Sustained high-fat diet intake differentially regulates hepatic lipophagy and metabolic adaptation after bariatric surgery in obese rats.

The global rise in obesity has been paralleled by an increasing burden of metabolic dysfunction-associated steatotic liver disease (MASLD). This study examined how metabolic bariatric surgery, sleeve gastrectomy (SG), under continued exposure to a high-fat diet (HFD), affects hepatic pathology, lipid metabolism, autophagy, and liver lipidomic profiles in diet-induced obese Wistar rats. After 14 weeks of HFD feeding, 25 male Wistar rats (n=5 per group) underwent SG or control procedures and were maintained on an HFD for up to 12 additional weeks. SG reduced the rats' serum alanine aminotransferase and aspartate aminotransferase levels and mitigated hepatic lipid accumulation. Immunohistochemistry demonstrated reduced perilipin 2 (PLIN2) expression; therefore, it is recommended that the time-dependent changes in lipophagic activity be studied after surgery. Lipidomic analysis also revealed changes in hepatic free fatty acid composition after SG, with reduced levels of pro-steatotic fatty acids and improved lipid metabolic balance. Multi-variate partial least squares discriminant analysis further revealed distinct metabolic states between the groups. Such results indicate that even with sustained HFD intake after surgery, the expression of lipid-synthesis-related enzymes in the liver remained upregulated, indicating enhanced postoperative hepatic metabolic activity. However, the physiological stress induced by the surgical procedure appeared to activate lipophagy, promoting the reprogramming of lipid metabolic pathways. Collectively, these findings indicate that SG alleviates hepatic steatosis and reprograms lipid metabolism despite ongoing HFD exposure, and that lipidomic signatures may serve as informative biomarkers for monitoring liver recovery in MASLD.