Sterol–protein interactions in cholesterol and bile acid synthesis

Abstract

Cholesterol and other cholesterol related metabolites, oxysterols, and bile acids, establish specific interactions with enzymes and other proteins involved in cholesterol and bile acid homeostasis, triggering a variety of biological responses. The substrate-enzyme binding represents the best-characterized type of complementary interaction between proteins and small molecules. Key enzymes in the pathway that converts cholesterol to bile acids belong to the cytochrome P450 superfamily. In contrast to the majority of P450 enzymes, those acting on cholesterol and related metabolites exhibit higher stringency with respect to substrate molecules. This stringency, coupled with the specificity of the reactions, dictates the chemical features of intermediate metabolites (oxysterols) and end products (bile acids). Both oxysterols and bile acids have emerged in recent years as new signalling molecules due to their ability to interact and activate nuclear receptors, and consequently to regulate the transcription of genes involved in cholesterol and bile acid homeostasis and metabolism, but also in glucose and fatty acid metabolism. Interestingly, other proteins function as bile acid or sterol receptors. New findings indicate that bile acids also interact with a membrane G protein-coupled receptor, triggering a signalling cascade that ultimately promote energy expenditure. On the other end, cholesterol and side chain oxysterols establish specific interactions with different proteins residing in the endoplasmic reticulum that result in controlled protein degradation and/or trafficking to the Golgi and the nucleus. These regulatory pathways converge and contribute to adapt cholesterol uptake and synthesis to the cellular needs.