Research Paper Volume 11, Issue 12 pp 4066—4074
Anti-aging interventions affect lifespan variability in sex, strain, diet and drug dependent fashion
- 1 Department of Internal Medicine, Geriatrics Research, Southern Illinois University School of Medicine, Springfield, IL 62794, USA
- 2 Illinois State Museum Research and Collections Center, Springfield, Illinois 62703, USA
- 3 Institute of Environmental Sciences, Leiden University, Leiden 2333 CC, The Netherlands
Received: February 5, 2019 Accepted: June 12, 2019 Published: June 24, 2019
https://doi.org/10.18632/aging.102037How to Cite
Copyright: Bartke et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Decreased forkhead box O1 (FoxO1) activity induces hyperlipidemia and increased PPARγ, 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 PPARγ 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 PPARγ-mediated lipid accumulation in aged rat livers. Our data showed that the FoxO1-induced hepatic lipid accumulation was negatively regulated by Akt signaling. PPARγ, 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 PPARγ expression and reduces lipid accumulation. In addition, the interaction between FoxO1 and PPARγ was shown to induce hepatic steatosis in aging and db/db mice.
We provide evidence that, in aged rats, FoxO1 interaction with PPARγ promotes hepatic steatosis, due to hyperglycemia-induced ER stress, which causes an impairment in Akt signaling, such in aging-related diabetes.