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, 11, 109-129

"Let My Liver Rather Heat With Wine" - A Review of Hepatic Fibrosis Pathophysiology and Emerging Therapeutics


"Let My Liver Rather Heat With Wine" - A Review of Hepatic Fibrosis Pathophysiology and Emerging Therapeutics

Carlos G Moscoso et al. Hepat Med.


Cirrhosis is characterized by extensive hepatic fibrosis, and it is the 14th leading cause of death worldwide. Numerous contributing conditions have been implicated in its development, including infectious etiologies, medication overdose or adverse effects, ingestible toxins, autoimmunity, hemochromatosis, Wilson's disease and primary biliary cholangitis to list a few. It is associated with portal hypertension and its stigmata (varices, ascites, hepatic encephalopathy, combined coagulopathy and thrombophilia), and it is a major risk factor for hepatocellular carcinoma. Currently, orthotopic liver transplantation has been the only curative modality to treat cirrhosis, and the scarcity of donors results in many people waiting years for a transplant. Identification of novel targets for pharmacologic therapy through elucidation of key mechanistic components to induce fibrosis reversal is the subject of intense research. Development of robust models of hepatic fibrosis to faithfully characterize the interplay between activated hepatic stellate cells (the principal fibrogenic contributor to fibrosis initiation and perpetuation), hepatocytes and extracellular matrix components has the potential to identify critical components and mechanisms that can be exploited for targeted treatment. In this review, we will highlight key cellular pathways involved in the pathophysiology of fibrosis from extracellular ligands, effectors and receptors, to nuclear receptors, epigenetic mechanisms, energy homeostasis and cytokines. Further, molecular pathways of hepatic stellate cell deactivation are discussed, including apoptosis, senescence and reversal or transdifferentiation to an inactivated state resembling quiescence. Lastly, clinical evidence of fibrosis reversal induced by biologics and small molecules is summarized, current compounds under clinical trials are described and efforts for treatment of hepatic fibrosis with mesenchymal stem cells are highlighted. An enhanced understanding of the rich tapestry of cellular processes identified in the initiation, perpetuation and resolution of hepatic fibrosis, driven principally through phenotypic switching of hepatic stellate cells, should lead to a breakthrough in potential therapeutic modalities.

Keywords: apoptosis; cirrhosis; fibrosis; hepatic stellate cell; reversal; senescence; transdifferentiation.

Conflict of interest statement

The authors report no conflicts of interest in this work.


Figure 1
Figure 1
Natural progression of liver disease. Liver insult of any etiology results in inflammatory changes in hepatic parenchyma which progress to fibrosis and ultimately cirrhosis if unaddressed. Cirrhosis culminates in liver failure and is a principal risk factor for hepatocellular carcinoma.
Figure 2
Figure 2
Extracellular signaling mechanisms initiated by and contributing to hepatic stellate cell activation. Activation of HSCs and initiation of fibrogenic, contractile, proliferative and chemotactile processes facilitate perpetuation of fibrogenesis. Chemotaxis through synthesis and secretion of various growth factors, such as CTGF (SWISS-MODEL accession P29279), VEGF (PDB ID 1TZH), PDGF (PDB ID 4QCI) and EGF (PDB ID 2KV4), promote proliferation, secretion of ECM components and maintenance of a profibrotic milieu via juxtacrine, paracrine and autocrine interactions. Upregulation of fibrogenic genes, including αSMA (red chains) to enable contractility and collagen III (PDB ID 6A0A), leads to expansion of ECM and fibrotic septa, and integrin-dependent matricrine interactions facilitate perpetuation of the activated state. Dysregulation of matrix degradation through differential expression of various MMPs, including MMP9 (PDB ID 1L6J), enables accumulation of ECM components and sustenance of a profibrotic microenvironment. Inflammatory signaling recruits various WBCs and macrophages with profibrotic downstream effectors through Th1 and Th17 juxtacrine and paracrine signaling. Activated HSCs proliferate via TGF-β-, Ras- and Hedgehog-dependent pathways. Resolution of HSC activation proceeds via apoptosis, senescence or reversal to a quiescent state; it is unclear whether reversal to the deactivated state fully occurs. Crystal structures rendered with NGL Viewer. Abbreviations: αSMA, alpha-smooth muscle actin; CTGF, connective tissue growth factor; ECM, extracellular matrix; EGF, epidermal growth factor; HSC, hepatic stellate cell; MMP, matrix metalloproteinase; PDB, Protein Data Bank; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor; WBC, white blood cell.
Figure 3
Figure 3
Intracellular signaling pathways involved in initiation and perpetuation of hepatic stellate cell activation. Initiation of the activated state involves engagement of proliferative and activating pathways, including TGFβR (PDB IDs 1KTZ, 3TZM, 5E8U, 5E8V); binding and downstream nuclear translocation of Smad2/3 and Smad 4 proteins, resulting in transcription and translation of profibrotic genes. Binding of PDGF to its receptor PDGFR (PDB ID 5GRN) results in activation of cytoplasmic Ras and MAPK effectors, with subsequent nuclear translocation and expression of proliferative genes. Engagement of the GPCR CCR5 (PDB ID 6AKX) results in clathrin-mediated endocytosis, activation and nuclear translocation of ERK1/2, and expression of proliferative genes, also allowing for migratory properties. Cytokines also have significant modulatory properties on fibrogenesis; for example, binding of IL-17 to its receptor IL-17R (PDB ID 4HSA) results in activation of the canonical NF-κB pathway, resulting in pro-inflammatory gene expression. Programmed cell death can be facilitated via innate immune signaling; engagement of TLRs (PDB IDs 6NIH, 2MKA, 2J67); with various TLR ligands propagates downstream signaling culminating in autophagy, apoptosis or pyroptosis. Nuclear membrane receptors also have large roles in modulating profibrogenic properties; engagement of ligands, including fatty acids and thiazolidinediones, with receptors of the PPAR family, including PPARγ (PDB ID 2Q8S), results in nuclear translocation, heterodimerization with RXR and binding with DNA (PDB ID 3DZU), with subsequent expression of antifibrogenic genes. Binding of obeticholic acid to FXR and of vitamin D to VDR results in receptor nuclear translocation, heterodimerization with RXR and expression of antifibrogenic genes. Meanwhile, binding of heme to Rev-Erb upregulates Rev-Erb expression, accumulation of Rev-Erb in the cytoplasm and promotion of a profibrogenic, contractile HSC phenotype. Crystal structures rendered with NGL Viewer. Abbreviations: CB1, cannabinoid receptor type 1; CCR5, C-C chemokine receptor type 5; CX3CR1, C-X3-C motif chemokine receptor 1; DNA, deoxyribonucleic acid; EKR1/2, extracellular signal-regulated protein kinases 1 and 2; FXR, farsenoid X receptor; GPCR, G-protein coupled receptor; HSC, hepatic stellate cell; IL-17, interleukin 17; IL-17R, IL-17 receptor; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; PPARγ, peroxisome proliferator-activated receptor gamma; RXR, retinoid X receptor; TGFβR, transforming growth factor beta receptor; TLR, Toll-like receptor; VDR, vitamin D receptor.

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