The Role of Nuclear Receptors in the Pathogenesis and Treatment of Non-alcoholic Fatty Liver Disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a global health burden closely linked to insulin resistance, obesity, and type 2 diabetes. The complex pathophysiology of NAFLD involves multiple cellular pathways and molecular factors. Nuclear receptors (NRs) have emerged as crucial regulators of lipid metabolism and inflammation in NAFLD, offering potential therapeutic targets for NAFLD. Targeting PPARs and FXRs has shown promise in ameliorating NAFLD symptoms and halting disease progression. However, further investigation is needed to address side effects and personalize therapy approaches. This review summarizes the current understanding of the involvement of NRs in the pathogenesis of NAFLD and explores their therapeutic potential. We discuss the role of several NRs in modulating lipid homeostasis in the liver, including peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptors (FXRs), REV-ERB, hepatocyte nuclear factor 4α (HNF4α), constitutive androstane receptor (CAR) and pregnane X receptor (PXR).The expanding knowledge of NRs in NAFLD offers new avenues for targeted therapies, necessitating exploration of novel treatment strategies and optimization of existing approaches to combat this increasingly prevalent disease.

Keywords: FXR; LXR; NAFLD; NRs; PPARs.

Figure 1

Spectrum of NAFLD.

Figure 2

Main functions of nuclear receptor related to NAFLD and NR phylogenetic tree. Abbreviations: NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; ER: Estrogen Receptor; ERR: Estrogen-Related Receptor; GR: Glucocorticoid Receptor PR: Progesterone Receptor; MR: Mineralocorticoid Receptor; AR: Androgen Receptor; GCBF: Glucocorticoid-Induced TNFR-Related Protein; TR: Thyroid Hormone Receptor; RAR: Retinoic Acid Receptor; PPAR: Peroxisome Proliferator-Activated Receptor; ROR: Retinoic Acid Receptor-Related Orphan Receptor; LXR: Liver X Receptor; FXR: Farnesoid X Receptor; VDR: Vitamin D Receptor; PXR: Pregnane X Receptor; CAR: Constitutive Androstane Receptor; NGFIβ: Nerve Growth Factor-Inducible Protein β; NURR: Nuclear Receptor Subfamily 4 Group A; NOR1: Neuron-Derived Orphan Receptor 1; RXR: Retinoid X Receptor; HNF: Hepatocyte Nuclear Factor; COUPTF: Chicken Ovalbumin Upstream Promoter-Transcription Factor; PNR: Photoreceptor-Specific Nuclear Receptor; TLX: Tailless Homolog; TR: Thyroid Receptor; SHP: Small Heterodimer Partner; DAX: Dosage-Sensitive Sex Reversal, Adrenal Hypoplasia Critical Region, on Chromosome X; SF1: Steroidogenic Factor 1; LRH1: Liver Receptor Homolog 1.

Figure 3

The role of PPARs in NAFLD. PPARα plays a crucial role in enhancing lipid metabolism by regulating the flow of lipids, controlling fatty acid transportation, and promoting β-oxidation. Moreover, it contributes to reducing inflammation by influencing liver cells, reducing visceral inflammation, and regulating intestinal permeability. On the other hand, PPARβ/δ suppresses the inflammatory phenotype in macrophages and facilitates the selective activation of a desired phenotype. As for PPARγ, it primarily regulates insulin sensitivity within adipose tissue and serves as the key regulator of hepatic stellate cell (HSC) fate. By preventing HSC activation, PPARγ plays a critical role in inhibiting fibrogenesis. Abbreviations: FFA: Free Fatty Acid; FA: Fatty Acid; TG: Triglyceride; ROS: Reactive Oxygen Species; KC: Kupffer Cell.

Figure 4

The role of FXR in NAFLD. Activation of FXR by bile acid (BA) ligands leads to a reduction in bile acid production and an enhancement of lipid and glucose metabolism. In terms of the bile acid pathway, this activation results in the upregulation of FGF19 and the downregulation of CYP7A1, consequently leading to a decrease in bile acid synthesis. Additionally, the activation of FXR increases the levels of SHP, which subsequently lowers the expression of SREBP1c, PEPCK, and G6Pase. As a result, there is an increase in both lipid and glucose metabolism. Abbreviations: GLP-1: Glucagon-Like Peptide 1; FGF19: Fibroblast Growth Factor 19; FGFR: Fibroblast Growth Factor Receptor; FA: Fatty Acid; BA: Bile Acid; LXRE: Liver X Receptor Response Element; SHP: Small Heterodimer Partner; CYP7A1: Cholesterol 7 Alpha-Hydroxylase.