Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation

Fei Chen, Saeed Esmaili, Geraint Rogers, Elisabetta Bugianesi, Salvatore Petta, Giulio Marchesini, Ali Bayoumi, Mayada Metwally, Mahmoud Karimi Azardaryany, Sally Coulter, Jocelyn M Choo, Ramy Younes, Chiara Rosso, Christopher Liddle, Leon A Adams, Antonio Craxì, Jacob George, Mohammed Eslam

Research output: Contribution to journalArticle

Abstract

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. We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor 19 (FGF19) 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 non-lean 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 to those with non-lean NAFLD (P < 0.05 for all). BA levels were significantly higher in NAFLD with advanced compared to 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 to advanced stages of fibrosis (P < 0.05 for both). Lean patients demonstrated an altered gut microbiota profile. Similar findings were demonstrated in lean and non-lean murine models of NAFLD. Treating mice with an apical sodium-dependent bile acid transporter inhibitor (ASBTi) (SC-435) resulted in marked increases in fgf15, a shift in the BA and microbiota profiles, and improved steatohepatitis in the lean model. CONCLUSION: Differences in metabolic adaptation between lean and non-lean NAFLD patients, at least in part, explain the pathophysiology and provide novel options for therapy. This article is protected by copyright. All rights reserved.

LanguageEnglish
JournalHepatology
DOIs
Publication statusE-pub ahead of print - 23 Aug 2019

Cite this

Chen, F., Esmaili, S., Rogers, G., Bugianesi, E., Petta, S., Marchesini, G., ... Eslam, M. (2019). Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation. Hepatology. https://doi.org/10.1002/hep.30908
Chen, Fei ; Esmaili, Saeed ; Rogers, Geraint ; Bugianesi, Elisabetta ; Petta, Salvatore ; Marchesini, Giulio ; Bayoumi, Ali ; Metwally, Mayada ; Azardaryany, Mahmoud Karimi ; Coulter, Sally ; Choo, Jocelyn M ; Younes, Ramy ; Rosso, Chiara ; Liddle, Christopher ; Adams, Leon A ; Craxì, Antonio ; George, Jacob ; Eslam, Mohammed. / Lean NAFLD : A Distinct Entity Shaped by Differential Metabolic Adaptation. In: Hepatology. 2019.
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title = "Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation",
abstract = "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. We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor 19 (FGF19) 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 non-lean 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 to those with non-lean NAFLD (P < 0.05 for all). BA levels were significantly higher in NAFLD with advanced compared to 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 to advanced stages of fibrosis (P < 0.05 for both). Lean patients demonstrated an altered gut microbiota profile. Similar findings were demonstrated in lean and non-lean murine models of NAFLD. Treating mice with an apical sodium-dependent bile acid transporter inhibitor (ASBTi) (SC-435) resulted in marked increases in fgf15, a shift in the BA and microbiota profiles, and improved steatohepatitis in the lean model. CONCLUSION: Differences in metabolic adaptation between lean and non-lean NAFLD patients, at least in part, explain the pathophysiology and provide novel options for therapy. This article is protected by copyright. All rights reserved.",
author = "Fei Chen and Saeed Esmaili and Geraint Rogers and Elisabetta Bugianesi and Salvatore Petta and Giulio Marchesini and Ali Bayoumi and Mayada Metwally and Azardaryany, {Mahmoud Karimi} and Sally Coulter and Choo, {Jocelyn M} and Ramy Younes and Chiara Rosso and Christopher Liddle and Adams, {Leon A} and Antonio Crax{\`i} and Jacob George and Mohammed Eslam",
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year = "2019",
month = "8",
day = "23",
doi = "10.1002/hep.30908",
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journal = "Hepatology",
issn = "0270-9139",
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Chen, F, Esmaili, S, Rogers, G, Bugianesi, E, Petta, S, Marchesini, G, Bayoumi, A, Metwally, M, Azardaryany, MK, Coulter, S, Choo, JM, Younes, R, Rosso, C, Liddle, C, Adams, LA, Craxì, A, George, J & Eslam, M 2019, 'Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation', Hepatology. https://doi.org/10.1002/hep.30908

Lean NAFLD : A Distinct Entity Shaped by Differential Metabolic Adaptation. / Chen, Fei; Esmaili, Saeed; Rogers, Geraint; Bugianesi, Elisabetta; Petta, Salvatore; Marchesini, Giulio; Bayoumi, Ali; Metwally, Mayada; Azardaryany, Mahmoud Karimi; Coulter, Sally; Choo, Jocelyn M; Younes, Ramy; Rosso, Chiara; Liddle, Christopher; Adams, Leon A; Craxì, Antonio; George, Jacob; Eslam, Mohammed.

In: Hepatology, 23.08.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Lean NAFLD

T2 - Hepatology

AU - Chen, Fei

AU - Esmaili, Saeed

AU - Rogers, Geraint

AU - Bugianesi, Elisabetta

AU - Petta, Salvatore

AU - Marchesini, Giulio

AU - Bayoumi, Ali

AU - Metwally, Mayada

AU - Azardaryany, Mahmoud Karimi

AU - Coulter, Sally

AU - Choo, Jocelyn M

AU - Younes, Ramy

AU - Rosso, Chiara

AU - Liddle, Christopher

AU - Adams, Leon A

AU - Craxì, Antonio

AU - George, Jacob

AU - Eslam, Mohammed

N1 - This article is protected by copyright. All rights reserved.

PY - 2019/8/23

Y1 - 2019/8/23

N2 - 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. We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor 19 (FGF19) 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 non-lean 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 to those with non-lean NAFLD (P < 0.05 for all). BA levels were significantly higher in NAFLD with advanced compared to 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 to advanced stages of fibrosis (P < 0.05 for both). Lean patients demonstrated an altered gut microbiota profile. Similar findings were demonstrated in lean and non-lean murine models of NAFLD. Treating mice with an apical sodium-dependent bile acid transporter inhibitor (ASBTi) (SC-435) resulted in marked increases in fgf15, a shift in the BA and microbiota profiles, and improved steatohepatitis in the lean model. CONCLUSION: Differences in metabolic adaptation between lean and non-lean NAFLD patients, at least in part, explain the pathophysiology and provide novel options for therapy. This article is protected by copyright. All rights reserved.

AB - 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. We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor 19 (FGF19) 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 non-lean 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 to those with non-lean NAFLD (P < 0.05 for all). BA levels were significantly higher in NAFLD with advanced compared to 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 to advanced stages of fibrosis (P < 0.05 for both). Lean patients demonstrated an altered gut microbiota profile. Similar findings were demonstrated in lean and non-lean murine models of NAFLD. Treating mice with an apical sodium-dependent bile acid transporter inhibitor (ASBTi) (SC-435) resulted in marked increases in fgf15, a shift in the BA and microbiota profiles, and improved steatohepatitis in the lean model. CONCLUSION: Differences in metabolic adaptation between lean and non-lean NAFLD patients, at least in part, explain the pathophysiology and provide novel options for therapy. This article is protected by copyright. All rights reserved.

U2 - 10.1002/hep.30908

DO - 10.1002/hep.30908

M3 - Article

JO - Hepatology

JF - Hepatology

SN - 0270-9139

ER -