AUTHOR=Aarnio Vuokko , Lehtonen Marko , Storvik Markus , Callaway James C., Lakso Merja , Wong Garry 

TITLE=Caenorhabditis Elegans Mutants Predict Regulation of Fatty Acids and Endocannabinoids by the CYP-35A Gene Family

JOURNAL=Frontiers in Pharmacology

VOLUME=2

YEAR=2011

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2011.00012

DOI=10.3389/fphar.2011.00012

ISSN=1663-9812

ABSTRACT=<p><bold>Background</bold>: Cytochrome P450s (CYPs) are mono-oxygenases that metabolize endogenous compounds, such as fatty acids and lipid signaling molecules, and furthermore have a role in metabolism of xenobiotics. In order to investigate the role of CYP genes in fat metabolism at the molecular level, four <italic>Caenorhabditis elegans</italic> mutants lacking functional CYP-35A1, CYP-35A2, CYP-35A4, and CYP-35A5 were characterized. Relative amounts of fatty acids, as well as endocannabinoids, which regulate weight gain and accumulation of fats in mammals, were measured while fat contents in worms were visualized using Oil-Red-O staining. <bold>Results</bold>: The <italic>cyp-35A1</italic> and <italic>cyp-35A5</italic> mutants had a significantly lower intestinal fat content than wild-type animals, whereas <italic>cyp-35A2</italic> and <italic>cyp-35A4</italic> mutants appeared normal. The overall fatty acid compositions of CYP mutants did not alter dramatically, although modest but significant changes were observed. <italic>cyp-35A1</italic> and <italic>cyp-35A5</italic> mutants had significantly higher levels of C18:1n7 and lower C18:2n6c. All four mutants had higher relative amounts of C18:1n7 than the wild-type. In the <italic>cyp-35A5</italic> mutant, the levels of the endocannabinoid anandamide were found to be 4.6-fold higher than in wild-type. Several fatty acid synthesis genes were over-expressed in <italic>cyp-35A1</italic> including <italic>fat-2</italic>. Feeding oleic or elaidic triglycerides to wild-type animals demonstrated that <italic>cyp-35A1</italic> transcriptional levels are insensitive to environmental exposure of these fats, while <italic>cyp-35A2, cyp-35A4</italic>, and <italic>cyp-35A5</italic> were significantly down regulated. <bold>Conclusion</bold>: These results demonstrate a dynamic role for <italic>CYP-35A</italic> subfamily members in maintaining the diversity of fatty acid profiles in <italic>C. elegans</italic>, and more generally highlight the importance of CYPs in generating both structural and signaling fatty acid functions in other organisms.</p>