Sterol and fatty acid regulatory pathways in a Giardia lamblia derived promoter: Evidence for SREBP as an ancient transcription factor

Tilla S. Worgall, Sara R. Davis-Hayman, Marissa M. Magana, Peter M. Oelkers, Fernando Zapata, Rebecca A. Juliano, Timothy F. Osborne, Theodore E. Nash, and Richard J. Deckelbaum

Dept of Pathology / Institute of Human Nutrition, Columbia University, New York, NY 10032

Corresponding Author: tpw7{at}columbia.edu

The sterol regulatory element binding-proteins (SREBP) are transcription factors that regulate genes of lipid metabolism. Cholesterol and unsaturated fatty acids regulate SREBP. Giardia lamblia is an intestinal parasite and one of the earliest derived members within the eukaryotic lineage. Giardia lamblia exist as trophozoites and cysts. Growth in cholesterol depletion induces transcription of cyst-wall protein genes that are upregulated during encystation. The hypothesis was investigated that SREBP-like pathways have a role in cyst-wall protein gene transcription. CHO cells were transfected with a cwp-2 promoter reporter construct. Incubation with cholesterol or oleate reduced cwp-2 mediated gene transcription to about half of control. Incubation in sterol depleted media or in the presence of either an inhibitor of intracellular cholesterol movement or inhibitor of cholesterol synthesis increased gene expression up to 3-fold. Over-expression of SREBP increased reporter gene activity 2.5 fold. In the absence of functional SREBP, cwp-2 was not regulated by cholesterol. Footprint analysis of cwp-2 reveals three novel binding sites for mammalian SREBP with no homologies in other species or humans. The data show that SREBP binds to and can modulate transcription of a regulatory element from an ancient eukaryote and suggest the existence of a SREBP homologue in Giardia lamblia.

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