phytosterols and 24-25-epoxycholesterol

Characterization of cholesterol homeostasis in male mice with a genetic inactivation of 3beta-hydroxysteroid-delta24-reductase, causing replacement of almost all cholesterol with desmosterol.. There was an increase in hepatic sterol synthesis and markedly increased fecal loss of neutral sterols. Fecal excretion of bile acids was similar in knockout mice and in controls. The composition of bile acids was changed, with reduced formation of cholic acid. It was shown that both Cyp7a1 and Cyp27a1 are active toward desmosterol, consistent with the formation of normal bile acids from this steroid. The levels of plant sterols were markedly reduced. Hepatic mRNA levels of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase, Srebp-1c, Srebp-2, Cyp7a1, Abcg5, Abcg8, and Fas were all significantly increased.. The changes in hepatic mRNA levels in combination with increased biliary and fecal excretion of neutral steroids, reduced tissue levels of plant sterols, increased plasma levels of triglyceride-rich VLDL, are consistent with a strong activation of LXR-targeted genes. The markedly increased fecal loss of neutral sterols may explain the fact that the Dhcr24-/- mice do not accumulate dietary cholesterol. The study illustrates the importance of the integrity of the cholesterol structure--presence of a double bond in the steroid side-chain is compatible with life but is associated with serious disturbances in sterol homeostasis.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP-Binding Cassette Transporters; Bile; Bile Acids and Salts; Cholestanetriol 26-Monooxygenase; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Desmosterol; DNA-Binding Proteins; Feces; Gene Expression Regulation; Homeostasis; Hydroxymethylglutaryl CoA Reductases; Lipid Metabolism; Lipids; Lipoproteins; Liver; Liver X Receptors; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Orphan Nuclear Receptors; Oxidoreductases Acting on CH-CH Group Donors; Phytosterols; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Substrate Specificity; Time Factors

The nuclear receptors liver X receptor (LXR) alpha and LXRbeta serve as oxysterol receptors and regulate the expression of genes involved in lipid metabolism. LXR activation induces the expression of ATP-binding cassette (ABC) transporters, such as ABCG5 and ABCG8, which inhibit intestinal absorption of cholesterol and phytosterols. Although several synthetic LXR agonists have been generated, these compounds have limited clinical application, because they cause hypertriglycemia by inducing the expression of lipogenic genes in the liver. We synthesized derivatives of phytosterols and found some of them to act as LXR agonists. Among them, YT-32 [(22E)-ergost-22-ene-1alpha,3beta-diol], which is related to ergosterol and brassicasterol, is the most potent LXR agonist. YT-32 directly bound to LXRalpha and LXRbeta and induced the interaction of LXRalpha with cofactors, such as steroid receptor coactivator-1, as effectively as the natural ligands, 22(R)-hydroxycholesterol and 24(S),25-epoxycholesterol. Although the nonsteroidal synthetic LXR agonist T0901317 induced the expression of intestinal ABC transporters and liver lipogenic genes, oral administration of YT-32 selectively activated intestinal ABC transporters in mice. Unlike T0901317 treatment, YT-32 inhibited intestinal cholesterol absorption without increasing plasma triglyceride levels. The phytosterol-derived LXR agonist YT-32 might selectively modulate intestinal cholesterol metabolism.

Topics: Animals; Anticholesteremic Agents; ATP-Binding Cassette Transporters; Biological Transport; Cell Line; Cell Nucleus; Cholesterol; DNA-Binding Proteins; Dose-Response Relationship, Drug; Ergosterol; Genes, Reporter; Glutathione Transferase; Humans; Hydrocarbons, Fluorinated; Hydroxycholesterols; Intestinal Mucosa; Ligands; Liver; Liver X Receptors; Mice; Models, Chemical; Orphan Nuclear Receptors; Phytosterols; Protein Binding; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides; Time Factors; Transfection