Dopamine receptor D1-mediated suppression of liver fibrosis via Hippo/Yes-associated protein 1 signaling in levodopa treatment.

Abstract

Background: Yes-associated protein 1 (YAP1), a downstream transcriptional coactivator regulated by the Hippo signaling pathway, has been shown to be involved in liver fibrosis. YAP activity is modulated by G-protein coupled receptors, including Gα s-coupled protein dopamine receptor D1 (DRD1). Levodopa, a dopamine precursor, activates DRD1 on cell surface, triggering its downstream signaling pathway.

Aim: To investigate the therapeutic effect of levodopa and the downstream mechanism on carbon tetrachloride (CCl₄)-induced liver fibrosis, including liver DRD1 expression.

Methods: SD rats were intraperitoneally injected with 40% CCl₄ for 8 weeks to induce liver fibrosis, followed by treatment with varying doses of levodopa for 2 weeks. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured, and liver pathology was assessed using hematoxylin and eosin and Masson's staining. Alpha-smooth muscle actin (α-SMA) content, along with the expressions of DRD1, YAP, and phosphorylated protein, was analyzed by Western blot, immunohistochemistry, and reverse transcription-quantitative real-time polymerase chain reaction.

Results: Compared with the controls, levodopa-treated rats showed a decrease in the proportion of collagen in the liver and a recovery from liver fibrosis (P = 0.0007). Western blot and immunohistochemistry indicated that DRD1 was upregulated in the fibrotic liver of rats treated with levodopa, showing an increase in DRD1 Level (P < 0.0001). In addition, the upregulation of DRD1 activated the Hippo signaling pathway, manifested as increased YAP phosphorylation (P < 0.05).

Conclusion: This was the first study to demonstrate that levodopa attenuates CCl₄-induced liver fibrosis by inhibiting the Hippo/YAP signaling pathways.