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Constituents-composed Chinese medicine of Dajianzhong Decoction ameliorates Non-alcoholic fatty liver disease via AMPK/PPARα/CPT1 signaling.

Chengxun He,Peipei Wang,Yuanyuan Zuo,Juan Guo,Qing Zhang,Shuyang Peng,Hong Zhang,Xueping Li,Chunjie Wu,Wei Peng

Published 2025 in Phytomedicine

ABSTRACT

BACKGROUND Nonalcoholic fatty liver disease (NAFLD) has attracted increasing interest because it has become one the most prevalent chronic liver diseases. The Dajianzhong decoction (DJZ) is a classical known TCM formula with anti-NAFLD effects; however, its underlying composition and molecular mechanisms remain unknown. METHODS To explore the underlying composition and molecular mechanisms of the anti-NAFLD effects of DJZ via a constituent-composed Chinese medicine strategy (cc-CM), high-fat diet (HFD)-induced mice and free fatty acid (FFA)-induced AML12 cells were used as animal and cellular models of NAFLD. Constituent-composed Chinese medicine DJZ (DJZ-cm) was prepared on the basis of its constituents absorbed into blood. RNA sequence analysis combined with qRT‒PCR verification was carried out to analyze the potential target genes of DJZ-cm. A bioinformatics enrichment analysis was subsequently performed to predict the underlying molecular pathways. Finally, western blotting, immunohistochemistry, immunofluorescence, histopathological examinations and biochemical index assays were carried out to verify the predicted molecular pathways. RESULTS DJZ improved NAFLD symptoms, including hepatic steatosis, liver function indices, oral glucose tolerance and insulin tolerance, in HFD-fed mice. Furthermore, we prepared DJZ-cm for the first time with these compounds according to the ratio of their contents in serum, including ginsenoside Rg1 (30.5 %), ginsenoside Re (9.52 %), ginsenoside Rb2 (10.5 %), ginsenoside Rb1 (15.1 %), hydroxy‑α-sanshool (11.45 %), hydroxy‑β-sanshool (5.11 %), vanillylacetone (8.77 %) and 6-gingerol (9 %). Interestingly, the anti-NAFLD effects of DJZ-cm (40 mg/kg) were equivalent to those of DJZ (400 mg/kg). RNA sequencing combined with qRT‒PCR analysis indicated that AMPK/PPARα/CPT1 signaling might be related to the anti-NAFLD effects of DJZ-cm. These results further verified the predicted results, and DJZ-cm treatment upregulated CPT1A expression by promoting the nuclear transfer of PPARα and increasing the phosphorylation of AMPK. Finally, our results suggested that DJZ-cm could exert anti-NAFLD effects via multiple drug targets, including TRPV1 and AMPK. CONCLUSION The use of cc-CM is a feasible approach for identifying the active substances and mechanisms of TCMs, and DJZ and DJZ-cm have reliable therapeutic effects against NAFLD through the regulation of AMPK/PPARα/CPT1 signaling and the targeting of TRPV1 and AMPK. Our present work would be bifacial for the further modern formulation development of DJZ for clinical treatment of NAFLD.

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