The study investigates the role of microRNAs (miR-33a/b) in cholesterol homeostasis, focusing on their interaction with the SREBP host genes. MiR-33a/b, located within introns of the SREBP genes, target the ATP-binding cassette transporter A1 (ABCA1), which is crucial for high-density lipoprotein (HDL) synthesis and reverse cholesterol transport. The research shows that miR-33a/b repress ABCA1 expression, leading to reduced cholesterol efflux. Antisense inhibition of miR-33 in cell lines and mice on a western-type diet results in increased ABCA1 expression and elevated plasma HDL levels. These findings suggest that miR-33 acts in concert with SREBP host genes to control cholesterol homeostasis and highlight miR-33 as a potential therapeutic target for cardiometabolic diseases.The study investigates the role of microRNAs (miR-33a/b) in cholesterol homeostasis, focusing on their interaction with the SREBP host genes. MiR-33a/b, located within introns of the SREBP genes, target the ATP-binding cassette transporter A1 (ABCA1), which is crucial for high-density lipoprotein (HDL) synthesis and reverse cholesterol transport. The research shows that miR-33a/b repress ABCA1 expression, leading to reduced cholesterol efflux. Antisense inhibition of miR-33 in cell lines and mice on a western-type diet results in increased ABCA1 expression and elevated plasma HDL levels. These findings suggest that miR-33 acts in concert with SREBP host genes to control cholesterol homeostasis and highlight miR-33 as a potential therapeutic target for cardiometabolic diseases.