Nuclear receptor DHR96 acts as a sentinel for low cholesterol concentrations in Drosophila melanogaster.
All eukaryotic cells have to maintain cholesterol concentrations within defined margins in order to function normally. Perturbing cholesterol homeostasis can result in a wide range of cellular and systemic defects, including cardiovascular diseases, as well as Niemann-Pick and Tangier diseases. Here, we show that DHR96 is indispensable for mediating the transcriptional response to dietary cholesterol and that it acts as a key regulator of the Niemann-Pick type C gene family, as well as of other genes involved in cholesterol uptake, metabolism, and transport. DHR96 mutants are viable and phenotypically normal on a standard medium but fail to survive on diets that are low in cholesterol. DHR96 mutants have aberrant cholesterol levels, demonstrating a defect in maintaining cholesterol homeostasis. Remarkably, we found that a high-cholesterol diet phenocopied the genomic profile of the DHR96 mutation, indicating that DHR96 resides at the top of a genetic hierarchy controlling cholesterol homeostasis in insects. We propose a model whereby DHR96 is activated when cellular cholesterol concentrations drop below a critical threshold in order to protect cells from severe cholesterol deprivation.
Bujold
Mattéa
M
Department of Biological Sciences, University of Alberta, Edmonton, Alberta T6G 2E9, Canada.
Gopalakrishnan
Akila
A
Nally
Emma
E
King-Jones
Kirst
K
D000818:Animals; D002791:Cholesterol, Dietary / Q000378:metabolism*; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D007814:Larva / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*
D002791:Cholesterol, Dietary; D029721:Drosophila Proteins; C096796:Hr96 protein, Drosophila; D018160:Receptors, Cytoplasmic and Nuclear