DRD2-Mediated AMPK Ubiquitination Regulates the Occurrence of Hepatic Steatosis

Abstract

Background & Aims

G protein-coupled receptors (GPCRs) are important potential drug targets for the treatment of metabolic disorders. The D2 dopamine receptor (DRD2), a GPCR receptor, is a member of the dopamine receptor family. However, the role of DRD2 in regulating lipid metabolism, especially in hepatic steatosis, is unclear.

Methods

Eight-week male mice were fed HFHC/MCD to induce the MASH model. AAV2/8 containing the TBG promoter was used to knock down and overexpress DRD2 in mouse liver. Co-immunoprecipitation, Western lotting, immunofluorescence, and immunohistochemistry were used to investigate the mechanisms and screen DRD2 antagonists.

Results

The study found that activation of PKC leads to the elevation and internalisation of DRD2 in a high-fat environment. Knockdown of DRD2 in mouse liver can effectively interfere with the progression of MASH, while overexpression of DRD2 significantly aggravates the process of MASH. The study on the mechanism of DRD2 regulating lipid metabolism found that the internalisation of DRD2 could lead to dephosphorylation of pAKT (T308) by binding to β-arrestin2 and pAKT, thereby inducing ubiquitin-dependent degradation of AMPK and exacerbating steatosis. L-741626, a DRD2 antagonist, was found to interfere with the internalisation of DRD2 in a high-fat environment. It has been shown that L-741626 can treat MASH by regulating the AKT-AMPK signalling axis in vitro and in vivo.

Conclusions

In conclusion, this study demonstrated that internalisation of DRD2 in a high-fat environment aggravated MASH progression through the AKT-AMPK signalling axis. Furthermore, L-741626, as a DRD2 antagonist, has the potential to treat MASH.