Altered FoxO1 and PPARγ interaction in age-related ER stress-induced hepatic steatosis

Decreased forkhead box O1 (FoxO1) activity induces hyperlipidemia and increased PPAR gamma, leading to hyperlipidemia in association with endoplasmic reticulum (ER) stress. In the liver, aging and comorbidities such as hyperlipidemia and diabetes significantly influence a wide variety of steatosis, but the underlying mechanisms are complex and remain elusive. To establish the modulatory role of FoxO1 and the functional consequences of its altered interaction with PPAR gamma, in the present study, we utilized a cell culture system, aged rats and diabetic db/db mice. We found that, under ER stress, FoxO1 induces PPAR gamma-mediated lipid accumulation in aged rat livers. Our data also showed that the FoxO1-induced hepatic lipid accumulation was negatively regulated by Akt signaling. PPAR gamma, a key lipogenesis transcription factor, was increased in aged liver, resulting in lipid accumulation via hepatic ER stress under hyperglycemic conditions. We further demonstrated that loss of FoxO1 causes a decline in PPAR gamma expression and reduces lipid accumulation. In addition, the interaction between FoxO1 and PPAR gamma was shown to induce hepatic steatosis in aging and db/db mice. We provide evidence that, in aged rats, FoxO1 interaction with PPAR gamma promotes hepatic steatosis, due to hyperglycemia-induced ER stress which causes an impairment in Akt signaling, such as aging-related diabetes.