Amelioration of free fatty acid-induced fatty liver by quercetin-3-O-β-D-glucuronide through modulation of peroxisome proliferator-activated receptor-alpha/sterol regulatory element-binding protein-1c signaling.

AIM: To investigate the therapeutic effect and potential mechanisms of the natural flavonoid quercetin-3-O-β-D-glucuronide (Q3GA) against lipid metabolism disorder in free fatty acid (FFA)-induced fatty liver in vivo and in vitro.

METHODS: Fat accumulation was documented by oil red O staining, and intracellular triglyceride levels were detected by triglyceride(TG) enzymatic assay. Flow cytometry and enzyme-linked immunoassay assay were performed to observe the effect of Q3GA on lipotoxicity and inflammation response of primary rat hepatocytes with FFA treatment. Administration with Q3GA at doses of 25 and 50 mg/kg from the fifth week during high fat diet (HFD) induced non-alcoholic fatty liver disease (NAFLD) model for 8 weeks. Expression of the genes involved in the lipogenesis and fatty acid β-oxidation were assayed by reverse transcription polymerase chain reaction.

RESULTS: Q3GA reduced bodyweight gain, liver weight, liver index, dyslipidemia and hepatic TG level in a dose-dependant manner. In the FFA-overloaded primary rat hepatocytes, Q3GA decreased the fat overload and TG content, inhibited hepatocyte apoptosis and reduced inflammation cytokine expression. Importantly, the histopathological examination of liver showed that Q3GA could decrease hepatic lipid accumulation and liver injury. Besides, Q3GA decreased the expression of sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase and increased the expression of peroxisome proliferator-activated receptor-α (PPAR-α), carnitine palmitoyl-transferase 1 and medium-chain acyl-coenzyme A dehydrogenase in vivo and in vitro.

CONCLUSION: The therapeutic effect of Q3GA on lipid metabolism disorder in FFA-induced fatty liver rats is partly due to downregulating SREBP-1c and upregulating PPAR-α-mediated metabolic pathways.