Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a fast growing, chronic liver disease affecting ∼25% of the global population. Nonalcoholic fatty liver disease severity ranges from the less severe simple hepatic steatosis to the more advanced nonalcoholic steatohepatitis (NASH). The presence of NASH predisposes individuals to liver fibrosis, which can further progress to cirrhosis and hepatocellular carcinoma. This makes hepatic fibrosis an important indicator of clinical outcomes in patients with NASH. Hepatic stellate cell activation dictates fibrosis development during NASH. Here, we discuss recent advances in the analysis of the profibrogenic pathways and mediators of hepatic stellate cell activation and inactivation, which ultimately determine the course of disease in nonalcoholic fatty liver disease/NASH.

Keywords: Fibrosis; Hepatic Stellate Cell; NAFLD; NASH.

Figure 1

Pathways of hepatic stellate cell activation and survival during NAFLD. Various factors, such as lipid mediators, free cholesterol accumulation, oxLDL, palmitic acid, LPS, and immune cell–derived profibrotic molecules and growth factors, promote hepatic stellate cell activation and survival during NAFLD. OPN, osteopontin; HH ligands, hedgehog ligands; ROS, reactive oxygen species; GM-CSF, granulocyte macrophage colony-stimulating factor; LPS, lipopolysaccharide; TLR4, toll like receptor-4; SHH, sonic hedgehog; IHH, Indian hedgehog; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; S1P, sphingosine-1-phosphate; oxLDL, oxidized low-density lipoprotein; LPA, lysophosphatidic acid; LPI, lysophosphatidylinositol; MSR1, macrophage scavenger receptor 1; miRNA, microRNA. Created with Biorender.com.

Figure 2

Inactivation of hepatic stellate cells during NAFLD. Activated hepatic stellate cells that accumulated during NASH fibrosis are removed during fibrosis resolution either by apoptosis or by reverting to an inactive phenotype. Additionally, activated hepatic stellate cells are removed by cell death induced by immune cells such as CD69+CD103-CD8+ T cells, γδ T cells and NK cells. The transcription factors PPARγ, GATA6, GATA4 and TCF21 play an important role in promoting and maintaining the inactivated phenotype of hepatic stellate cells. FasL, Fas ligand; HSC, hepatic stellate cells; NK, natural killer; TCF21, transcription factor 21. Created with Biorender.com.