Table 1 Interactions and potential therapeutic implications of nuclear receptors in metabolic dysfunction-associated steatotic liver disease (MASLD)
Number | Receptors involved | Putative Crosstalk interaction mechanism | Single ligand/ modulator targeting both NR | Signaling pathways affected in the liver | MODEL/effect of dual NR targeting in the MASLD and MASH context |
|---|---|---|---|---|---|
1 | PPARs (PPARα, PPARβ, PPARγ) | Indirect | Lanifibranor | FA breakdown Downregulation de novo lipogenesis Anti-inflammatory effects Glucose homeostasis | Improved MASLD, MASH and fibrosis in various MASLD mice models. Awaiting results of lanifibranor Phase 3 clinical trials. |
2 | PPARα and ERRα | Indirect and/or direct | Respective ligands affect reciprocal receptor levels in non-hepatocyte systems | ERRα serves as a rheostat for PPARα activity | Not yet investigated |
3 | PPARα and GR | Indirect and/or direct | GR agonists can affect PPARα receptor levels | Anti-inflammatory effects FA breakdown Gluconeogenesis | Not yet investigated |
4 | PPARα and LXR | Indirect | None | Induction of lipogenesis Suppression of SREBP1c Reduction of steatosis | Not yet investigated |
5 | FXR and LXR | Indirect | Acanthoic acid Sesamol | Anti-inflammatory effect Reduced lipid accumulation | Improved MASLD and fibrosis in mice model |
6 | PPARα and FXR | Indirect | Diosgenin | Regulation of hepatic lipid metabolism FAO upregulation Regulation of hepatic de novo lipogenesis Regulation of hepatokine FGF21 | ApoE-deficient mice Rats fed with HFD underwent RYGB bariatric surgery. Patients who underwent RYGB bariatric surgery. |
7 | LHR1 and GR | Indirect | None | Largely unexplored (LRH-1 regulates glucose and lipid metabolism and intestinal inflammation by controlling GC synthesis) | Not yet investigated |
8 | HNF4α and GR | Indirect | Nonsteroidal GR antagonist FX5 | FX5 suppressed gluconeogenic genes FX5 treatment improved glucose homeostasis and ameliorated hyperglycemia in T2DM mice | Liver-specific GR-KO mice on a high-fat diet Diabetic mouse models such as db/db mice and HFD/STZ-induced |
9 | VDR and HNF4α | Indirect and/or direct | Oleanolic acid | Normalized fasting serum glucose, insulin levels, insulin resistance, and decreased intrahepatic TG content Oleanolic acid upregulates both NR | HFD-fed mice with a VDR hepatic-KO |
10 | THRβ and ERRα | Indirect | None | Upregulates FAO Enhances OXPHOS | Not yet investigated |
