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• W2047301774 abstract "See “Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency,” by Setchell KDR, Heubi JE, Shah S, et al, on page 945. Bile acids are attracting increasing attention in the medical community because they do not only fulfill a long-known role of micellar solubilizers,1Hofmann A.F. Bile acids: trying to understand their chemistry and biology with the hope of helping patients.Hepatology. 2009; 49: 1403-1418Crossref PubMed Scopus (145) Google Scholar mediating the intestinal uptake of dietary fats and fat-soluble vitamins, but have been unraveled more recently as potent signaling molecules and metabolic integrators both in and outside the liver.2Häussinger D. Beuers U. Trauner M. Hepatic and extrahepatic targets of bile acid signaling - XXII International Bile Acid Meeting. Karger, Basel2013Google Scholar Consequently, a number of bile acid analogs are being tested as potential therapeutic agents for hepatic and extrahepatic diseases.2Häussinger D. Beuers U. Trauner M. Hepatic and extrahepatic targets of bile acid signaling - XXII International Bile Acid Meeting. Karger, Basel2013Google Scholar Bile acid synthesis3Russell D.W. The enzymes, regulation, and genetics of bile acid synthesis.Annu Rew Biochem. 2003; 72: 137-174Crossref PubMed Scopus (1361) Google Scholar as well as secretion and re-uptake of mainly glycine- and taurine-conjugated bile salts4Stieger B. The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation.Handb Exp Pharmacol. 2011; : 205-259Crossref PubMed Scopus (219) Google Scholar represent key functions of the human liver: Conjugated bile salts form two thirds of organic compounds in human bile and are efficiently recycled via the enterohepatic circulation, as first described by Reverhorst and Borelli 3 centuries ago. In liver, bile acids directly modulate their hepatocellular uptake, synthesis, and biliary secretion at both the transcriptional level (via activation of bile acid-sensitive nuclear receptors such as farnesoid X receptor or pregnane X receptor), and at the posttranscriptional and posttranslational levels via modulation of diverse signaling cascades.5Trauner M. Halilbasic E. Nuclear receptors as new perspective for the management of liver diseases.Gastroenterology. 2011; 140: 1120-1125Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar In extrahepatic tissues, expression of the membrane bile acid receptor TGR5 sensitizes cells to high levels of hydrophobic bile salts.6Pols T.W. Noriega L.G. Nomura M. et al.The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation.J Hepatol. 2011; 54: 1263-1272Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar Bile acid synthesis from cholesterol is restricted to the liver and represents the major catabolic pathway of cholesterol responsible for about 90% of its breakdown. Bile acid synthesis requires 17 enzymatic reactions in different subcellular compartments of the hepatocyte (Figure 1)3Russell D.W. The enzymes, regulation, and genetics of bile acid synthesis.Annu Rew Biochem. 2003; 72: 137-174Crossref PubMed Scopus (1361) Google Scholar and its key enzymatic steps are tightly regulated by nuclear hormone receptors, other transcription factors, and posttranscriptional signaling chains.2Häussinger D. Beuers U. Trauner M. Hepatic and extrahepatic targets of bile acid signaling - XXII International Bile Acid Meeting. Karger, Basel2013Google Scholar The end products are glycine- and taurine-conjugated bile acids, which are effectively secreted into bile with <2% of bile acids remaining in the unconjugated form.7Dilger K. Hohenester S. Winkler-Budenhofer U. et al.Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health.J Hepatol. 2012; 57: 133-140Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Various genetic defects in bile acid synthesis have been identified in the past (Figure 1). Their clinical manifestations may range from liver failure in early childhood to cirrhosis or progressive neuropathy in the adolescent or adult.8Clayton P.T. Disorders of bile acid synthesis.J Inherit Metab Dis. 2011; 34: 593-604Crossref PubMed Scopus (113) Google Scholar, 9Heubi J.E. Setchell K.D. Bove K.E. Inborn errors of bile acid metabolism.Semin Liver Dis. 2007; 27: 282-294Crossref PubMed Scopus (98) Google Scholar In the present issue of Gastroenterology, Setchell et al10Setchell K.D.R. Heubi J.E. Shah S. et al.Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency.Gastroenterology. 