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Lean Nafld: A Distinct Entity Shaped by Differential Metabolic Adaptation Publisher Pubmed



Chen F1 ; Esmaili S1, 2 ; Rogers GB3 ; Bugianesi E4 ; Petta S5 ; Marchesini G6 ; Bayoumi A1 ; Metwally M1 ; Azardaryany MK1 ; Coulter S1 ; Choo JM3 ; Younes R4 ; Rosso C4 ; Liddle C1 Show All Authors
Authors
  1. Chen F1
  2. Esmaili S1, 2
  3. Rogers GB3
  4. Bugianesi E4
  5. Petta S5
  6. Marchesini G6
  7. Bayoumi A1
  8. Metwally M1
  9. Azardaryany MK1
  10. Coulter S1
  11. Choo JM3
  12. Younes R4
  13. Rosso C4
  14. Liddle C1
  15. Adams LA7
  16. Craxi A5
  17. George J1
  18. Eslam M1
Show Affiliations
Authors Affiliations
  1. 1. Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW, Australia
  2. 2. Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. SAHMRI Infection and Immunity Theme, School of Medicine, Flinders University, Adelaide, Australia
  4. 4. Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy
  5. 5. Section of Gastroenterology and Hepatology, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.), University of Palermo, Palermo, Italy
  6. 6. Unit of Metabolic Diseases & Clinical Dietetics, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
  7. 7. Medical School, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, WA, Australia

Source: Hepatology Published:2020


Abstract

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult population. A significant subset of patients are lean, but their underlying pathophysiology is not well understood. Approach and Results: We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor (FGF) 19 levels (a surrogate for intestinal farnesoid X receptor [FXR] activity), patatin-like phospholipase domain containing 3 (PNPLA3), and transmembrane 6 superfamily member 2 (TM6SF2) variants, and gut microbiota profiles in lean and nonlean NAFLD were investigated in a cohort of Caucasian patients with biopsy-proven NAFLD (n = 538), lean healthy controls (n = 30), and experimental murine models. Patients with lean NAFLD had a more favorable metabolic and histological profile compared with those with nonlean NAFLD (P < 0.05 for all). BA levels were significantly higher in NAFLD with advanced compared with earlier stages of liver fibrosis. Patients with lean NAFLD had higher serum secondary BA and FGF19 levels and reduced 7-alpha-hydroxy-4-cholesten-3-one (C4) levels (P < 0.05 for all). These differences were more profound in early compared with advanced stages of fibrosis (P < 0.05 for both). Lean patients demonstrated an altered gut microbiota profile. Similar findings were demonstrated in lean and nonlean murine models of NAFLD. Treating mice with an apical sodium-dependent BA transporter inhibitor (SC-435) resulted in marked increases in fgf15, a shift in the BA and microbiota profiles, and improved steatohepatitis in the lean model. Conclusions: Differences in metabolic adaptation between patients with lean and nonlean NAFLD, at least in part, explain the pathophysiology and provide options for therapy. © 2019 by the American Association for the Study of Liver Diseases.
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