Nuclear Receptor Modulation for the Treatment of Nonalcoholic Fatty Liver Disease

Abstract

Nuclear receptors (NRs) are ligand-activated transcriptional regulators of several key metabolic processes including hepatic lipid and glucose metabolism, bile acid homeostasis, and energy expenditure as well as inflammation, fibrosis, and cellular proliferation in the liver. Dysregulation of these processes contributes to the pathogenesis and progression of nonalcoholic fatty liver disease (NAFLD). This places NRs at the forefront of novel therapeutic approaches for NAFLD. Some NRs are already pharmacologically targeted in metabolic disorders such as hyperlipidemia (peroxisomal proliferator-activated receptor α [PPARα], fibrates) and diabetes (PPARγ, glitazones) with potential applications for NAFLD. Other NRs with potential therapeutic implications are the vitamin D receptor (VDR) and xenobiotic sensors such as constitutive androstane receptor (CAR) and pregnane X receptor (PXR). Further new perspectives include combined ligands for NR isoforms such as PPARα/δ ligands. Other novel key players represent the nuclear bile acid receptor farnesoid X receptor (FXR; targeted by synthetic FXR ligands such as obeticholic acid) and RAR-related orphan receptor gamma two (RORγt). In this review the authors provide an overview of the preclinical and clinical evidence of current and future treatment strategies targeting NRs in metabolism, inflammation, and fibrogenesis of NAFLD.

Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

“…New selective PPAR modulators have been developed to overcome the limitations of the current fibrates. These include the dual PPARα/γ agonist aleglitazar and the dual PPARα/δ agonist elafibranor (GFT505) 80, 81. These dual agonists can improve insulin resistance and fasting hypertriglycemia and low‐density lipoprotein (LDL) cholesterol levels as well as liver enzymes in obese and insulin‐resistant males and in rodent NASH and fibrosis models.…”

Farnesoid X receptor (FXR) as a potential therapeutic target in nonalcoholic fatty liver disease and associated syndromes

“…2). Так, активация FXR в энтероцитах под-вздошной кишки после активного захвата ими желчных кислот приводит к продукции фактора роста фибробла-стов 15 (FGF15, ортолог у человека -FGF19) [14], репрес-сирующего синтез желчных кислот, способствующего снижению уровня de novo липогенеза в печени и опо-средованно стимулирующего β-окисление жирных кис-лот в митохондриях [15,16].…”

“…Агонисты FXR, такие как его естественные лиганды (холевая и хенодезоксихолевая кислоты), синтетически модифицированные желчные кислоты (6α-этилхеноде-зоксихолевая (обетихолевая) кислота, INT-747), а также синтетические нестероидные молекулы (GW4064 и WAY-362450) продемонстрировали эффективность при тера-пии НАЖБП и НАСГ в нескольких доклинических иссле-дованиях на лабораторных животных [12,16,17].…”

“…В различных мышиных моделях введение агонистов FXR животным с избыточным весом оказывало протек-тивное действие в отношении развития жирового ге-патоза и инсулинорезистентности [12,16,18]. Введение WAY-362450 мышам на богатой фруктозой диете также демонстрировало противостеатозный эффект, по-види-мому, за счет усиления барьерных функций эпителия тон-кого кишечника и снижения уровня перилипина 2 (ади-пофилина) в тканях печени [19].…”

1-Carbon Cycle Metabolites Methylate Their Way to Fatty Liver

“…NHRs may bind a variety of ligands, however, two NHRs that can act in the liver have been shown to bind specific PC species. PPARα has a well established role as a regulator of fatty acid oxidation, lipid transport and gluconeogenesis [55] and it is the target of therapeutics [56]. The Semenkovich lab used tandem mass spectrometry to identify endogenous ligands for PPARα in the mouse liver and found that a specific species of phosphatidylcholine (16:0/18:1 GPC) was associated with the active transcription factor [57].…”