At Least Twenty Genes Regulate Cellular Cholesterol Metabolism

Maintaining the proper level of cholesterol is critical to avoiding vascular lipid deposits that are the prelude to heart disease. To manage this task cells utilize a panel of at least 20 enzymes.

To study how cells maintain their cholesterol balance at the molecular level investigators at the University of Heidelberg (Germany) first used genome-wide gene-expression profiling of sterol-depleted cells and systematic literature queries to identify candidate genes. To further refine the list of candidate genes they developed two microscopic assays that allowed them to observe how blocking individual genes with siRNA (small interfering RNA) affected cholesterol metabolism. One assay used the cholesterol-binding dye Filipin to visualize cellular cholesterol levels, while the other employed fluorescence-labeled LDL (low density lipoprotein) to show cellular internalization.

Results published in the July 8, 2009, issue of the journal Cell Metabolism revealed that 20 genes acted as functional regulators of cellular cholesterol homeostasis. Of these, the TMEM97 gene was identified as an SREBP (sterol regulatory element binding protein) target gene that under sterol-depleted conditions localized to lysosomal compartments and bound to the LDL cholesterol transport-regulating protein Niemann-Pick C1 (NPC1).

SREBPs are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. When not activated, SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that migrates to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences and up regulate the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs, and therefore synthesis of additional sterols is reduced through a negative feed back loop.

"High cholesterol in the blood is considered to be responsible for excess cardiovascular morbidity and mortality," said Dr. Heiko Runz, professor of human genetics at the University of Heidelberg. "Blood cholesterol levels are controlled by cholesterol in cells. Therefore, some of the genes identified by us as regulators of cellular cholesterol in future studies might turn out to be disease genes that contribute to hypercholesterolemia in some cases. Moreover, the strategy we used could open a new avenue to identify risk factors for cardiovascular disease."

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