Understanding the cellular interactome of non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions, with a global prevalence of 25% in the adult population. Non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis, has become the leading indication for liver transplantation in both Europe and the USA. Liver fibrosis is the consequence of sustained, iterative liver injury, and the main determinant of outcomes in NASH. The liver possesses remarkable inherent plasticity, and liver fibrosis can regress when the injurious agent is removed, thus providing opportunities to alter long-term outcomes through therapeutic interventions. Although hepatocyte injury is a key driver of NASH, multiple other cell lineages within the hepatic fibrotic niche play major roles in the perpetuation of inflammation, mesenchymal cell activation, extracellular matrix accumulation as well as fibrosis resolution. The constituents of this cellular interactome, and how the various subpopulations within the fibrotic niche interact to drive fibrogenesis is an area of active research. Important cellular components of the fibrotic niche include endothelial cells, macrophages, passaging immune cell populations and myofibroblasts. In this review, we will describe how rapidly evolving technologies such as single-cell genomics, spatial transcriptomics and single-cell ligand-receptor analyses are transforming our understanding of the cellular interactome in NAFLD/NASH, and how this new, high-resolution information is being leveraged to develop rational new therapies for patients with NASH.

Keywords: BAs, bile acids; CCL, C-C motif chemokine ligand; CCR, C-C motif chemokine receptor; CLD, chronic liver disease; CTGF, connective tissue growth factor; CXCL, C-X-C motif chemokine ligand; CXCR, C-X-C motif chemokine receptor; DAMP, damage-associated molecular pattern; ECM, extracellular matrix; ER, endoplasmic reticulum; FGF, fibroblast growth factor; FXR, farnesoid X receptor; HSCs, hepatic stellate cells; IL, interleukin; ILC, innate lymphoid cell; KCs, Kupffer cells; LSECs, liver sinusoidal endothelial cells; MAIT, mucosal-associated invariant T; MAMPS, microbiota-associated molecular patterns; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NK(T), natural killer (T); NLR, Nod like receptors; Non-alcoholic fatty liver disease (NAFLD); PDGF, platelet-derived growth factor; PFs, portal fibroblasts; SASP, senescence-associated secretory phenotype; TGF, transforming growth factor; TLR, Toll-like receptor; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor; antifibrotic therapies; cellular interactome; cirrhosis; fibrosis; single-cell genomics.

Fig. 1

Signalling from injured hepatocytes and cholangiocytes to non-parenchymal cells in the fibrotic niche. Injured hepatocytes activate immune cells through DAMPs-TLR9, IL-1β, IL-18 and CXCL10 and directly stimulate myofibroblast differentiation and activation through TGFβ1/2, SHH and PDGFRBB signalling. Immune cell-mediated mechanisms of myofibroblast activation include TGFβ1/2- and amphiregulin-mediated pathways. Ligands are represented in blue and receptors in red.

Fig. 2

Immune cell interactome table. Summary of macrophage, neutrophil, NK cell and T lymphocyte populations within the hepatic fibrotic niche, with key roles in inflammation/fibrosis; activation pathways and ligand/receptor expression are highlighted. The known role and interactions of NKT cells and B cells are addressed in the text. BMD, bone marrow-derived; HSCs, hepatic stellate cells; KCs, Kupffer cells; MFBs, myofibroblasts; NK(T), natural killer (T).

Fig. 3

Multi-lineage regulation of myofibroblast formation in the hepatic fibrotic niche. The central red arrow represents activation of mesenchymal cells into myofibroblasts which deposit ECM and drive scar formation. Macrophages, liver sinusoidal endothelial cells and natural killer cells can all exert regulatory effects on myofibroblast activation. Furthermore, myofibroblasts can also secrete MMPs that break down and remodel the ECM. ECM, extracellular matrix.