title: Increased Bile Acid Synthesis and Impaired Bile Acid Transport in Human Obesity.
abstract: Alterations in bile acid (BA) synthesis and transport have the potential to affect multiple metabolic pathways in the pathophysiology of obesity.
  
  
  
  The objective of the study was to investigate the effects of obesity on serum fluctuations of BAs and markers of BA synthesis.
  
  
  
  We measured BA fluctuations in 11 nonobese and 32 obese subjects and BA transporter expression in liver specimens from 42 individuals and specimens of duodenum, jejunum, ileum, colon, and pancreas from nine individuals.
  
  
  
  We analyzed serum BAs and markers of BA synthesis after overnight fasting, during a hyperinsulinemic-euglycemic clamp, or a mixed-meal tolerance test and the association of BA transporter expression with body mass index.
  
  
  
  BA synthesis markers were 2-fold higher (P < .01) and preferentially 12α-hydroxylated (P < .05) in obese subjects, and both measures were correlated with clamp-derived insulin sensitivity (r = -0.62, P < .0001, and r = -0.39, P = .01, respectively). Insulin infusion acutely reduced serum BAs in nonobese subjects, but this effect was blunted in obese subjects (δBAs -44.2% vs -4.2%, P < .05). The rise in serum BAs postprandially was also relatively blunted in obese subjects (δBAs +402% vs +133%, P < .01). Liver expression of the Na+-taurocholate cotransporting polypeptide and the bile salt export pump were negatively correlated with body mass index (r = -0.37, P = .02, and r = -0.48, P = .001, respectively).
  
  
  
  Obesity is associated with increased BA synthesis, preferential 12α-hydroxylation, and impaired serum BA fluctuations. The findings reveal new pathophysiological aspects of BA action in obesity that may lend themselves to therapeutic targeting in metabolic disease.
authors.affiliation: Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Haeusler
authors.affiliation: Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Camastra
authors.affiliation: Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Nannipieri
authors.affiliation: Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy.
authors.forename: Brenno
authors.initials: B
authors.lastname: Astiarraga
authors.affiliation: Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy.
authors.forename: Jose
authors.initials: J
authors.lastname: Castro-Perez
authors.affiliation: Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy.
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.affiliation: Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy.
authors.forename: Liangsu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy.
authors.forename: Manu
authors.initials: M
authors.lastname: Chakravarthy
authors.affiliation: Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy.
authors.forename: Ele
authors.initials: E
authors.lastname: Ferrannini
mesh_terms: D000328:Adult; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000378:metabolism*; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; C037643:bile acid binding proteins