Evolutionary conservation of drug action on lipoprotein metabolism-related targets

Abdelmadjid Hihi, Marie-Claude Beauchamp, Robyn Branicky, Annick Desjardins, Isabel Casanova, Marie-Pierre Guimond, Melissa Carroll, Melanie Ethier, Irenej Kianicka, Kevin McBride, and Siegfried Hekimi

Biology, McGill University, Montreal, Quebec H3A 1B1

Corresponding Author: siegfried.hekimi{at}mcgill.ca

Genetic analysis has shown that the slower than normal rhythmic defecation behavior of the clk-1 mutants of C. elegans is due to altered lipoprotein metabolism. We show here that this phenotype can be suppressed by drugs that affect lipoprotein metabolism, including drugs that affect HMG-CoA reductase activity, reverse cholesterol transport, or HDL levels. These pharmacological effects are highly specific as these drugs affect defecation only in clk-1 mutants, and not in the wild type, and do not affect other behaviors of the mutants. Furthermore, drugs that affect processes not directly related to lipid metabolism show no or minimal activity. Based on these findings we have carried out a compound screen that identified 190 novel molecules that are active on clk-1 mutants, 15 of which also specifically lower the secretion of ApoB from HepG2 hepatoma cells. The other 175 compounds are potentially active on lipid-related processes that cannot be targeted in cell culture. One compound, CHGN005, was tested in a mouse model of dyslipidemia, and found to lower plasma cholesterol and triglyceride levels. Thus, target processes for pharmacological intervention on lipoprotein synthesis, transport and metabolism are conserved between nematodes and vertebrates, which allows the use of C. elegans for drug discovery.

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