2013; 144: 945-955Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar describe 10 pediatric patients with a defect of the last step of bile acid synthesis, a peroxisomal bile acid conjugation defect, namely, amidation with glycine or taurine in the C24 position of the bile acid molecule (Figure 1). A key clinical finding in these pediatric patients, in whom the diagnosis was made between 3 months and 14 years of age, was the deficit of fat-soluble vitamins and its sequelae, severe coagulopathies and/or rickets in half of them. In contrast with most other defects in bile acid synthesis, serum liver tests and/or liver histology were not regularly affected in those children who had undergone blood testing or liver biopsy. The biochemical and clinical data clearly show the importance of conjugated bile acids for the absorption of fat-soluble vitamins in the small intestine. Conjugation of bile acids with glycine or taurine, in healthy humans at a ratio of about 3:1,7Dilger K. Hohenester S. Winkler-Budenhofer U. et al.Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health.J Hepatol. 2012; 57: 133-140Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar increases the molecular weight and, at least for the taurine conjugate, markedly lowers the pKa, thereby enhancing aqueous solubility and decreasing carrier-independent uptake into duodenal or jejunal mucosa cells of the negatively charged bile salt molecule at the pH of the small intestine. In contrast, unconjugated protonated bile acids are passively absorbed already in the proximal small intestine and are, thereby, insufficiently available for micellar solubilization of dietary fat and fat-soluble vitamins in the small intestinal lumen. The clinical presentation of the patients studied closely matched the phenotype predicted by Hofmann and Strandvik >20 years ago.11Hofmann A.F. Strandvik B. Defective bile acid amidation: predicted features of a new inborn error of metabolism.Lancet. 1988; 2: 311-313Abstract PubMed Scopus (15) Google Scholar Still, the predicted occurrence of diarrhea owing to increased bile acid concentrations in the colon was not observed. Absence of diarrhea in the cohort studied by Setchell et al10Setchell K.D.R. Heubi J.E. Shah S. et al.Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency.Gastroenterology. 2013; 144: 945-955Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar could be explained by efficient absorption of unconjugated bile acids in the small intestine, thereby preventing development of bile acid malabsorption-induced diarrhea. Hofmann and Strandvik also predicted absence of cholestasis in patients with defective bile acid amidation.11Hofmann A.F. Strandvik B. Defective bile acid amidation: predicted features of a new inborn error of metabolism.Lancet. 1988; 2: 311-313Abstract PubMed Scopus (15) Google Scholar However, this was not generally found. In some of the available liver biopsies, cholestatic features and small duct cholangiopathy were found. Indeed, Hofmann and Strandvik based their considerations on findings with side-chain shortened C23 nor-bile acids.12Yoon Y.B. Hagey L.R. Hofmann A.F. et al.Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents.Gastroenterology. 1986; 90: 837-852Abstract Full Text PDF PubMed Scopus (199) Google Scholar However, these compounds are conjugated with glycine or taurine to a much lesser degree than C24 bile acids,12Yoon Y.B. Hagey L.R. Hofmann A.F. et al.Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents.Gastroenterology. 1986; 90: 837-852Abstract Full Text PDF PubMed Scopus (199) Google Scholar and are prone to intrahepatic “cholehepatic shunting,”13Yeh H.Z. Schteingart C.D. Hagey L.R. et al.Effect of side chain length on biotransformation, hepatic transport, and choleretic properties of chenodeoxycholyl homologues in the rodent: studies with dinorchenodeoxycholic acid, norchenodeoxycholic acid, and chenodeoxycholic acid.Hepatology. 1997; 26: 374-385Crossref PubMed Scopus (31) Google Scholar thereby markedly inducing biliary HCO3− secretion. The recently proposed concept of the “biliary HCO3− umbrella”14Beuers U. Hohenester S. de Buy Wenniger L.J. et al.The biliary HCO3− umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies.Hepatology. 2010; 52: 1489-1496Crossref PubMed Scopus (255) Google Scholar may in part explain why the bile acid conjugation defects described by Setchell et al lead to comparably mild biliary alterations as stimulation of biliary HCO3− secretion by unconjugated bile acids might protect bile ductules against uncontrolled cholangiocyte invasion and injury by protonated unconjugated hydrophobic bile acids.14Beuers U. Hohenester S. de Buy Wenniger L.J. et al.The biliary HCO3− umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies.Hepatology. 