Novel therapeutic targets for cholestatic and fatty liver disease

Abstract

Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are currently developed for both areas. Nuclear receptors (NRs) are ligand-activated transcriptional regulators of key metabolic processes including hepatic lipid and glucose metabolism, energy expenditure and bile acid (BA) homoeostasis, as well as inflammation, fibrosis and cellular proliferation. Dysregulation of these processes contributes to the pathogenesis and progression of cholestatic as well as fatty liver disease, placing NRs at the forefront of novel therapeutic approaches. This includes BA and fatty acid activated NRs such as farnesoid-X receptor (FXR) and peroxisome proliferator-activated receptors, respectively, for which high affinity therapeutic ligands targeting specific or multiple isoforms have been developed. Moreover, novel liver-specific ligands for thyroid hormone receptor beta 1 complete the spectrum of currently available NR-targeted drugs. Apart from FXR ligands, BA signalling can be targeted by mimetics of FXR-activated fibroblast growth factor 19, modulation of their enterohepatic circulation through uptake inhibitors in hepatocytes and enterocytes, as well as novel BA derivatives undergoing cholehepatic shunting (instead of enterohepatic circulation). Other therapeutic approaches more directly target inflammation and/or fibrosis as critical events of disease progression. Combination strategies synergistically targeting metabolic disturbances, inflammation and fibrosis may be ultimately necessary for successful treatment of these complex and multifactorial disorders.

Keywords: fibrosis; inflammation.

Figure 1

Failed metabolic homoeostasis results in sublethal cell stress, inflammation and fibrosis. In both non-alcoholic fatty liver disease and cholestasis, inadequate metabolic adaptation to substrate overload results in sublethal cell stress or even cell death with release of mediators (eg, cytokines, chemokines, microRNAs), in part as cargo of extracellular vesicles, driving inflammation and fibrosis. The ideal therapeutic strategy would be expected to impact on several if not all critical steps involved in the initiation and progression of liver diseases. Combination strategies synergistically targeting metabolic disturbances, inflammation and fibrosis may be ultimately necessary for successful treatment of complex cholestatic and metabolic liver diseases.

Figure 2

Therapeutic strategies along the enterohepatic and cholehepatic bile acid (BA) circulation. After hepatic synthesis via cytochrome P450 7A1 (CYP7A1) and excretion into bile through the bile salt export pump (BSEP/ABCB11) BAs undergo an enterohepatic circulation, that is, they are reabsorbed in the ileum by apical sodium-dependent bile acid transporter (ASBT/SLC10A2) and transported back to the liver through portal blood where hepatic reuptake of conjugated BAs is mediated via sodium/taurocholate cotransporting polypeptide (NTCP/SLC10A1) and organic anion transporting polypeptides (OATPs) for unconjugated BAs (not shown). In hepatocytes, farnesoid-X receptor (FXR) induces the transcriptional repressor SHP which in turn inhibits CYP7A1 (BA synthesis) and NTCP transcription (BA uptake). FXR induces BSEP, phospholipid export pump/floppase (MDR3/ABCB4; Mdr2 in mice) and cholesterol export pump (ABCG5/8). At the basolateral membrane organic solute transporter (OSTα/OSTβ), multidrug resistance-related proteine (MRP)3 and MRP4 facilitate alternative hepatic BA pump which is also in part induced by FXR (not shown). After uptake of BAs via ASBT into enterocytes (lower panel), BA-activated FXR induces sinusoidal OSTα/OSTβ heterodimer for BA efflux into portal blood. Intestinal FXR via DIET1 induces fibroblast growth factor (FGF) 19, which circulates to the liver and binds to its receptor FGFR4, subsequently inhibiting BA synthesis. Gut microbiota deconjugate and dehydroxylate primary BAs into secondary BAs. Enterohepatic drugs acting within the gut-liver axis: (non-)steroidal FXR agonists (eg, obeticholic acid) and FGF19 mimetics. Cholehepatic drugs, such as nor-ursodeoxycholic acid (norUDCA), undergo cholehepatic shunting between hepatocytes and cholangiocytes, thereby cutting short the enterohepatic circulation. Transport blockers: ASBT inhibitors and BA sequestrants as well as NTCP inhibitors, prevent intestinal or hepatic BA reuptake. TJ, tight junction.

Figure 3

Nuclear receptors as therapeutic targets regulating metabolism and inflammation. Hepatocyte, left panel: farnesoid X receptor (FXR) represses hepatic bile acid (BA) uptake sodium/taurocholate cotransporting polypeptide (NTCP) and BA synthesis cytochrome P450 7A1 (CYP7A1) via induction of the transcriptional repressor SHP (not shown). Moreover intestine‐derived fibroblast growth factor (FGF) 19 (binding to the FGFR4/βKlotho dimer) also downregulates CYP7A1 expression. Conversely, FXR promotes biliary excretion of BAs, phospholipids (PL) and bilirubin via induction of canalicular bile salt export pump (BSEP), multidrug resistant protein 3 (MDR3) and multidrug resistance-related protein 2 (MRP2), respectively (centre), and also facilitates BA elimination via alternative basolateral BA transporter such as organic solute transporter (OSTα/β) (not shown). BA detoxification by phase 1 and 2 enzymes is stimulated through FXR and peroxisome proliferator-activated receptor (PPAR)α. PPARα stimulates phospholipid secretion (via MDR3), thus counteracting intrinsic bile toxicity. Right panel: FXR as well as PPAR α and δ reduce inflammation via suppression of NFκΒ. FXR and PPARγ improve hepatic insulin sensitivity. FGF19, FGF21, FXR and thyroid hormone receptor beta (THRβ) suppress de novo lipogenesis, while PPAR α and δ stimulate β−oxidation. In cholangiocytes (lower panel), activation of FXR, vitamin D receptor (VDR) and glucocorticoid receptor (GR) exert cholangioprotective effects via upregulation of vasoactive intestinal polypeptide receptor 1 (VPAC1), anion exchanger (AE) 2 and cathelicidin. Activation of PPARγ in cholangiocytes reduces vascular cell adhesion molecule (VCAM‐1) expression, thereby counteracting reactive cholangiocyte phenotype. Anti-fibrotic effects of nuclear receptors (NRs) in hepatic stellate cells (HSCs, far right panel): PPARα and γ and VDR reduce expression of profibrogenic genes such as alpha smooth muscle actin (αSMA), Collagen 1a1 (Col1α1), TIMP1, platelet-derived growth factor (PDGF), transforming growth factor beta (TGFβ) and angiopoietin-2 (ANG2). Furthermore, NRs reduce migration, proliferation as well as trans-differentiation of HSC into myofibroblasts. Anti-inflammatory effects of NRs are related to their activation in immune cells such as macrophages and Kupffer cells (as well as adaptive immune cells, not shown). Activation of FGF21, PPARα, γ, δ and VDR reduce expression of proinflammatory cytokines such as tumour necrosis factor alpha (TNFα) and interleukin 1 beta (IL1β) (lower right panel). Cenicriviroc (CVC) an antagonist for C-C chemokine receptor type 2 and 5 (CCR2/5) on macrophages, Kupffer cells and HSCs exerts anti-inflammatory and anti-fibrotic effects, As result of FGF21 and PPARγ activation in adipocytes, insulin sensitivity is increased (lower left panel).