Metabolism of hepatic stellate cells in chronic liver diseases: emerging molecular and therapeutic interventions

Abstract

Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic and metabolic dysfunction-associated alcoholic liver disease (MetALD), and viral hepatitis, can lead to liver fibrosis, cirrhosis, and cancer. Hepatic stellate cell (HSC) activation plays a central role in the development of myofibroblasts and fibrogenesis in chronic liver diseases. However, HSC activation is influenced by the complex microenvironments within the liver, which are largely shaped by the interactions between HSCs and various other cell types. Changes in HSC phenotypes and metabolic mechanisms involve glucose, lipid, and cholesterol metabolism, oxidative stress, activation of the unfolded protein response (UPR), autophagy, ferroptosis, senescence, and nuclear receptors. Clinical interventions targeting these pathways have shown promising results in addressing liver inflammation and fibrosis, as well as in modulating glucose and lipid metabolism and metabolic stress responses. Therefore, a comprehensive understanding of HSC phenotypes and metabolic mechanisms presents opportunities for novel therapeutic approaches aimed at halting or even reversing chronic liver diseases.

Keywords: cellular crosstalk; clinical treatment; hepatic stellate cells; liver diseases.

Figure 1

The initiation and perpetuation of HSCs in chronic liver diseases. Conversion of quiescent HSCs to their activated state is triggered by in chronic liver diseases. This activation is characterized by distinct phenotypic changes, including fibrogenesis, increased contractility, proliferation, altered matrix degradation, chemotaxis, and enhanced immunological and inflammatory signaling. During the resolution of hepatic fibrosis, activated HSCs can be eliminated through three mechanisms: apoptosis, senescence, or reversion to an inactivated state. Adapted with permission from , Copyright 2021 Cell Press.

Figure 2

The activation and deactivation of HSCs in chronic liver diseases. When profibrotic stimulation in chronic liver diseases activates HSCs, quiescent HSCs convert into myofibroblasts. This transformation results in a decrease in their vitamin A content, stimulation of α-SMA, and synthesis of collagen type I. The conversion of HSCs is induced by TGF-β, which is produced by infiltrating lymphocytes, monocytes/macrophages, and damaged hepatocytes. TGF-βRII is upregulated by IL-17, which is generated by T_H17 cells and neutrophils, thereby increasing HSC sensitivity to TGF-β stimulation. When latent TGF-β binds to ECM proteins, it becomes inactive but can be released when activated HSCs contract through the action of αV integrin. In a feed-forward cycle, activated HSCs perpetuate their activation by producing TGF-β. HSC activation is also stimulated by PDGF, which is secreted by macrophages and endothelial cells. Additionally, HSC activation is sustained by lipid mediators, P2Y₁₄ signaling, and extracellular vesicles released by injured hepatocytes. Following the resolution of fibrosis, HSCs undergo either apoptosis or revert to an inactive state, a process mediated by the overexpression of transcription factors such as TCF21, GATA4, GATA6, and PPARγ. Lymphocytes, including NK cells, γδ T cells, and CD8⁺ T cells can effectively eliminate activated HSCs and myofibroblasts by inducing apoptosis. FASL, Fas ligand; GATA 4/6, GATA-binding factor 4/6; IL-17, interleukin-17; MoMFs, monocyte-derived macrophages; NKG2D, NK receptor group 2 member D; PDGF, platelet-derived growth factor; PDGFRβ, platelet-derived growth factor receptor β; PPAR, peroxisome proliferator-activated receptor; α-SMA, α-smooth muscle actin; TCF21, transcription factor 21; TGF-βRII, TGF-β receptor II; T_H 17, T helper 17; TRAIL, tumour necrosis factor-related apoptosis-inducing ligand. Adapted with permission from , Copyright 2023 Springer Nature.

