SIRT1 antagonizes liver fibrosis by blocking hepatic stellate cell activation in mice

Abstract

Hepatic stellate cells (HSCs) are a major source of fibrogenesis in the liver, contributing to cirrhosis. When activated, HSCs transdifferentiate into myofibroblasts and undergo profound functional alterations paralleling an overhaul of the transcriptome, the mechanism of which remains largely undefined. We investigated the involvement of the class III deacetylase sirtuin [silent information regulator 1 (SIRT1)] in HSC activation and liver fibrosis. SIRT1 levels were down-regulated in the livers in mouse models of liver fibrosis, in patients with cirrhosis, and in activated HSCs as opposed to quiescent HSCs. SIRT1 activation halted, whereas SIRT1 inhibition promoted, HSC transdifferentiation into myofibroblasts. Liver fibrosis was exacerbated in mice with HSC-specific deletion of SIRT1 [conditional knockout (cKO)], receiving CCl (1 mg/kg) injection or subjected to bile duct ligation, compared to wild-type littermates. SIRT1 regulated peroxisome proliferator activated receptor γ (PPARγ) transcription by deacetylating enhancer of zeste homolog 2 (EZH2) in quiescent HSCs. Finally, EZH2 inhibition or PPARγ activation ameliorated fibrogenesis in cKO mice. In summary, our data suggest that SIRT1 plays an essential role guiding the transition of HSC phenotypes.-Li, M., Hong, W., Hao, C., Li, L., Wu, D., Shen, A., Lu, J., Zheng, Y., Li, P., Xu, Y. SIRT1 antagonizes liver fibrosis by blocking hepatic stellate cell activation in mice.

Norisoboldine, a natural AhR agonist, promotes Treg differentiation and attenuates colitis via targeting glycolysis and subsequent NAD+/SIRT1/SUV39H1/H3K9me3 signaling pathway

“… 26 indicate that SIRT1 interacts with MLL1 and mediates the deacetylation of MLL1 at two conserved residues, termed K1130 and K1133; Bosch-Presegué and colleagues. 27 demonstrate that SIRT1 inhibits MDM2 polyubiquitination of lysine 87 in the chromodomain of SUV39H1; Zhao and colleagues 28 report that SIRT1 knockdown increases EZH2 acetylation, resulting in enhanced stability. Furthermore, expressions of histone KMTs and histone KDMs are altered in hypoxia.…”

Sirtuins and Accelerated Aging in Scleroderma

“…In some cases, the observed mechanistic effects of SIRTs are so diverse, that it is difficult to narrowly classify them [69, 88, 91, 120]. Specific intracellular signaling molecules or pathways interacting functionally with or targeted directly by SIRTs include adenosine monophosphate-activated protein kinase (AMPK) – angiotensin-converting enzyme 2 (ACE2) signaling [69, 104], peroxisome proliferator-activated receptor (PPAR)γ [97], signal transducer and activator of transcription (STAT)3 [108], mammalian target of rapamycin (mTOR) [99, 102], nuclear factor erythroid 2-related factor 2 (Nrf2) [91, 117], Krüppel-like factor (KLF)15 [110], forkhead fox O1 (FOXO1) [66] and O3 (FOXO3) [67, 68], nuclear factor κB (NF-κB) [115], Notch1 [95], matrix metalloproteinase (MMP)-14 [92], manganese superoxide dismutase (MnSOD) [65, 87], and c-Jun [13]. …”

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].…”