The role of sirtuin1 in liver injury: molecular mechanisms and novel therapeutic target

Abstract

Liver disease is a common and serious threat to human health. The progression of liver diseases is influenced by many physiologic processes, including oxidative stress, inflammation, bile acid metabolism, and autophagy. Various factors lead to the dysfunction of these processes and basing on the different pathogeny, pathology, clinical manifestation, and pathogenesis, liver diseases are grouped into different categories. Specifically, Sirtuin1 (SIRT1), a member of the sirtuin protein family, has been extensively studied in the context of liver injury in recent years and are confirmed the significant role in liver disease. SIRT1 has been found to play a critical role in regulating key processes in liver injury. Further, SIRT1 seems to cause divers outcomes in different types of liver diseases. Recent studies have showed some therapeutic strategies involving modulating SIRT1, which may bring a novel therapeutic target. To elucidate the mechanisms underlying the role of sirtuin1 in liver injury and its potentiality as a therapeutic target, this review outlines the key signaling pathways associated with sirtuin1 and liver injury, and discusses recent advances in therapeutic strategies targeting sirtuin1 in liver diseases.

Keywords: Acute liver injury; Molecular mechanisms; Non-alcoholic fatty liver disease; Targeted therapy; Sirtuin1.

Figure 1. Local structure diagram of the liver.

(A) Local structure of normal liver; (B) General condition after liver injury.

Figure 2. The pathophysiological changes caused by SIRT1 inhibition in different liver diseases.

Figure 3. Overview of the roles of SIRTs in hepatocytes.

(A) SIRT1 plays an anti-inflammatory effect by regulating inflammatory mediators; (B) SIRT1 is a key factor in BA regulation; (C) SIRT1 plays an anti-oxidative stress role in hepatocytes; (D) MicroRNAs are inhibitors of SIRT1; (E) The upstream proteins of SIRT1; (F) SIRT1 is involved in fatty acid oxidation; (G) SIRT1 reduces hepatocytes apoptosis; (H) autophagy is regulated by SIRT1. (AMPK) adenosine 5′-monophosphate-activated protein kinase, (ATF6) activating transcription factor 6, (ATG7) autophagy-related gene 7, (DEPTOR) DEP domain-containing mTOR-interacting protein, (CHOP) C/EBP-homologous protein, (CTSB/S) cathepsin B/S, (FASTK) fas-activated serine/threonine kinase, (FoxO1) forkhead box-containing protein O 1, (FXR) farnesoid X receptor, (GRP-78) 78-kD glucose-regulated protein, (HMGB1) high mobility group box 1, (HNF-1a) hepatic nuclear receptor-1a, (LAMP-2) lysosomal-associated membrane protein 2, (LCN2) lipocalin-2, (LC3) light chain 3, (LRH-1) liver receptor homolog-1, (MFN2) mitofusin 2, (mTOR) mechanistic target of rapamycin, (NF-κ B) nuclear factor-κ B, (NGF) nerve growth factor, (NLRP3) NOD-like receptor pyrin domain containing 3, (Nrf2) Nuclear factor erythroid 2-related factor 2, (PGC-1α) peroxisome proliferator-activated receptor-gamma coactivator 1-alpha, (PPAR) peroxisome proliferator-activated receptor, (SHP) small heterodimer partner, (SFRS10) serine-rich 10.

Figure 4. Overview of the roles of SIRTs in human hepatic stellate cells.

(AMPK) adenosine 5′-monophosphate-activated protein kinase, (ATF6) activating transcription factor 6, (CTSB/S) cathepsin B/S, (GRP-78) 78-kD glucose-regulated protein, (HSF1) heat shock factor 1, (IRE-1α) inositol-requiring protein 1α, (NF-κ B) nuclear factor-κ B, (Nrf2) Nuclear factor erythroid 2-related factor 2, (PDGFR-α) platelet-derived growth factor receptor alpha, (PERK) protein kinase R-like ER kinase, (PPAR) peroxisome proliferator-activated receptor, (Smad) small mothers against decapentaplegic protein, (SREBP-1) sterol regulatory element-binding protein-1.

Figure 5. Overview of the roles of SIRTs in Kupffer cells.

(AMPK) adenosine 5′-monophosphate-activated protein kinase, (CTSB/S) cathepsin B/S, (GSDMD) Gasdermin D, (HMGB1) high mobility group box 1, (HO-1) heme oxygenase-1, (Iκ Bα) inhibitor of kappa B alpha, (MDM2) mouse double minute 2, (PKCδ) protein kinase C-delta, (TAK1) TGF-β1 activated kinase.