Biochemical Studies of Inherited Diseases Related to Abnormal Cholesterol Metabolism. II : Absence of Unusual C2s and C29 Bile Acid Homologs in Bile and Urine of Sitosterolemia

Bile acids, bile alcohols and sterols excreted in bile and urine from a patient with sitosterolemia were studied. Glycine- and taurine-conjugated cholic acid, deoxycholic acid and chenodeoxycholic acid were identified as the major constituents of both the bile and urine. Lesser amounts of unconjugated cholic acid and 3a, 7a, 12a, 24-tetrahydroxy-5B-cholestan-26-oic acid were found in the bile, but cholic acid was the only unconjugated bile acid in the urine. Relatively high proportions of campesterol and sitosterol compared to cholesterol were excreted in the bile, while cholesterol was the only sterol detected in the urine. Bile alcohols were not detected in the bile, but the following bile alcohols were excreted in the urine as glucurono-conjugates: 5β-cholestane-3α, 7α,12α,25-tetrol; 27-nor-5β-cholestane-3α, 7α,12α,24,25-pentol; 5β-cholestane-3α, 7α,12α,23 ,25-pentol; 5β-cholestane-3α, 7α,12α,24,25-pentol; 5β-cholestane-3α, 7α,12α,25,26-pentol. In neither the bile nor urine, were C28 and C29 bile acid homologs detected. Thus, the main route for the excretion of plant sterols in sitosterolemia is thought to be secretion into the bile as neutral sterols

Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies

TGR5, a metabotropic receptor that is G-protein-coupled to the induction of adenylate cyclase, has been recognized as the molecular link connecting bile acids to the control of energy and glucose homeostasis. With the aim of disclosing novel selective modulators of this receptor and at the same time clarifying the molecular basis of TGR5 activation, we report herein the biological screening of a collection of natural occurring bile acids, bile acid derivatives, and some steroid hormones, which has resulted in the discovery of new potent and selective TGR5 ligands. Biological results of the tested collection of compounds were used to extend the structure-activity relationships of TGR5 agonists and to develop a binary classification model of TGR5 activity. This model in particular could unveil some hidden properties shared by the molecular shape of bile acids and steroid hormones that are relevant to TGR5 activation and may hence be used to address the design of novel selective and potent TGR5 agonists

Novel Potent and Selective Bile Acid Derivatives as TGR5 Agonists: Biological Screening, Structure-Activity Relationships, and Molecular Modeling Studies

TGR5, a metabotropic receptor that is G-protein-coupled to the induction of adenylate cyclase, has been recognized as the molecular link connecting bile acids to the control of energy and glucose homeostasis. With the aim of disclosing novel selective modulators of this receptor and at the same time clarifying the molecular basis of TGR5 activation, we report herein the biological screening of a collection of natural occurring bile acids, bile acid derivatives, and some steroid hormones, which has resulted in the discovery of new potent and selective TGR5 ligands. Biological results of the tested collection of compounds were used to extend the structure-activity relationships of TGR5 agonists and to develop a binary classification model of TGR5 activity. This model in particular could unveil some hidden properties shared by the molecular shape of bile acids and steroid hormones that are relevant to TGR5 activation and may hence be used to address the design of novel selective and potent TGR5 agonists