Therapeutic Potential of Peroxisome Proliferator-Activated Receptor Modulation in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

Abstract

Abstract. A long neglected hepatic manifestation of the metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) arise as serious health burden with alarming global prevalence. The disease complex is currently attracting considerable interest of drug discovery and many experimental approaches are studied in all stages of clinical development. Peroxisome proliferator-activated receptors (PPARs) have a successful history as pharmaceutical targets in the treatment of several aspects of the metabolic syndrome and, therefore, a putative therapeutic value of PPAR modulators in NAFLD/NASH is obvious. However, so far only the PPAR / agonist elafibranor has revealed clear efficacy and reached an advanced stage of development while the far more established PPAR subtypes PPAR and PPAR have disappointed. Still, clinical trial design and population might have obscured beneficial activities and, in addition, synergistic multi-target approaches as well as selective PPAR modulators could generate safer approaches with higher therapeutic efficacy.

Allosteric modulation of the farnesoid X receptor by a small molecule

“…Such gene-selective activity might be due to differential recruitment of distinct co-activators as it has been described e.g. for some selective PPAR modulators 27 . Our results indicate that FXR activity can be modulated via an allosteric mechanism in both, synergistic ago-positive and allosteric antagonistic fashion.…”

Urate transporter inhibitor lesinurad is a selective peroxisome proliferator-activated receptor gamma modulator (sPPARγM) in vitro

“…Of note, the term “selective” here refers to the mode of PPARγ modulation in terms of tissue-selectivity or selective effects compared to full PPARγ agonists such as pioglitazone but not to the selectivity over related molecular targets such as other PPAR subtypes. Several sPPARγMs 11 , 42 , 43 have been developed that differentially induce PPARγ-regulated genes potentially due to differential recruitment of different coactivators to the nuclear receptor. According to our results, lesinurad also constitutes such sPPARγM and is free from the adipogenic effect of classical PPARγ agonists in vitro .…”

“…In addition, weight gain as a common side-effect of PPARγ agonists is an obstacle for their use especially in metabolic diseases. Still, PPARγ stays in focus of drug discovery for a variety of indications including metabolic 11 and inflammatory 12 disorders. Recent progress in PPARγ research has yielded selective PPARγ modulators (reviewed in 11 ) that exploit beneficial effects of PPARγ activation in vivo while partly avoiding its adverse effects.…”

Boosting Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology

“…On PPARγ, replacement of the urethane moiety by urea hardly affected the EC 50 value but significantly diminished transactivation efficacy. Considering that weight gain is a common adverse effect of full PPARγ agonists and that partial agonists lack this undesired activity while retaining anti-inflammatory effects of PPARγ modulation, − partial agonistic activity on PPARγ appears favorable and safer.…”