Hepatocyte nuclear factor 4α (HNF4α) is a
nuclear receptor that regulates the expression of genes involved in the secretion of
apolipoprotein B (
apoB)-containing
lipoproteins and in
glucose metabolism. In the present study, we identified a naturally occurring
flavonoid,
luteolin, as a repressor of HNF4α by screening for effectors of the human
microsomal triglyceride transfer protein (MTP) promoter.
Luciferase reporter gene assays revealed that the activity of the MTP gene promoter was suppressed by
luteolin and that the mutation of HNF4α-binding
element abolished
luteolin responsiveness.
Luteolin treatment caused a significant decrease in the
mRNA levels of HNF4α target genes in HepG2 cells and inhibited
apoB-containing
lipoprotein secretion in HepG2 and differentiated Caco2 cells. The interaction between
luteolin and HNF4α was demonstrated using absorption spectrum analysis and
luteolin-immobilized beads.
Luteolin did not affect the
DNA binding of HNF4α to the promoter region of its target genes but suppressed the acetylation level of
histone H3 in the promoter region of certain HNF4α target genes. Short term treatment of mice with
luteolin significantly suppressed the expression of HNF4α target genes in the liver. In addition, long term treatment of mice with
luteolin significantly suppressed their diet-induced
obesity and improved their serum
glucose and
lipid parameters. Importantly, long term
luteolin treatment lowered serum VLDL and
LDL cholesterol and serum
apoB protein levels, which was not accompanied by fat accumulation in the liver. These results suggest that the
flavonoid luteolin ameliorates an atherogenic
lipid profile in vivo that is likely to be mediated through the inactivation of HNF4α.