Interaction between CHOP and FoxO6 promotes hepatic lipid accumulation

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. Methods: 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. Results: FoxO6 activation induced hepatic lipogenesis and the expression of ER stress-inducible genes. The expression and transcriptional activity of peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 PPAR gamma 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 PPAR gamma expression through interactions between CHOP and FoxO6 corresponding to findings in the in vivo study. On the other hand, the expression of PPAR alpha and beta-oxidation were decreased in constitutively active FoxO6 allele which implied that lipid catabolism is also regulated by FoxO6. Conclusion: Our data present significant evidence demonstrating that CHOP and FoxO6 interact to induce hepatic lipid accumulation through PPAR gamma expression during ER stress.