Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation
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- Fei Chen
- Storr Liver Centre,Westmead Institute for Medical Research, Westmead Hospital and University of Sydney,Westmead,NSW,Australia
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- Saeed Esmaili
- Storr Liver Centre,Westmead Institute for Medical Research, Westmead Hospital and University of Sydney,Westmead,NSW,Australia
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- Geraint B. Rogers
- SAHMRI Infection and Immunity Theme, School of Medicine,Flinders University,Adelaide,Australia
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- Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Science,University of Turin,Turin,Italy
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- Salvatore Petta
- Section of Gastroenterology and Hepatology, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.),University of Palermo,Palermo,Italy
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- Giulio Marchesini
- Unit of Metabolic Diseases & Clinical Dietetics, Department of Medical and Surgical Sciences,University of Bologna,Bologna,Italy
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- Ali Bayoumi
- Storr Liver Centre,Westmead Institute for Medical Research, Westmead Hospital and University of Sydney,Westmead,NSW,Australia
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- Mayada Metwally
- Storr Liver Centre,Westmead Institute for Medical Research, Westmead Hospital and University of Sydney,Westmead,NSW,Australia
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- Mahmoud Karimi Azardaryany
- Storr Liver Centre,Westmead Institute for Medical Research, Westmead Hospital and University of Sydney,Westmead,NSW,Australia
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- Sally Coulter
- Storr Liver Centre,Westmead Institute for Medical Research, Westmead Hospital and University of Sydney,Westmead,NSW,Australia
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- Jocelyn M. Choo
- SAHMRI Infection and Immunity Theme, School of Medicine,Flinders University,Adelaide,Australia
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- Ramy Younes
- Division of Gastroenterology and Hepatology, Department of Medical Science,University of Turin,Turin,Italy
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- Chiara Rosso
- Division of Gastroenterology and Hepatology, Department of Medical Science,University of Turin,Turin,Italy
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- Christopher Liddle
- Storr Liver Centre,Westmead Institute for Medical Research, Westmead Hospital and University of Sydney,Westmead,NSW,Australia
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- Leon A. Adams
- Medical School, Sir Charles Gairdner Hospital Unit,University of Western Australia,Nedlands,WA,Australia
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- Antonio Craxì
- Section of Gastroenterology and Hepatology, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.),University of Palermo,Palermo,Italy
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- Jacob George
- Storr Liver Centre,Westmead Institute for Medical Research, Westmead Hospital and University of Sydney,Westmead,NSW,Australia
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- Mohammed Eslam
- Storr Liver Centre,Westmead Institute for Medical Research, Westmead Hospital and University of Sydney,Westmead,NSW,Australia
抄録
<jats:sec> <jats:title>Background and Aims</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Approach and Results</jats:title> <jats:p>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 (<jats:italic toggle="yes">PNPLA3</jats:italic>), and transmembrane 6 superfamily member 2 (<jats:italic toggle="yes">TM6SF2</jats:italic>) 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 (<jats:italic toggle="yes">P</jats:italic> < 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 (<jats:italic toggle="yes">C4</jats:italic>) levels (<jats:italic toggle="yes">P</jats:italic> < 0.05 for all). These differences were more profound in early compared with advanced stages of fibrosis (<jats:italic toggle="yes">P</jats:italic> < 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Differences in metabolic adaptation between patients with lean and nonlean NAFLD, at least in part, explain the pathophysiology and provide options for therapy.</jats:p> </jats:sec>
収録刊行物
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- Hepatology
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Hepatology 71 (4), 1213-1227, 2020-01-24
Ovid Technologies (Wolters Kluwer Health)