Figure 3

Multiple cell types influence the activation of HSCs in chronic liver diseases. Hepatocytes, macrophages, biliary epithelial cells, liver progenitor cells, LESCs, NK cells, NKT cells, platelets, and B cells can either stimulate (indicated in blue font) or inhibit (indicated in red font) HSC activation by releasing various hormones, cytokines, and other signaling molecules. CCL2/18, C-C motif ligand 2/18; CTGF, connective tissue growth factor; CXCL4, C-X-C motif ligand 4; CXCR4, C-X-C chemokine receptor 4; EGF, epidermal growth factor; ET1, endothelin-1; FGF1/2, fibroblast growth factor 1/2; HGF, hepatocyte growth factor; 5-HT, 5-hydroxytryptamine; IFN-γ, interferon-γ; IL-6/4/13, interleukin-6/4/13; IGF1, insulin-like growth factor 1; IGFBP5, insulin-like growth factor-binding protein-5; MCP1, monocyte chemoattractant protein 1; MMP9/12, Matrix metalloproteinase-9/12; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; TGF-α/β, transforming growth factor-α/β; VEGF, vascular endothelial growth factor.

Figure 4

HSC activation is influenced by immune cells in chronic liver diseases. Chronic liver inflammation is initiated by hepatocellular damage, which releases DAMP and PAMP signals, including HMGB1, mtDNA, ADP, FFA, oxLDL, and others. These signaling molecules, along with cytokines and chemokines produced by activated emKCs, attract immune cells from the bloodstream, particularly resident macrophages to the liver, leading to significant phenotypic alterations. These immune cells respond promptly to disruptions in extrahepatic signals, primarily BAs and bacterial products such as LPS from the intestine, as well as lipid mediators like FFAs and leptin from adipose tissue and damaged hepatocytes, resulting in a pro-inflammatory response. Monocytes, driven by CCL2, are the first immune cells to arrive in the liver following injury. They release profibrogenic molecules, including TGF-β, and differentiate into MoMFs, which subsequently prolong the inflammatory response. MoMFs may further differentiate into SAM, which produce TGF-β and activate HSCs. Neutrophils may arrive early during the inflammatory response and promote fibrogenesis by producing IL-17, which stimulates HSCs. Auto-aggressive CD8⁺ T lymphocytes accelerate hepatocyte destruction. Injured hepatocytes emit danger signals, such as P2Y₁₄L and alarmins, which include IL-33 and mitochondrial metabolites, potentially activating HSCs. Lymphocytes are attracted by various chemokines, including CXCL16 released by NKT cells, CXCL9 and CXCL10 released by conventional T cells, and CCL20 released by γδ T cells. TH17 cells and MAIT cells produce IL-17, which promotes fibrogenesis. However, certain CD8⁺ T cells, γδ T cells, and NK cells inhibit fibrosis formation by inducing apoptosis in myofibroblasts. The activation of caspase-3/7 in apoptotic hepatocytes leads to the production of apoptotic bodies, which can activate HSCs directly or indirectly through macrophage activation. DAMPs, particularly HMGB1, can be released through necroptosis, pyroptosis, ferroptosis, cuproptosis, and PANoptosis, causing macrophages, monocytes, and DCs to aggregate, secrete inflammatory factors, and further amplify the inflammatory response. ADP, adenosine diphosphate; BA, bile acid; CCL2/5, C-C motif ligand 2/5; CXCL, C-X-C motif ligand16; DCs, dendritic cells; DAMPs, damage-associated molecular patterns; ECM, extracellular matrix; emKCs, embryonic KCs; FFA, free fatty acids; HMGB1, high-mobility group box 1; HSCs, hepatic stellate cells; IL-33, interleukin-33; LPS, lipopolysaccharide; MAIT, Mucosal-associated invariant T; MoMF, monocyte-derived macrophage; NKT, natural killer T; oxLDL, oxidized low-density lipoprotein; PAMP, pathogen-associated molecular pattern; SAM, scar-associated macrophage; TGF, transforming growth factor; T_H17, T helper 17. Adapted with permission from , Copyright 2023 Springer Nature.

