Reduced NR2F6 expression reshapes the VPA-induced transcriptome in human hepatocytes and increases lipid accumulation

Area of Science:

• Hepatology
• Molecular Biology
• Pharmacology

Background:

• Valproic acid (VPA) is an antiepileptic drug linked to liver steatosis (fatty liver).
• The specific molecular mechanisms and regulators controlling susceptibility to VPA-induced steatosis are not fully understood.

Purpose of the Study:

• To identify nuclear regulators that influence liver cell response to VPA.
• To elucidate the role of NR2F6 in VPA-induced hepatic steatosis.

Main Methods:

• Time-series RNA-sequencing in primary human liver spheroids.
• shRNA screen of nuclear receptors in HepG2 cells.
• Functional validation in HepG2 and HepaRG cell models.
• RNA-sequencing of NR2F6 knockdown cells exposed to VPA.

Main Results:

• NR2F6 was identified as a key regulator sensitizing liver cells to VPA toxicity.
• NR2F6 knockdown exacerbated VPA-induced lipid accumulation, but not lipid accumulation from fatty acids.
• NR2F6 deficiency amplified VPA's transcriptomic effects, including upregulation of nuclear-encoded oxidative phosphorylation genes and altered lipid metabolism pathways (CPT1A, PLIN2).

Conclusions:

• NR2F6 is a critical modulator of hepatocellular adaptation to VPA.
• NR2F6 links nuclear receptor signaling to mitochondrial and lipid metabolic reprogramming in drug-induced steatosis.
• NR2F6 deficiency creates a VPA-specific vulnerability to steatosis.