Citri reticulatae pericarpium viride attenuates metabolic dysfunction-associated steatotic liver disease by activating PGC-1α-mediated fatty acid oxidation in mice.

Abstract

Citri reticulatae pericarpium viride, a fruit peel from immature Citrus reticulata Blanco known as Qing Pi (QP) in Chinese, is a traditional food ingredient widely employed for culinary flavoring and aroma enhancement. Although QP exerts various metabolic benefits, the impacts and mechanisms of QP on preventing metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear. Here, we found that QP extracts (extracted with 75% concentrated ethanol and ethyl acetate) not only decreased high-fat diet (HFD)-induced hepatic triglyceride accumulation and oxidative damage, ameliorated glucose intolerance and enhanced insulin sensitivity after oral administration in mice, but also inhibited free fatty acid-induced steatosis and oxidative stress in QP extract-treated primary mouse hepatocytes. Furthermore, we profiled the absorbed components in the serum of mice by UHPLC-Orbitrap MS after oral gavage of QP extracts, and a total of fifteen flavonoid components were identified. By integrating the results of network pharmacology, molecular docking and transcriptomic sequencing, we analyzed the mechanism of action of QP extracts and found that the PGC-1α-PPARα axis and fatty acid oxidation pathway were highly enriched. QP treatment increased fatty acid oxidation (FAO) and the protein expression of p-AMPK, PGC-1α and PPARα, along with increased mRNA expression of key CYP450 enzymes involved in FAO. Pharmacological inhibition of AMPK or PPARα partially abrogated these effects. Therefore, our results highlight QP's potential as a functional food for the management of MASLD.