Figure 5

Metabolic reprogramming in fibrogenic HSCs activation in chronic liver diseases. A, HSCs are activated by exosomes containing GLUT1 and PKM2. The overexpression of glucose transporters GLUT1, GLUT2, and GLUT4 facilitates excessive glucose uptake by HSCs, leading to increased glycolysis. Pyruvate, a byproduct of PKM2-catalyzed glycolysis, is largely diverted toward lactate synthesis, resulting in lactate accumulation within HSCs, despite the increased expression of the lactate transporter monocarboxylate transporter 4 (MCT4) and enhanced lactate efflux. In a separate metabolic pathway, pyruvate is converted to acetyl-CoA, which enhances the activity of the TCA cycle and releases lipids that are stored for β-oxidation. PKM2 regulates the expression of metabolic genes, which elevates ROS production and overall mitochondrial activity. Additionally, glutamine enters the cell via the ASCT1 and is metabolized to produce glutamate and α-ketoglutarate, which are subsequently integrated into the TCA cycle. Hedgehog signaling through leptin represents a significant pro-fibrotic signal that may reprogram glucose metabolism, primarily converging on the transcription factor HIF-1α. Since AGEs result from hyperglycemia, TGF-β signaling enhances HSC expression of RAGE, rendering activated HSCs more susceptible to global glucose metabolism. B, The lipid metabolism of activated HSCs is characterized by the loss of retinyl ester-containing cytoplasmic droplets. HSCs utilize enhanced fatty acid β-oxidation to degrade the contents of lipid droplets within the autolysosome. Lipid droplets are transported to the autolysosome, where they undergo degradation. The contents of lipid droplets are degraded in the autolysosome under LAL activity, and REH activity is also increased in the lysosome, releasing free retinol into the extracellular space. SREBP-1c and PPAR-γ are adipogenic markers of quiescent HSCs that are downregulated upon activation. The conversion of some intracellular retinol to retinoic acid facilitates elevated transcription of RARβ and RXRβ. C, Free cholesterol in activated HSCs is partially absorbed through PCSK9, which interacts with low-density LRP5 and LDLR, promoting the degradation of endosomes and lysosomes. Free cholesterol enhances the expression of TLR4 and is converted into cholesterol esters through ACAT1, sensitizing HSCs to TGF-β signaling. oxLDL increases the expression of profibrogenic genes such as TNF-α and IL-1β through the pJNK. D, Metabolic stress responses in HSCs lead to the conversion of latent TGF-β into activated TGF-β. Unfolded proteins and TGF-β signaling trigger ER stress responses via IRE1α, resulting in increased expression of fibrogenic genes through ASK1/JNK signaling and the canonical splicing of XBP1 into its active form. This process promotes the expression of C/EBPβ, COL1A1, TGF-β, and XBP1 in the cell nucleus, leading to increased collagen accumulation. TGF-β signaling activates NADPH oxidase in a self-replicating cycle, producing H2O2, which promotes fibrogenic gene expression and activates latent TGF-β in extracellular spaces. Reduced nuclear receptor signaling, such as that of LXR, FXR, or THRα, is a hallmark of HSC activation. Nevertheless, active HSCs also exhibit increased PPARβ/δ, which stimulates HSC proliferation. ACAT1, acyl-CoA:cholesterol acyltransferase 1; ADAM17, ADAM metallopeptidase domain 17; AGE, advanced glycation end product; ASCT2, alanine serine cysteine transporter 2; ASK1, apoptosis-signal-regulating kinase 1; C/EBPβ, CCAAT-enhancer-binding protein; COL1A1, collagen type 1 alpha 1; DNL, de novo lipogenesis; FXR, farnesoid X receptor; GLUT, glucose transporter protein 1; HIF-1α, hypoxia-inducible factor 1-α; H₂O₂, hydrogen peroxide; HSCs, hepatic stellate cells; IL, interleukin; IRE1α, inositol-requiring enzyme 1 alpha; LD, lipid droplet; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LRP5, low-density lipoprotein-related protein 5; LXR, liver X receptor; MCT4, monocarboxylate transporter 4; NOX, NADPH oxidase; oxLDL, oxidized low-density lipoprotein; PCSK9, proprotein convertase subtilisin/kexin 9; PKM2, pyruvate kinase M2; PPAR, peroxisome proliferator-activated receptor; RAGE, receptor for advanced glycation end product; RARα/β, retinoic acid receptor α/β; REH, retinyl ester hydrolase; ROS, reactive oxygen species; SREBP-1c, sterol regulatory element-binding protein-1c; TGF, transforming growth factor; THR, thyroid hormone receptors; TLR4, toll-like receptor 4; TNF, tumor necrosis factor; TREM2, triggering receptor expressed on myeloid cells 2; XBP1s, IRE1α-X-box binding protein 1.