SIRT1 Modulators in Experimentally Induced Liver Injury

Abstract

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.

WITHDRAWN: Silent information regulator 1 ameliorates oxidative stress injury via PGC-1α/PPARγ-Nrf2 pathway after ischemic stroke in rat.

“…SIRT1 is an NAD+-dependent protein lysine deacetylase of the sirtuin family and exerts many physiological effects, mediating inflammation, cell survival, tissue regeneration, and stress responses [31]. SIRT also plays roles in modulating histone and nonhistone substrates, including DNA repair proteins and transcription factors (e.g., p53, nuclear factor-κB, and PGC-1α) [32].…”

“…xanthine oxidase and thiobarbituric acid, respectively. All assays were performed with kits (Nanjing Jiancheng Bioengineering Research Institute, Nanjing) [31]. A lipid peroxidase MDA detection kit (Jiancheng Biotechnology, Nanjing, Jiangsu, China) was used to determine the MDA content, and a micro flat-panel reader was used to determine the absorbance at 530 nm.…”

Nephroprotective effect of umbelliferone against cisplatin‐induced kidney damage is mediated by regulation of NRF2, cytoglobin, SIRT1/FOXO‐3, and NF‐kB‐p65 signaling pathways

“…[ 15 ] With oxidative stress, SIRT1 greatly protects the cell through the deacetylation of substrate proteins, which results in cell survival. [ 16 ] SIRT1 has the ability to deacetylate key metabolic players including peroxisome proliferator‐activated receptor (PPAR) gamma coactivator 1 alpha (PGC1α), a strategic controller of oxidative metabolism, and it induces enzymatic antioxidants. [ 17‐19 ] The forkhead box O (FOXO) transcription factor is involved in diverse cellular and physiological processes including cell proliferation, apoptosis, ROS response, longevity, cancer, and regulation of cell cycle and metabolism, [ 20 ] and it is one of the targets of SIRT.…”

N1-Methylnicotinamide Improves Hepatic Insulin Sensitivity via Activation of SIRT1 and Inhibition of FOXO1 Acetylation

“…Palmitate (PA) is a saturated fatty acid that induces IR in various scenarios, including hepatocytes [11]. Studies have shown that deacetylase sirtuin-1 (SIRT1) plays an important role in the regulation of liver metabolism [12][13][14]. SIRT1 agonists can cause the translocation of nuclear transcription factor FOXO1 in liver cells, inhibit gluconeogenesis, and improve insulin sensitivity [15].…”