Corosolic acid alleviates hepatic metabolic disorders by regulating de novo lipogenesis and bile acid metabolism pathways in HFD-induced MASLD.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with aberrant lipid accumulation, but effective natural therapeutic agents for MASLD are still lacking. Corosolic acid (CA) is a natural product from the fruits of Rosa roxburghii Tratt. However, the effects and mechanisms of CA on hepatic metabolic disorders have not been sufficiently investigated in detail. PURPOSE: This study aimed to investigate the effect of CA on high-fat diet (HFD)-fed hepatic metabolic disorders and elucidate underlying mechanisms in vivo and in vitro. METHODS: The effect of CA was evaluated using HFD mice, high-glucose Caenorhabditis elegans (C. elegans), and oleic acid-induced HepG2 cells as in vivo and in vitro models. Hematoxylin and eosin (H&E) and Oil Red O staining were performed to assess lipid accumulation. Serum triglyceride (TG), total cholesterol (T-CHO), and low-density lipoprotein cholesterol (LDL-C) were measured. Hepatic non-targeted metabolomics, proteomics, and transcriptomics analyses were conducted to examine the effect of CA, followed by RT-qPCR, western blotting, and GFP fluorescence observation for validation. The cellular thermal shift assay (CETSA), molecular docking, and dynamics simulations were performed to evaluate the binding proteins of CA. RESULTS: Our findings revealed that CA reduced weight gain and hepatic lipid accumulation in HFD-induced MASLD mice. CA significantly improved the abnormal profile by regulating metabolic pathways related to lipids, amino acids, carbohydrates, and vitamins. Key metabolites such as palmitoleic acid, L-glutamine, lactose, and vitamin B3 were restored to normal levels with CA intervention. Correlation analysis of RNA-seq and proteomic results revealed that CA was particularly effective in modulating biological processes related to fatty acid, cholesterol, and bile acid metabolism. Mechanistically, CA inhibited Scd1 by activating the AMPK-Acc1 axis and promoted Slco1b2 via suppressing the Fxr-Hmgcr-Cyp7a1 axis. Furthermore, CA binds to Scd1 and Slco1b2 to improve hepatic metabolic homeostasis. CONCLUSIONS: This study demonstrates that CA exhibits a strong anti-MASLD effect on reducing lipid accumulation by the AMPK-Acc1-Scd1 pathway, activating Slco1b2-mediated hepatic uptake, and facilitating the conversion of hepatic cholesterol to bile acids via the Fxr-Hmgcr-Cyp7a1 pathway. These findings support the potential of CA as a functional analogue of statins for MASLD treatment.