Dopamine receptor D2 regulates inflammation and fibrosis in metabolic dysfunction-associated steatohepatitis disease

As the global obesity rate continues to rise, obesity-related liver diseases, especially metabolic dysfunction-associated steatohepatitis (MASH), hasrapidly becomea major health challenge globally. Currently, the pathogenesis of MASH remains unclear. This study reveals that LPS + TNFα or TGFβ1 can enhance the expression of Dopamine Receptor D2 (DRD2) in hepatocytes and facilitate the internalization of DRD2 through protein kinase C (PKC) activation. Subsequent investigations have demonstrated that internalized activated DRD2 is involved in the regulation of inflammation and fibrosis. Mechanistic studies indicate that internalization-activated DRD2 can interfere with p65 ubiquitination and promote liver cell inflammation. In addition, this study identified an E3 Ligase Makorin Ring Finger Protein 1 (MKRN1) for p65 in hepatocytes, which plays a role in regulating the ubiquitination of p65. Our study demonstrates that DRD2 can modulate the protein levels of p65 and regulate inflammatory responses through its interaction with Par-4, and the regulation of DRD2 on Yes-associated protein (YAP) nuclear localization is due to the regulation of protein kinase B (Akt) dephosphorylation in LX2 cells. Finally, the study demonstrates that L-741626, a DRD2 antagonist, has the potential to ameliorate inflammation and fibrosis, thus showing promise as a therapeutic strategy for MASH. In summary, this study reveals the role of DRD2 in the inflammation and fibrosis of MASH disease, thereby offering a novel therapeutic strategy for treating MASH.

Dopamine receptor D2 (DRD2); Fibrosis; Inflammation; Metabolic dysfunction-associated steatohepatitis (MASH); P65.