examined Sirt6's role in bile duct ligation-induced ALF.

Main Results:

• Sirt6 expression was reduced in ALF livers.
• Sirt6 overexpression protected against APAP hepatotoxicity, while Sirt6 knockout exacerbated it.
• Sirt6 attenuated hepatocyte damage by downregulating oxidative stress, inflammation, JNK, and caspase activation.
• Sirt6 negatively modulated PARP1.
• MDL-800 showed therapeutic potential, outperforming acetylcysteine.
• Sirt6 also impacted bile duct ligation-induced ALF.

Conclusions:

• Sirt6 activation confers significant protection against acute liver failure.
• Targeting Sirt6 represents a novel therapeutic strategy for ALF, particularly for acetaminophen overdose.