Identification and characterization of novel dietary cholesterol regulated genes
Dr. Breslow's laboratory has also been studying gene-diet interactions that might influence atherosclerosis susceptibility. C57BL/6J mice were fed high and low cholesterol diets and liver genes regulated by dietary cholesterol identified using gene expression microarrays. Several novel genes emerged, including Pcsk9 and StARD4. Pcsk9 was shown to enhance degradation of liver LDL receptors, thereby raising plasma LDL cholesterol levels. This led to a major effort by PHARMA to develop Pcsk9 inhibitors as a new LDL cholesterol lowering modality. StARD4 is a member of the START domain-containing gene family and was shown to be a cholesterol transporter. StARD4 is down regulated by cholesterol through an SREBP2-dependent mechanism. The crystal structure of StARD4 was determined. Studies in StARD4 knockdown HepG2 cells revealed that under conditions of lipid deficiency this protein plays a role in cholesterol transport from the plasma membrane to intracellular organelles, such as the endoplasmic reticulum. Further studies are underway to reveal the precise role StARD4 in hepatocyte intracellular cholesterol transport. StARD4 knockout mice have also been created and are currently under study.
Researcher:
Jeanne Garbarino, jgarbarino@rockefeller.edu
