Orphan Nuclear Receptors in Metabolic Dysfunction-associated Steatotic Liver Disease Development (IMAGE)
Caption
Orphan nuclear receptors influence the onset and progression of MASLD, particularly in lipid metabolism, inflammation, autophagy, and cholesterol metabolism. These receptors may play either similar or opposing roles within the same pathological and physiological processes, forming an intricate network of interactions. Among them, SHP and HNF4α have been studied extensively. SHP participates in MASLD progression by influencing lipid synthesis, liver inflammation, fibrosis, and circadian rhythms, while also interacting with other orphan nuclear receptors such as RORγ and LRH-1. HNF4α, in contrast, influences MASLD progression primarily through its impact on lipid and bile acid metabolism. Although orphan nuclear receptors play important roles in MASLD, few drugs currently target these receptors for MASLD treatment. Therefore, the development of therapeutics aimed at orphan nuclear receptors is essential. Moreover, the fact that some orphan nuclear receptors exert opposing effects in the same physiological processes is both intriguing and worthy of further investigation. Additional research is necessary to elucidate these underlying mechanisms, thereby providing a theoretical foundation for the potential clinical use of orphan nuclear receptors as therapeutic targets in the future. In this review, we discuss the contributions of distinct nuclear orphan receptors to MASLD pathogenesis, evaluate emerging therapeutic strategies targeting these receptors, and highlight promising avenues for future MAFLD intervention.
Credit
Mingkai Chen
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License
CC BY-NC