Department of Pharmacy, College of Pharmacy, Pusan National University, Geumjeong-Gu, Busan, Korea.
Department of Pharmacy, College of Pharmacy, Kyungsung University, Nam-gu, Busan, Korea.
Liver Int. 2020 Nov;40(11):2706-2718. doi: 10.1111/liv.14594. Epub 2020 Jul 26.
BACKGROUND & AIMS: Endoplasmic reticulum (ER) stress is one of the major causes of hepatic insulin resistance through increasing de novo lipogenesis. Forkhead box O6 (FoxO6) is a transcription factor mediating insulin signalling to glucose and lipid metabolism, therefore, dysregulated FoxO6 is involved in hepatic insulin resistance. In this study, we elucidated the role of FoxO6 in ER stress-induced hepatic lipogenesis.
Hepatic ER stress responses and lipogenesis were monitored in mice overexpressed with constitutively active FoxO6 allele and FoxO6-null mice. In the in vitro study, HepG2 cells overexpressing constitutively active FoxO6 were treated with palmitate, and then alterations in ER stress and lipid metabolism were measured.
FoxO6 activation induced hepatic lipogenesis and the expression of ER stress-inducible genes. The expression and transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ) were significantly increased in constitutively active FoxO6 allele. Interestingly, we found that the active FoxO6 physically interacted with C/EBP homologous protein (CHOP), an ER stress-inducible transcription factor, which was responsible for PPARγ expression. Palmitate treatment caused the expression of ER stress-inducible genes, which was deteriorated by FoxO6 activation in HepG2 cells. Palmitate-induced ER stress led to PPARγ expression through interactions between CHOP and FoxO6 corresponding to findings in the in vivo study. On the other hand, the expression of PPARα and β-oxidation were decreased in constitutively active FoxO6 allele which implied that lipid catabolism is also regulated by FoxO6.
Our data present significant evidence demonstrating that CHOP and FoxO6 interact to induce hepatic lipid accumulation through PPARγ expression during ER stress.
内质网（ER）应激是导致肝胰岛素抵抗的主要原因之一，其通过增加从头合成脂肪来实现。叉头框 O6（FoxO6）是一种转录因子，介导胰岛素信号转导至葡萄糖和脂质代谢，因此，失调的 FoxO6 参与肝胰岛素抵抗。在本研究中，我们阐明了 FoxO6 在 ER 应激诱导的肝脂肪生成中的作用。
在过表达组成型激活 FoxO6 等位基因的小鼠和 FoxO6 缺失小鼠中监测肝 ER 应激反应和脂肪生成。在体外研究中，用棕榈酸处理过表达组成型激活 FoxO6 的 HepG2 细胞，然后测量 ER 应激和脂质代谢的变化。
FoxO6 激活诱导肝脂肪生成和 ER 应激诱导基因的表达。过表达组成型激活 FoxO6 的细胞中，过氧化物酶体增殖物激活受体 γ（PPARγ）的表达和转录活性显著增加。有趣的是，我们发现活性 FoxO6 与内质网应激诱导转录因子 C/EBP 同源蛋白（CHOP）发生物理相互作用，后者负责 PPARγ 的表达。棕榈酸处理导致 ER 应激诱导基因的表达，而 FoxO6 激活在 HepG2 细胞中则使这种表达恶化。棕榈酸诱导的 ER 应激导致 PPARγ 表达，这与体内研究的结果一致，是通过 CHOP 和 FoxO6 之间的相互作用实现的。另一方面，组成型激活 FoxO6 等位基因中 PPARα 和 β-氧化的表达减少，这意味着脂质分解代谢也受到 FoxO6 的调节。
我们的数据提供了重要证据，证明在 ER 应激期间，CHOP 和 FoxO6 通过相互作用诱导 PPARγ 表达，从而导致肝脂肪堆积。
