Kim Dae Hyun, Ha Sugyeong, Choi Yeon Ja, Dong H Henry, Yu Byung Pal, Chung Hae Young
Department of Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Korea.
Department of Biopharmaceutical Engineering, Division of Chemistry and Biotechnology, Dongguk University, Gyeongju 38066, Korea.
Aging (Albany NY). 2019 Jun 25;11(12):4125-4144. doi: 10.18632/aging.102042.
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.
叉头框蛋白O1（FoxO1）活性降低会诱发高脂血症并增加过氧化物酶体增殖物激活受体γ（PPARγ），进而导致与内质网（ER）应激相关的高脂血症。在肝脏中，衰老以及高脂血症和糖尿病等合并症会显著影响多种脂肪变性，但潜在机制复杂且仍不清楚。在本研究中，为了确定FoxO1的调节作用及其与PPARγ相互作用改变的功能后果，我们使用了细胞培养系统、老年大鼠和糖尿病db/db小鼠。我们发现，在内质网应激条件下，FoxO1会在老年大鼠肝脏中诱导PPARγ介导的脂质蓄积。我们的数据表明，FoxO1诱导的肝脏脂质蓄积受到Akt信号通路的负调控。PPARγ是关键的脂肪生成转录因子，在老年肝脏中表达增加，在高血糖条件下通过肝脏内质网应激导致脂质蓄积。我们进一步证明，FoxO1缺失会导致PPARγ表达下降并减少脂质蓄积。此外，FoxO1与PPARγ之间的相互作用在衰老小鼠和db/db小鼠中会诱发肝脏脂肪变性。我们提供的证据表明，在老年大鼠中，由于高血糖诱导的内质网应激导致Akt信号通路受损，FoxO1与PPARγ的相互作用会促进肝脏脂肪变性，这在衰老相关的糖尿病中也是如此。
