Lean NAFLD: A Distinct Entity Shaped by Differential... : Hepatology (original) (raw)

Original Articles: STEATOHEPATITIS/METABOLIC LIVER DISEASE

Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation

Chen, Fei1,†; Esmaili, Saeed1,2,†; Rogers, Geraint B.3; Bugianesi, Elisabetta4; Petta, Salvatore5; Marchesini, Giulio6; Bayoumi, Ali1; Metwally, Mayada1; Azardaryany, Mahmoud Karimi1; Coulter, Sally1; Choo, Jocelyn M.3; Younes, Ramy4; Rosso, Chiara4; Liddle, Christopher1; Adams, Leon A.7; Craxì, Antonio5; George, Jacob*,1; Eslam, Mohammed*,1

1Storr Liver CentreWestmead Institute for Medical Research, Westmead Hospital and University of SydneyWestmeadNSWAustralia

2Liver and Pancreatobiliary Diseases Research CenterDigestive Disease Research Institute, Shariati Hospital, Tehran University of Medical SciencesTehranIran

3SAHMRI Infection and Immunity Theme, School of MedicineFlinders UniversityAdelaideAustralia

4Division of Gastroenterology and Hepatology, Department of Medical ScienceUniversity of TurinTurinItaly

5Section of Gastroenterology and Hepatology, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.)University of PalermoPalermoItaly

6Unit of Metabolic Diseases & Clinical Dietetics, Department of Medical and Surgical SciencesUniversity of BolognaBolognaItaly

7Medical School, Sir Charles Gairdner Hospital UnitUniversity of Western AustraliaNedlandsWAAustralia

*Address Correspondence and Reprint Requests to:
Jacob George, Ph.D.
Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney
176 Hawkesbury Rd.
2145 Westmead, NSW, Australia
E‐mail: [email protected]
Tel.: +1‐612‐88907705
or
Mohammed Eslam, Ph.D.
Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney
176 Hawkesbury Rd.
2145 Westmead, NSW, Australia
E‐mail: [email protected]
Tel.: +1‐612‐88907705

†These authors contributed equally to this work.

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.