2010; 52: 1489-1496Crossref PubMed Scopus (255) Google Scholar It is surprising that, at least in those patients who showed signs of liver damage, serum levels of gamma glutamyl transferase were low as in progressive familiar intrahepatic cholestasis types 1 and 2 or various defects of bile acid synthesis (Figure 1). It has been argued that cholestatic liver damage accompanied by normal gamma glutamyl transferase may indicate purely hepatocellular, but not cholangiocellular, damage. This assumption is largely supported by the patients under study. One might speculate about the mechanism by which large amounts of unconjugated bile salts are excreted into bile in patients with defective bile acid amidation. An apical hepatocyte export pump for unconjugated bile salts has not been clearly defined in humans so far.4Stieger B. The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation.Handb Exp Pharmacol. 2011; : 205-259Crossref PubMed Scopus (219) Google Scholar Still, the bile salt export pump, BSEP (ABCB11), seems to be the most likely candidate: In polarized MDCK monolayers transfected with rat Ntcp and Bsep in vitro, vectorial transport of unconjugated bile salts such as chenodeoxycholate, ursodeoxycholate, and cholate has been demonstrated.15Mita S. Suzuki H. Akita H. et al.Vectorial transport of unconjugated and conjugated bile salts by monolayers of LLC-PK1 cells doubly transfected with human NTCP and BSEP or with rat Ntcp and Bsep.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G550-G556Crossref PubMed Scopus (76) Google Scholar All but 1 patient were homozygous for a mutation in the gene encoding the second step in bile acid amidation, bile acid CoA: aminoacid N-acyltransferase (BAAT). In the remaining patient, no mutation was found in the gene encoding the first step in bile acid amidation, SLC27A5. However, the bile acid conjugation defect in this particular patient was solely based on FAB-MS analysis of urine demonstrating absence of amidated bile acids that might have been found in other compartments. With their unique case series, Setchell et al confirm that bile acid amidation is critical both for effective micellar solubilization of dietary fat1Hofmann A.F. Bile acids: trying to understand their chemistry and biology with the hope of helping patients.Hepatology. 2009; 49: 1403-1418Crossref PubMed Scopus (145) Google Scholar as well as hepatobiliary integrity.16Denk G.U. Maitz S. Wimmer R. et al.Conjugation is essential for the antichole-static effect of norursodeoxycholic acid in taurolithocholic acid-induced cholestasis in rat liver.Hepatology. 2010; 52: 1758-1768Crossref PubMed Scopus (35) Google Scholar The authors are to be congratulated for their long-term efforts to unravel this as well as other defects of bile acid synthesis both at the clinical and molecular level. A close follow-up into adulthood of the cohort reported is warranted. Genetic Defects in Bile Acid Conjugation Cause Fat-Soluble Vitamin DeficiencyGastroenterologyVol. 144Issue 5PreviewThe final step in bile acid synthesis involves conjugation with glycine and taurine, which promotes a high intraluminal micellar concentration to facilitate lipid absorption. We investigated the clinical, biochemical, molecular, and morphologic features of a genetic defect in bile acid conjugation in 10 pediatric patients with fat-soluble vitamin deficiency, some with growth failure or transient neonatal cholestatic hepatitis. Full-Text PDF Covering the CoverGastroenterologyVol. 144Issue 5PreviewGluten-free diets are recommended with increasing frequency for irritable bowel syndrome (IBS) symptoms in the absence of celiac disease. Patients who do not have celiac disease, but possess a consistent genotype of HLA DQ2/8, have also reported benefit from a gluten-free diet. In this issue of Gastroenterology, Vazquez–Roque et al report on a randomized, controlled trial designed to explore whether a gluten-free diet benefits patients with diarrhea-predominant IBS (IBS-D). The study was performed at the Mayo Clinic where 45 patients with known IBS-D were recruited. Full-Text PDF" @default.
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• W2047301774 title "When Bile Acids Don't Get Amidated" @default.
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