Objective  To explore hypolipidemic effect of nobiletin and its mechanism related to phosphatidyl inositol kinase/serine/threonine specific protein kinase (PI3K/Akt) autophagy signal pathway in rats with nonalcoholic fatty liver (NAFL).

  Methods  Of the 60 clean male Sprague-Dawley (SD) rats, 50 were fed with high-fat feeding to establish a NAFL model and the other 10 were the controls with normal feeding. The 50 rats with NAFL were then randomly divided into a model group with normal saline, a positive control group with 30 mg/kg tiopronin, and three groups with low, moderate and high (10, 20 and 40 mg/kg) nobiletin; the treatments were administered by gavage once a day continuously for two weeks. All the rats′ tissues and blood specimens were collected at the end of the treatments. Haematoxylin-eosin (HE) staining was used to observe pathological changes in of liver tissues. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG) and total cholesterol (TC) were measured with biochemical method. The expressions of autophagy related proteins light chain 3-II (LC3-II), LC3-I, p62 and PI3K/Akt signaling pathway related proteins were detected with Western blot.

  Results  No abnormalities were observed in liver tissues of the normal control rats. In the model rats, microscopic observation on liver tissues revealed destroyed structures of hepatic lobules, uneven size and biased nucleus of hepatocytes, lipid droplets of various size in hepatocytic cytoplasm, and a large number of inflammatory cells in liver lobule tissues. In the rats treated with different doses of nobiletin, the lipid droplets in hepatocytic cytoplasm were decreased and hepatic steatosis was alleviated in a dose-effect manner. Compared to the normal control rats, the model rats had significantly higher liver body index, serum ALT, AST, TC, TG level, and expression of p62, phosphorylated PI3K (p-PI3K)/PI3K, phosphorylated Akt (p-Akt)/Akt, mammalian target of rapamycin (mTOR) but lower level of LC3-II/LC3-I (P < 0.05 for all). In comparison with those in the model rats, the liver body index, serum level of ALT, AST, TC and TG, and the expression of p62, p-PI3K/PI3K, p-Akt/Akt and mTOR decreased in a dose-effect manner in the rats treated with different doses of nobiletin (all P < 0.05); while the level of LC3-II/LC3-I increased (P < 0.05).

  Conclusion  Nobiletin could reduce liver injury in rats with nonalcoholic fatty liver and the effect may be related to the inhibition of PI3K/Akt autophagy signal pathway.