Abstract
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.
Highlights
In mammals, cholesterol is necessary for the structure and function of membranes, and is the substrate for the biosynthesis of signalling molecules such as sexual steroids, bioactive compounds such as vitamin D, and bile acids (BAs) [1]
Using the hypotheses that dsc-3 is involved in lipoprotein metabolism we identified tat-2 as a candidate gene in that chromosomal region
This last observation suggests that the abnormal cholesterol metabolism is caused by the deregulated metabolism of the BA-like molecules that are affected by clk-1 and tat-2
Summary
Cholesterol is necessary for the structure and function of membranes, and is the substrate for the biosynthesis of signalling molecules such as sexual steroids, bioactive compounds such as vitamin D, and bile acids (BAs) [1]. The oxidation of the side-chain takes place in the mitochondria, but side-chain shortening takes place in the peroxisomes. In vertebrates, these reactions occur predominantly in hepatocytes. BAs regulate cholesterol and lipid metabolism in a variety of ways. They participate in cholesterol, lipid and hydrophobic vitamin uptake through their properties as detergents. They participate in cholesterol elimination as they are secreted into the gut from where a fraction is lost every day in the feces. BAs are signalling molecules that integrate several aspects of metabolism, including fat, glucose, and energy metabolism by regulating gene expression through nuclear hormone receptors such as the farnesoid X receptor (FXR), the pregnane X receptor (PXR), and the vitamin D receptor (VDR) (BA biology is reviewed in detail in [2,3])
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