A Novel 3-Hydroxysteroid Dehydrogenase That Regulates Reproductive Development and Longevity

Abstract

A multidisciplinary approach identifies novel biochemical activities involved in the synthesisof C. elegans bile acid-like steroids, which act as hormones that regulate sterol metabolism and longevity.

Abstract

Endogenous small molecule metabolites that regulate animal longevity are emerging as a novel means to influence health and life span. In C. elegans, bile acid-like steroids called the dafachronic acids (DAs) regulate developmental timing and longevity through the conserved nuclear hormone receptor DAF-12, a homolog of mammalian sterol-regulated receptors LXR and FXR. Using metabolic genetics, mass spectrometry, and biochemical approaches, we identify new activities in DA biosynthesis and characterize an evolutionarily conserved short chain dehydrogenase, DHS-16, as a novel 3-hydroxysteroid dehydrogenase. Through regulation of DA production, DHS-16 controls DAF-12 activity governing longevity in response to signals from the gonad. Our elucidation of C. elegans bile acid biosynthetic pathways reveals the possibility of novel ligands as well as striking biochemical conservation to other animals, which could illuminate new targets for manipulating longevity in metazoans.

Author Summary

Although well known for their role in the absorption of dietary fat, bile acids have emerged as important metabolic signaling molecules that regulate cholesterol, fat, and glucose metabolism. Bile acids work through nuclear receptors, a class of transcription factors that bind to fat soluble hormones to directly control target gene expression. In the roundworm C. elegans, DAF-12 is a nuclear receptor for bile acids, called the dafachronic acids, which are known to regulate development and longevity, however the synthesis and regulation of these molecules remain unclear. Here we identify novel biochemical activities, including a conserved 3-hydroxysteroid dehydrogenase, involved in the production of the dafachronic acids, illuminating their role in cholesterol and bile acid metabolism, and longevity. The identified activities reveal remarkable evolutionary conservation to those seen in mammalian bile acid synthesis, potentially providing novel ways to manipulate animal lifespan and cholesterol homeostasis.