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Updated: Oct 17, 2025
Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
Novel therapeutic targets for cholestatic and fatty liver disease
Michael Trauner1, Claudia Daniela Fuchs2
1Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria michael.trauner@meduniwien.ac.at.
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.
Insights
Novel therapeutic strategies targeting nuclear receptors (NRs) show promise for treating liver diseases like cholestasis and non-alcoholic fatty liver disease (NAFLD). These approaches address metabolic dysfunction, inflammation, and fibrosis, crucial for disease progression.
Area of Science:
- Hepatology
- Endocrinology
- Molecular Biology
Background:
- Cholestatic and non-alcoholic fatty liver disease (NAFLD) share common pathophysiological pathways.
- Nuclear receptors (NRs) regulate key metabolic processes, including lipid and bile acid homeostasis, inflammation, and fibrosis in the liver.
- Dysregulation of these NR-controlled processes contributes significantly to liver disease progression.
Purpose of the Study:
- To explore novel therapeutic concepts targeting nuclear receptors for cholestatic and NAFLD treatment.
- To review current NR-targeted drug development, including ligands for FXR, PPARs, and TRbeta1.
- To discuss alternative strategies modulating bile acid signaling and targeting inflammation/fibrosis.
Main Methods:
- Review of current literature on nuclear receptor-targeted therapies for liver diseases.
- Analysis of therapeutic ligands targeting farnesoid-X receptor (FXR), peroxisome proliferator-activated receptors (PPARs), and thyroid hormone receptor beta 1 (TRbeta1).
- Evaluation of strategies involving fibroblast growth factor 19 (FGF19) mimetics, bile acid circulation modulators, and direct anti-inflammatory/anti-fibrotic agents.
Main Results:
- Development of high-affinity therapeutic ligands for specific or multiple NR isoforms (FXR, PPARs, TRbeta1).
- Emerging strategies include FGF19 mimetics, bile acid uptake inhibitors, and novel bile acid derivatives.
- Direct targeting of inflammation and fibrosis represents another therapeutic avenue.
Conclusions:
- Nuclear receptors are central targets for novel therapies in cholestatic and NAFLD.
- Targeting bile acid signaling, metabolic pathways, inflammation, and fibrosis offers multifaceted treatment options.
- Combination strategies may be essential for effectively managing these complex liver disorders.
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