Nuclear receptors (NRs) are a superfamily of
transcription factors which sense hormonal signals or nutrients to regulate various biological events, including development, reproduction, and metabolism. Here, this study identifies
nuclear receptor subfamily 2, group F, member 6 (NR2F6), as an important regulator of hepatic
triglyceride (TG) homeostasis and causal factor in the development of
non-alcoholic fatty liver disease (
NAFLD). Adeno-associated virus (AAV)-mediated overexpression of NR2F6 in the liver promotes TG accumulation in lean mice, while hepatic-specific suppression of NR2F6 improves
obesity-associated hepatosteatosis,
insulin resistance, and
methionine and
choline-deficient (MCD) diet-induced non-
alcoholic steatohepatitis (NASH). Mechanistically, the
fatty acid translocase CD36 is identified as a transcriptional target of NR2F6 to mediate its steatotic role. NR2F6 is able to bind directly onto the CD36 promoter region in hepatocytes and increases the enrichment of
nuclear receptor coactivator 1 (SRC-1) and
histone acetylation at its promoter. Of pathophysiological significance, NR2F6 is significantly upregulated in the livers of obese mice and
NAFLD patients. Moreover, treatment with
metformin decreases NR2F6 expression in obese mice, resulting in suppression of CD36 and reduced hepatic TG contents. Therefore, these results provide evidence for an unpredicted role of NR2F6 that contributes to
liver steatosis and suggest that NR2F6 antagonists may present a therapeutic strategy for reversing or treating
NAFLD/NASH pathogenesis.