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Updated: Jan 13, 2026
An Advanced Murine Model for Nonalcoholic Steatohepatitis in Association with Type 2 Diabetes
Published on: April 26, 2019
Dopamine receptor D2 regulates inflammation and fibrosis in metabolic dysfunction-associated steatohepatitis disease
Peng Ma1, Yan Zhao Guo1, Long Long Wang1
1School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China.
Abstract:
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.
Insights
Metabolic dysfunction-associated steatohepatitis (MASH) involves liver inflammation and fibrosis. This study shows dopamine receptor D2 (DRD2) contributes to MASH pathogenesis by regulating inflammation and fibrosis, offering a potential therapeutic target.
Area of Science:
- Hepatology
- Molecular Biology
- Metabolic Diseases
Background:
- Metabolic dysfunction-associated steatohepatitis (MASH) is a growing global health concern with unclear pathogenesis.
- Obesity rates are rising, increasing the prevalence of liver diseases like MASH.
Purpose of the Study:
- To elucidate the role of dopamine receptor D2 (DRD2) in the pathogenesis of MASH.
- To investigate the mechanisms by which DRD2 influences liver inflammation and fibrosis.
- To evaluate the therapeutic potential of DRD2 antagonists in MASH.
Main Methods:
- Investigated DRD2 expression in hepatocytes stimulated by LPS + TNFα or TGFβ1.
- Utilized protein kinase C (PKC) activation to study DRD2 internalization.
- Examined the effects of internalized DRD2 on p65 ubiquitination and inflammatory signaling.
- Identified Makorin Ring Finger Protein 1 (MKRN1) as an E3 ligase for p65.
- Assessed DRD2's interaction with Par-4 and its effect on inflammatory responses.
- Studied DRD2's regulation of Yes-associated protein (YAP) nuclear localization via AKT dephosphorylation.
- Evaluated the efficacy of the DRD2 antagonist L-741626 in ameliorating MASH-related inflammation and fibrosis.
Main Results:
- LPS + TNFα or TGFβ1 enhances DRD2 expression and PKC-mediated internalization in hepatocytes.
- Internalized DRD2 regulates inflammation and fibrosis by interfering with p65 ubiquitination.
- MKRN1 is identified as a key E3 ligase for p65 in hepatocytes.
- DRD2 modulates p65 protein levels and inflammatory responses via Par-4 interaction.
- DRD2 influences YAP nuclear localization through AKT dephosphorylation.
- The DRD2 antagonist L-741626 shows potential in reducing liver inflammation and fibrosis.
Conclusions:
- DRD2 plays a significant role in MASH-associated liver inflammation and fibrosis.
- DRD2 internalization and subsequent signaling pathways are critical in MASH pathogenesis.
- Targeting DRD2 with antagonists like L-741626 presents a promising therapeutic strategy for MASH.
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