▪ Abstract The synthesis and excretion of bile acids comprise the major pathway of cholesterol catabolism in mammals. Synthesis provides a direct means of converting cholesterol, which is both hydrophobic and insoluble, into a water-soluble and readily excreted molecule, the bile acid. The biosynthetic steps that accomplish this transformation also confer detergent properties to the bile acid, which are exploited by the body to facilitate the secretion of cholesterol from the liver. This role in the elimination of cholesterol is counterbalanced by the ability of bile acids to solubilize dietary cholesterol and essential nutrients and to promote their delivery to the liver. The synthesis of a full complement of bile acids requires 17 enzymes. The expression of selected enzymes in the pathway is tightly regulated by nuclear hormone receptors and other transcription factors, which ensure a constant supply of bile acids in an ever changing metabolic environment. Inherited mutations that impair bile acid synth...

The Enzymes, Regulation, and Genetics of Bile Acid Synthesis

The metabolic nuclear receptors act as metabolic and toxicological sensors, enabling the organism to quickly adapt to environmental changes by inducing the appropriate metabolic genes and pathways. Ligands for these metabolic receptors are compounds from dietary origin, intermediates in metabolic pathways, drugs, or other environmental factors that, unlike classical nuclear receptor ligands, are present in high concentrations. Metabolic receptors are master regulators integrating the homeostatic control of (a) energy and glucose metabolism through peroxisome proliferator-activated receptor gamma (PPARgamma); (b) fatty acid, triglyceride, and lipoprotein metabolism via PPARalpha, beta/delta, and gamma; (c) reverse cholesterol transport and cholesterol absorption through the liver X receptors (LXRs) and liver receptor homolog-1 (LRH-1); (d) bile acid metabolism through the farnesol X receptor (FXR), LXRs, LRH-1; and (e) the defense against xeno- and endobiotics by the pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR). The transcriptional control of these metabolic circuits requires coordination between these metabolic receptors and other transcription factors and coregulators. Altered signaling by this subset of receptors, either through chronic ligand excess or genetic factors, may cause an imbalance in these homeostatic circuits and contribute to the pathogenesis of common metabolic diseases such as obesity, insulin resistance and type 2 diabetes, hyperlipidemia and atherosclerosis, and gallbladder disease. Further studies should exploit the fact that many of these nuclear receptors are designed to respond to small molecules and turn them into therapeutic targets for the treatment of these disorders.

Nuclear receptors and the control of metabolism.

27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells.

Bile acids derived from cholesterol and oxysterols derived from cholesterol and bile acid synthesis pathways are signaling molecules that regulate cholesterol homeostasis in mammals. Many nuclear receptors play pivotal roles in the regulation of bile acid and cholesterol metabolism. Bile acids activate the farnesoid X receptor (FXR) to inhibit transcription of the gene for cholesterol 7α-hydroxylase, and stimulate excretion and transport of bile acids. Therefore, FXR is a bile acid sensor that protects liver from accumulation of toxic bile acids and xenobiotics. Oxysterols activate the liver orphan receptors (LXR) to induce cholesterol 7α-hydroxylase and ATP-binding cassette family of transporters and thus promote reverse cholesterol transport from the peripheral tissues to the liver for degradation to bile acids. LXR also induces the sterol response element binding protein-1c that regulates lipogenesis. Therefore, FXR and LXR play critical roles in coordinate control of bile acid, cholesterol, and trigly...

Bile Acid Regulation of Gene Expression: Roles of Nuclear Hormone Receptors

Oxysterol biosynthetic enzymes.

Elimination of cholesterol as cholestenoic acid in human lung by sterol 27-hydroxylase: evidence that most of this steroid in the circulation is of pulmonary origin.

Björn Wiklund

Papers

Elimination of cholesterol as cholestenoic acid in human lung by sterol 27-hydroxylase: evidence that most of this steroid in the circulation is of pulmonary origin.