Bile salts in twenty six species of fish were examined to investigate the bile salt composition and the distribution of D-cysteinolic acid conjugated bile salts by high-performance liquid chromatography and/or thin-layer chromatography densitometry. Their major bile salts were cholyltaurine and/or chenodeoxycholyltaurine except for the bile salt in Japanese dace which exclusively consists of cyprinol sulfate. A considerable amount of unconjugated cholate was also found in ayu fish. D-Cysteinolic acid conjugates were detected in the bile of wild and aquacultured guelly jack, brackish goby and marbled rockfish as well as red seabream. No D-cysteinolic acid conjugates was found in biles of Japanese sardine and mackerel in spite of existences of D-cysteinolic acid in their muscle and liver.

Based on these data, cholangiocyte senescence and SASP caused by LPC are potential pathogenic mechanisms in the development of biliary tract cancer.

This article is available online at http://www.jlr.org the transcription of their own biosynthetic enzymes and of transporter proteins for bile acids. In humans, more than 99% of all bile acids are localized in tissues participating in enterohepatic circulation. However, some bile acids are also present in the systemic circulation at concentrations of 15 M after a meal or at concentrations of 5 M even between meals ( 4 ), whereas their concentrations are several ten-to several hundred-fold higher in the gallbladder, liver, and intestine ( 5 ). In addition, bile acids are known to exhibit immunosuppressive effects on cell-mediated immunity and macrophage functions ( 6-8 ). In view of these fi ndings, bile acids might be expected to function not only in the limited tissues involved in enterohepatic circulation, but also in the whole body as signaling molecules.Recently, a G-protein-coupled plasma membrane receptor responsive to bile acids was discovered using highthroughput screening ( 9, 10 ). This receptor, named TGR5, has been shown to stimulate adenylate cyclase, causing a subsequent increase in the intracellular production of cAMP. This signal transduction occurs independently of FXR. Also, the stimulation of TGR5 by bile acids further enhances energy expenditure in adipocytes and myocytes via these cell-specifi c signal transductions ( 11 ). Furthermore, TGR5 expression has been demonstrated in enteroendocrine cells, where bile acids stimulate the secretion of glucagon -like peptide-1 via TGR5 ( 12 ). These observations suggest that TGR5 might be an attractive target for the treatment of obesity, diabetes, and metabolic syndrome.During the course of the development of new reagents with the ability to activate TGR5, a diverse variety of bile acids and chemically modifi ed bile acid analogs were evaluated and their structure-activity relationships were studied in regard to TGR5 activation ( 13 ). In a previous study, Abstract TGR5 is a G protein-coupled receptor that is activated by bile acids, resulting in an increase in cAMP levels and the subsequent modulation of energy expenditure in brown adipose tissue and muscle. Therefore, the development of a TGR5-specifi c agonist could lead to the prevention and treatment of various metabolic disorders related to obesity. In the present study, we evaluated the ability of bile alcohols, which are structurally and physiologically similar to bile acids and are produced as the end products of cholesterol catabolism in evolutionarily primitive vertebrates, to act as TGR5 agonists. In a cell-based reporter assay and a cAMP production assay performed in vitro, most bile alcohols with a side chain containing hydroxyl group(s) were highly effi cacious agonists for TGR5 comparable to its most potent ligand in the naturally occurring bile acid , lithocholic acid. However, the abilities of the bile alcohols to activate TGR5 varied with the position and number of the hydroxyl substituent in the side chain. Additionally, the conformation of the steroidal nucleus of bile alcohols ...

Many hypoglycemic and hyperglycemic episodes associated with clinical use of gatifloxacin (GFLX), a novel fluoroquinolone antimicrobial agent, have been reported in recent years. Some have reported hypoglycemia induced by fluoroquinolones, indicating that these agents may stimulate insulin secretion from pancreatic islet cells. In this study, we investigated the effect of GFLX on insulin homeostasis in islet cells using the insulin secreting cell line, HIT-T15. After 1 h incubation with over 100 m mM of GFLX, insulin secretion from the cells was significantly augmented. However, the augmentation of insulin release induced by GFLX subsequently reached a plateau. Coincidentally, cellular insulin was decreased by 120 h incubation, and reactivity to re-stimulation by sulfonylurea was suppressed. The GFLX insulin depletion effect was stronger than the effects produced by such other fluoroquinolones as levofloxacin and ciprofloxacin. This study suggests that GFLX should induce insulin oversecretion from pancreatic islet cells in the short-term, and decrease insulin productivity or increase insulin disintegration in the long-term. These results are consistent with the clinical results of GFLX finding that hypoglycemic episodes were seen after a first single administration, and most hyperglycemic episodes were seen more than 2 d after the start of administration.