Nuclear Receptor Modulation for the Treatment of Nonalcoholic Fatty Liver Disease

Claudia D. Fuchs; Stefan A. Traussnigg; Michael Trauner

doi:10.1055/s-0036-1571296

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2016; 36(01): 069-086
DOI: 10.1055/s-0036-1571296

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Nuclear Receptor Modulation for the Treatment of Nonalcoholic Fatty Liver Disease

Claudia D. Fuchs

¹Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

^*These authors contributed equally to this publication.

,

Stefan A. Traussnigg

¹Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

^*These authors contributed equally to this publication.

,

Michael Trauner

¹Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

› Author Affiliations

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.

Keywords

bile acids - farnesoid X receptor - TGR5 - FGF15/19 - fatty acids - peroxisomal proliferator-activated receptor - xenobiotic sensors - vitamin D - RAR-related orphan receptor gamma two

Full Text

References

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