Bile Acid Alterations Are Associated With Insulin Resistance, but Not With NASH, in Obese Subjects

• Published in: The journal of clinical endocrinology and metabolism Vol. 102; no. 10; pp. 3783 - 3794
• Main Authors: Legry, Vanessa, Francque, Sven, Haas, Joel T, Verrijken, An, Caron, Sandrine, Chávez-Talavera, Oscar, Vallez, Emmanuelle, Vonghia, Luisa, Dirinck, Eveline, Verhaegen, Ann, Kouach, Mostafa, Lestavel, Sophie, Lefebvre, Philippe, Van Gaal, Luc, Tailleux, Anne, Paumelle, Réjane, Staels, Bart
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.10.2017; Copyright Oxford University Press; Oxford University Press
• Subjects: Adult; Bile; Bile acids; Bile Acids and Salts - metabolism; Biopsy; Body mass index; Case-Control Studies; Energy balance; Enzyme-linked immunosorbent assay; Fatty liver; Female; Fibroblast growth factors; Fibroblasts; Gene Expression Regulation; Growth factors; Homeostasis; Humans; Insulin; Insulin Resistance; Intestine; Liquid chromatography; Liver; Liver - metabolism; Male; Mass spectroscopy; Metabolism; Metabolomics; Middle Aged; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - epidemiology; Non-alcoholic Fatty Liver Disease - metabolism; Obesity; Obesity - complications; Obesity - epidemiology; Obesity - metabolism; Phenotypes; Plasma; Transcriptomics; Vitamin D; Vitamin D receptors
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2017-01397

ContextBile acids (BAs) are signaling molecules controlling energy homeostasis that can be both toxic and protective for the liver. BA alterations have been reported in obesity, insulin resistance (IR), and nonalcoholic steatohepatitis (NASH). However, whether BA alterations contribute to NASH independently of the metabolic status is unclear.ObjectiveTo assess BA alterations associated with NASH independently of body mass index and IR.Design and SettingPatients visiting the obesity clinic of the Antwerp University Hospital (a tertiary referral facility) were recruited from 2006 to 2014.PatientsObese patients with biopsy-proven NASH (n = 32) and healthy livers (n = 26) were matched on body mass index and homeostasis model assessment of IR.Main Outcome MeasuresTranscriptomic analyses were performed on liver biopsies. Plasma concentrations of 21 BA species and 7α-hydroxy-4-cholesten-3-one, a marker of BA synthesis, were determined by liquid chromatography–tandem mass spectrometry. Plasma fibroblast growth factor 19 was measured by enzyme-linked immunosorbent assay.ResultsPlasma BA concentrations did not correlate with any hepatic lesions, whereas, as previously reported, primary BA strongly correlated with IR. Transcriptomic analyses showed unaltered hepatic BA metabolism in NASH patients. In line, plasma 7α-hydroxy-4-cholesten-3-one was unchanged in NASH. Moreover, no sign of hepatic BA accumulation or activation of BA receptors—farnesoid X, pregnane X, and vitamin D receptors—was found. Finally, plasma fibroblast growth factor 19, secondary-to-primary BA, and free-to-conjugated BA ratios were similar, suggesting unaltered intestinal BA metabolism and signaling.ConclusionsIn obese patients, BA alterations are related to the metabolic phenotype associated with NASH, especially IR, but not liver necroinflammation.Transcriptomic and metabolomic analyses of bile acid metabolism/signaling reveals no alteration in NASH patients compared with BMI- and insulin resistance–matched controls, unlike in insulin resistance.