[
International Worm Meeting,
2019]
Cholesterol is one of the hallmarks building blocks of animals. However, well-studied invertebrates such as Drosophila melanogaster and Caenorhabditis elegans show an intriguing cholesterol auxotrophy. The prevalent of this auxotrophy in the animal kingdom and how cholesterol auxotrophs can thrive remain unknown. Our bioinformatic analysis identified the loss of the first three enzymes of the cholesterol synthesis pathway as a characteristic signature for cholesterol auxotrophy. We found that many invertebrates, including nematodes and arthropods, lack these first three enzymes. Interestingly, however, many of these invertebrates have proteins with sequence similarity to enzymes known to act downstream to the three initial steps of cholesterol syntesis. We discovered that the activity of these proteins facilitate the conversion of dietary fungal and plant sterols to cholesterol. In this previously undescribed pathway, C. elegans orthologues of the human NSDHL enzyme convert fungal and plant sterols such as ergosterol and b-sitosterol to desmosterol. Desmosterol is further converted to cholesterol by the orthologue of human DHCR24. This pathway is essential for normal development and reproduction of C. elegans when fed fungal and plant sterols- the primary source of dietary sterols in the wild. Conservation and loss of this pathway in other cholesterol auxotrophs determine their feeding requirements and thus the level of interkingdom interaction between cholesterol auxotrophs and fungal or plant dietary sources. Our study suggests that most animals on earth, including nematodes and arthropods, are cholesterol auxotrophs. In these auxotrophs, the co-opting of the activity of cholesterol synthesis enzymes is the molecular mechanism that enables widespread cholesterol auxotrophy in the animal kingdom.