Cordycepin alleviates hepatic lipid accumulation by inducing protective autophagy via PKA/mTOR pathway

As the major active ingredient of Cordyceps militaris, cordycepin (3′-deoxyadenosine) has been well documented to possess lipid-lowering and anti-oxidative activities, making it a promising candidate for treatment of NAFLD. Autophagy was recently identified as a critical protective mechanism during NAFLD development. Therefore, this study aims to elucidate the mechanism of cordycepin regulating autophagy and lipid metabolism. Here, we found that cordycepin decreased palmitate-induced lipid accumulation by Oil Red O staining, Nile Red staining assays, triglyceride and total cholesterol measurements. Based on Western blot assay and immunocytochemistry, we found that cordycepin induced autophagy in PA-induced steatotic HepG2 cells. Whereas pretreatment with CQ, an autophagy inhibitor, substantially deteriorated the mitigative effects of cordycepin on PA-induced hepatic lipid accumulation. These data taken together indicate that cordycepin protects against PA-induced hepatic lipid accumulation via autophagy induction. Further, cordycepin remarkably increased the expression of P-PKA and decreased P-mTOR, whereas pretreatment with H89, a PKA inhibitor, abolished the ability of cordycepin to activate autophagy via mTOR activation. These data suggested that cordycepin protects against PA-induced hepatic lipid accumulation through the promotion of autophagy. The underlying mechanism might be associated with the PKA/mTOR pathway.