An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH

Abstract

Successful development of treatments for non-alcoholic fatty liver disease and its progressive form, non-alcoholic steatohepatitis (NASH), has been challenging. Because NASH and fibrosis lead to progression towards cirrhosis and clinical outcomes, approaches have either sought to attenuate metabolic dysregulation and cell injury, or directly target the inflammation and fibrosis that ensue. Targets for reducing the activation of inflammatory cascades include nuclear receptor agonists (e.g. resmetirom, lanifibranor, obeticholic acid), modulators of lipotoxicity (e.g. aramchol, acetyl-CoA carboxylase inhibitors) or modification of genetic variants (e.g. PNPLA3 gene silencing). Extrahepatic inflammatory signals from the circulation, adipose tissue or gut are targets of hormonal agonists (semaglutide, tirzepatide, FGF19/FGF21 analogues), microbiota or lifestyle interventions. Stress signals and hepatocyte death activate immune responses, engaging innate (macrophages, innate lymphocyte populations) and adaptive (auto-aggressive T cells) mechanisms. Therapies have also been developed to blunt immune cell activation, recruitment (chemokine receptor inhibitors), and responses (e.g. galectin-3 inhibitors, anti-platelet drugs). The disease-driving pathways of NASH converge to elicit fibrosis, which is reversible. The activation of hepatic stellate cells into matrix-producing myofibroblasts can be inhibited by antagonising soluble factors (e.g. integrins, cytokines), cellular crosstalk (e.g. with macrophages), and agonising nuclear receptor signalling. In advanced fibrosis, cell therapy with restorative macrophages or reprogrammed (CAR) T cells may accelerate repair through hepatic stellate cell deactivation or killing, or by enhancing matrix degradation. Heterogeneity of disease - either due to genetics or divergent disease drivers - is an obstacle to defining effective drugs for all patients with NASH that will be overcome incrementally.

Keywords: FGF-19; FGF-21; FXR; GLP-1; HSC; ILC; NAFLD; OCA; PPAR; TGFβ; THR-β; TR-β; gut-liver axis; scRNA-seq; thyromimetics.

Fig. 1.. From metabolic injury to inflammation: Targeting the activation of inflammatory cascades.

Metabolic injury is influenced by various non-modifiable and modifiable, intra- and extrahepatic (risk) factors resulting in pathogenic cascades including ER stress, oxidative stress and mitochondrial dysfunction in hepatocytes. Lipotoxicity, as a consequence of FFA overload and increased de novo lipogenesis, leads to release of stress signals and induction of cell death mechanisms of the metabolically stressed hepatocyte, which in turn activate immune responses. Pharmacologic strategies target the metabolic dysregulation and injury of hepatocytes as well as extrahepatic inflammatory signals. Other approaches include modification of genetic risk factors or inflammatory activation of immune cells. ACC, acetyl-CoA carboxylase; ASK1, apoptosis signal-regulating kinase 1; ATP, adenosine triphosphate; CCL, chemokine (C–C motif) ligand; IL, interleukin; DAMPs, damage-associated molecular patterns; DGAT, diglyceride acyltransferase; ER, endoplasmic reticulum; EVs, extracellular vesicles; FASN, fatty acid synthase; FFA, free fatty acids; FGF, fibroblast growth factor; FMT, faecal microbiota transplantation; FXR, farnesoid X receptor; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1; LPS, lipopolysaccharide; LXR, liver X receptors; NASH, non-alcoholic steatohepatitis; PAMPs, pathogen-associated molecular patterns; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; SCD1, stearoyl-CoA desaturase 1; SEFAs, structurally engineered fatty acids; THR, thyroid hormone receptor; TNF, tumour necrosis factor.

Fig. 2.. Establishing inflammation in NAFLD: Targeting immune cell activation, recruitment and cellular crosstalk.

Upon metabolic injury, parenchymal and non-parenchymal immune cells release inflammatory mediators such as chemokines, leading to the recruitment and hepatic accumulation of further immune cells. Pharmacologic strategies target the activation and polarisation of immune cells (macrophages, T cells), inhibit the hepatic infiltration of inflammatory immune cells (neutrophils, monocytes, macrophages) or modulate intercellular crosstalk. New therapeutic approaches include cell therapies with “reprogrammed” immune cells. ASA, acetylsalicylic acid; CAR-iMAC, CAR-expressing macrophages; CCL, chemokine (C–C motif) ligand; CCR, CC chemokine receptor; cDC, conventional (classical) DCs; CSF1, colony stimulating factor 1; CXCL1, C-X-C chemokine ligand 1; CXCR, C-X-C chemokine receptor; ECM, extracellular matrix; HSC, hepatic stellate cell; ICAM1, intercellular adhesion molecule-1; IFNγ, interferon gamma; IL, interleukin; iPSC, induced pluripotent stem cells; KC, Kupffer cell; LSEC, liver sinusoidal endothelial cells; MoMF, monocyte-derived macrophage; PPAR, peroxisome proliferator-activated receptors; uPAR, urokinase-type plasminogen activator receptor.

Fig. 3.. From inflammation to fibrosis: Targeting fibrogenesis.

During progression of chronic liver injury, pro-fibrogenic mediators and cell-cell interactions lead to activation and transdifferentiation of quiescent HSCs to extracellular matrix-producing myofibroblasts. Upon cessation of metabolic injury, pro-resolving factors and anti-inflammatory reprogrammed immune cells revert myofibroblasts to a “quiescent”-like HSC phenotype or support elimination of activated HSCs, initiating tissue repair and regeneration. Pharmacologic strategies target the interaction of HSCs with inflammatory cells and HSC-activating mediators, metabolic dysregulation in HSCs and energy dependent signalling pathways needed for transdifferentiation to myofibroblasts. Drug delivery systems enable HSC-specific gene silencing approaches. ACC, acetyl-CoA carboxylase; ECM, extracellular matrix; EVs, extracellular vesicles; FASN, fatty acid synthase; FXR, farnesoid X receptor; HSC, hepatic stellate cell; LXR, liver X receptors; MMP, matrix metalloproteinases; NK cell, natural killer cells; PDGF, platelet-derived growth factor; PPAR, peroxisome proliferator-activated receptor; SCD1, stearoyl-CoA desaturase 1; SGLT2, sodium glucose linked transporter 2; SPM, specialised pro-resolving mediators; TGFβ, transforming growth factor beta; THR, thyroid hormone receptor; TIMP, tissue inhibitor of matrix metalloproteinases; VEGF, vascular endothelial growth factor.