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Mammalian bile acids (BAs) are oxidized metabolites of cholesterol whose amphiphilic properties serve in lipid and cholesterol uptake. BAs also act as hormone-like substances that regulate metabolism. The  Caenorhabditis elegans clk-1  mutants sustain elevated mitochondrial oxidative stress and display a slow defecation phenotype that is sensitive to the level of dietary cholesterol. We found that: 1) The defecation phenotype of  clk-1  mutants is suppressed by mutations in  tat-2  identified in a previous unbiased screen for suppressors of  clk-1 . TAT-2 is homologous to ATP8B1, a flippase required for normal BA secretion in mammals. 2) The phenotype is suppressed by cholestyramine, a resin that binds BAs. 3) The phenotype is suppressed by the knock-down of  C. elegans  homologues of BA–biosynthetic enzymes. 4) The phenotype is enhanced by treatment with BAs. 5) Lipid extracts from  C. elegans  contain an activity that mimics the effect of BAs on  clk-1 , and the activity is more abundant in  clk-1  extracts. 6)  clk-1  and  clk-1;tat-2  double mutants show altered cholesterol content. 7) The  clk-1  phenotype is enhanced by high dietary cholesterol and this requires TAT-2. 8) Suppression of  clk-1  by  tat-2  is rescued by BAs, and this requires dietary cholesterol. 9) The  clk-1  phenotype, including the level of activity in lipid extracts, is suppressed by antioxidants and enhanced by depletion of mitochondrial superoxide dismutases. These observations suggest that  C. elegans  synthesizes and secretes molecules with properties and functions resembling those of BAs. These molecules act in cholesterol uptake, and their level of synthesis is up-regulated by mitochondrial oxidative stress. Future investigations should reveal whether these molecules are in fact BAs, which would suggest the unexplored possibility that the elevated oxidative stress that characterizes the metabolic syndrome might participate in disease processes by affecting the regulation of metabolism by BAs.

plos genetics

Mitochondrial Oxidative Stress Alters a Pathway in Caenorhabditis elegans Strongly Resembling That of Bile Acid Biosynthesis and Secretion in Vertebrates