In the present study, we observed SR4 activates AMPK in the liver of HFD obese mice and reduced the mRNA expression of key lipogenic genes including Acaca, Fasn, Scd1, Cpt1a, Pparγ, Hmgcr, as well as the transcription factor Srebf1, leading to the suppression of de novo lipid production and eventually inhibition of hepatic steatosis. Here, PRKAA2 is linked to fatty liver disease.