Interaction between CHOP and FoxO6 promotes hepatic lipid accumulation

Area of Science:

• Molecular Biology
• Cell Biology
• Metabolic Diseases

Background:

• Endoplasmic reticulum (ER) stress is a key driver of hepatic insulin resistance by promoting de novo lipogenesis.
• Forkhead box O6 (FoxO6), a transcription factor regulating glucose and lipid metabolism, is implicated in hepatic insulin resistance when dysregulated.

Purpose of the Study:

• To investigate the role of FoxO6 in ER stress-induced hepatic lipogenesis.
• To elucidate the molecular mechanisms linking ER stress, FoxO6, and lipid metabolism.

Main Methods:

• Utilized mice with overexpressed constitutively active FoxO6 and FoxO6-null mice to study hepatic ER stress and lipogenesis.
• Employed HepG2 cells overexpressing active FoxO6, treated with palmitate, to assess ER stress and lipid metabolism alterations in vitro.

Main Results:

• FoxO6 activation enhanced hepatic lipogenesis and ER stress-inducible gene expression.
• Active FoxO6 increased peroxisome proliferator-activated receptor γ (PPARγ) expression and transcription, interacting with C/EBP homologous protein (CHOP).
• Palmitate-induced ER stress exacerbated lipogenesis with FoxO6 activation, mediated by CHOP-FoxO6 interaction and subsequent PPARγ upregulation. FoxO6 also decreased PPARα and β-oxidation, indicating regulation of lipid catabolism.

Conclusions:

• FoxO6 and CHOP interaction is a critical mechanism inducing hepatic lipid accumulation via PPARγ during ER stress.
• FoxO6 plays a significant role in regulating both lipid synthesis and catabolism under ER stress conditions.