Targeting nuclear receptors for NASH/MASH: From bench to bedside

Abstract

The onset of metabolic dysfunction-associated steatohepatitis (MASH) or non-alcoholic steatohepatitis (NASH) represents a tipping point leading to liver injury and subsequent hepatic complications in the natural progression of what is now termed metabolic dysfunction-associated steatotic liver diseases (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). With no pharmacological treatment currently available for MASH/NASH, the race is on to develop drugs targeting multiple facets of hepatic metabolism, inflammation, and pro-fibrotic events, which are major drivers of MASH. Nuclear receptors (NRs) regulate genomic transcription upon binding to lipophilic ligands and govern multiple aspects of liver metabolism and inflammation. Ligands of NRs may include hormones, lipids, bile acids, and synthetic ligands, which upon binding to NRs regulate the transcriptional activities of target genes. NR ligands are presently the most promising drug candidates expected to receive approval from the United States Food and Drug Administration as a pharmacological treatment for MASH. This review aims to cover the current understanding of NRs, including nuclear hormone receptors, non-steroid hormone receptors, circadian NRs, and orphan NRs, which are currently undergoing clinical trials for MASH treatment, along with NRs that have shown promising results in preclinical studies.

Keywords: Drug; Liver; Metabolic dysfunction-associated steatohepatitis (MASH); Metabolic dysfunction-associated steatotic liver disease (MASLD); Nuclear receptor (NR); Transcription factor.

Fig. 1

Molecular mechanisms of NRaction. Nuclear receptor (NR) ligands which may include hormones, lipids, cholesterol derivatives, and xenobiotics may bind to either cytosolic or nuclear resident NRs which results in the binding of NRs to their cognate response elements such as hormone response elements (HREs) on the promoter/enhancer region of the target genes. Upon ligand binding NRs evoke a dynamic exchange of nuclear receptor corepressor (CoR) with nuclear receptor coactivator (CoA) complexes. The CoA has a histone acetylase activity which helps in the opening of the nucleosomes and initiation of RNA polymerase II (POL II) mediated transcription. The mRNA synthesized in response to NR activation further results in protein synthesis and alteration of cellular function. Besides the classical genomic action of NRs, cytosolic NRs may also induce non-genomic signaling via interaction with cytoplasmic proteins.

Fig. 2

Cell-specific NRs modulation of metabolism, inflammation, and fibrosis response in MASH. Multiple nuclear receptors (NRs) as shown in this schematic play both distinct and overlapping cellular roles in regulating diverse aspects of hepatic lipid metabolism, immunomodulation, and fibrosis response during metabolic dysfunction-associated steatohepatitis (MASH) pathogenesis via their distinct action on hepatocytes, immune cells (Kupffer cells & T cells), and hepatic stellate cells (HSCs). The green font color denotes NRs that negatively regulate the pathogenic processes of hepatosteatosis, immune cell activation (inflammation), and HSC activation (fibrosis), and the red font color denotes NRs that positively regulate them. Abbreviations: THRs, thyroid hormone receptors; GRs, glucocorticoid receptors; ERs, estrogen receptors; VDRs, vitamin D receptors; RARs, retinoic acid receptors; PPARα, peroxisome proliferator-activated receptor α; FXR, farnesoid X receptor; LXR, liver X receptor; PXR, pregnane X receptor; RORs, RAR-related orphan receptors; ERR, estrogen-related receptor; RXR, retinoid X receptor.