Hnf4α initiates hepatic lipid mobilization via activating fatty acid β-oxidation during starvation in tiger puffer (Takifugu rubripes)

Abstract

Starvation is a natural stressor for fish, during which the liver adapts lipid metabolism to supply energy. Although our previous research clarified the effects of starvation on body composition in tiger puffer, the impact on hepatic lipid metabolism and the underlying molecular mechanism remains unknown. Here, 900 juvenile tiger puffer (19.50 ± 0.05 g) were randomly divided into 18 tanks (six tanks per group), and fed diets containing 8%, 12%, or 16% lipid for nine weeks, followed by a 31-day starvation period. Samples were collected at the end of the feeding trial and at Day 0, 1, 4, 9, 16, and 31 of the starvation periods. The results revealed that starvation remodeled hepatic lipid metabolism. Specifically, with prolonged starvation, lipogenesis was initially inhibited and then activated, whereas lipolysis, fatty acid β‑oxidation and lipid transport were promoted, indicating a suppression of lipid anabolism and an enhancement of mobilization to meet energy demands. Among the lipid metabolism-related transcription factors, hnf4α expression was significantly influenced by the interaction between starvation and dietary lipid level, and increased over the starvation period. Subsequent in vivo and in vitro experiments using the Hnf4α agonist benfluorex hydrochloride or inhibitor BI6015 confirmed that Hnf4α activation lowered hepatic lipid contents and enhanced fatty acid β‑oxidation, whereas its inhibition produced the opposite effects. These findings indicate that Hnf4α regulates hepatic lipid mobilization in tiger puffer, offering insights into lipid metabolic adaptation during starvation and identifying Hnf4α as a potential target for improving lipid utilization.