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Concomitant PPARα and FXR Activation as a Putative Mechanism of NASH Improvement after Gastric Bypass Surgery: a GEO Datasets Analysis

  • 2018 SSAT Plenary Presentation
  • Published:
Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background

Compared to non-surgical weight loss (Diet), weight loss after Roux-en-Y gastric bypass (RYGB) results in greater rates of non-alcoholic steatohepatitis (NASH) resolution. Changes in bile acid physiology and farnesoid X receptor (FXR) signaling are suspected mediators of postoperative NASH improvement. Recent experimental evidence suggests that upregulation of hepatic peroxisome proliferator-activated receptor α (PPARα) activity might also impact NASH improvement. As FXR partly regulates PPARα, we compared resolution of NASH and changes in hepatic PPARα and FXR gene expression following Diet and RYGB.

Methods

We searched the Gene Expression Omnibus database to identify human studies with liver biopsies containing genomic data and histologic NASH features, at baseline and after Diet or RYGB. Microarray data were extracted for PPARα and FXR gene expression analyses using GEOquery R package v.2.42.0.

Results

We identified one study (GSE83452) where patients underwent either Diet (n = 29) or RYGB (n = 25). NASH prevalence was similar at baseline (Diet 76% versus RYGB 60%, P = ns). After 1 year, NASH resolved in 93.3% of RYGB but only in 27.3% of Diet (P < 0.001). Hepatic PPARα and FXR gene expression increased only after RYGB (P < 0.001). These changes were also found when analyzing only patients that resolved NASH (P < 0.01), and patients without NASH at baseline and follow-up (P < 0.05).

Conclusions

Compared to Diet, RYGB results in greater NASH resolution with concurrent upregulation of hepatic PPARα and FXR. Our findings point to concurrent PPARα and FXR activation, triggered by RYGB, as a potential mechanism to improve NASH.

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Acknowledgements

The authors would like to thank CAPES (88887.145322/2017-00).

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Authors and Affiliations

  1. Division of Bariatric and Gastrointestinal Surgery, Department of Surgery, Virginia Commonwealth University, 1200 East Broad Street, Richmond, VA, USA

    Guilherme S. Mazzini, Jad Khoraki, Matthew G. Browning, Luke Wolfe & Guilherme M. Campos

  2. Postgraduate Program in Medicine: Surgical Sciences, Federal University of Rio Grande do Sul, 2400 Ramiro Barcelos Street, Porto Alegre, RS, Brazil

    Guilherme S. Mazzini & Richard R. Gurski

  3. Department of Biostatistics, Virginia Commonwealth University, 1200 E. Clay Street, Richmond, VA, USA

    Mikhail Dozmorov

  4. Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, 410 N. 12th Street, Richmond, VA, USA

    Dayanjan Wijesinghe

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  1. Guilherme S. Mazzini
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Contributions

Mazzini: conception, analysis, drafting, and final approval. Khoraki: GEO search and final approval. Dozmorov: GEO query and extraction, statistical analyses, drafting, and final approval. Browning: design, interpretation of data, drafting, and final approval. Wijesinghe: design, interpretation of data, drafting, and final approval. Wolfe: study design, statistical analyses, and final approval. Gurski: interpretation of data, revising critically, and final approval. Campos: study conception, design, interpretation of data, drafting, revision, and final approval.

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Correspondence to Guilherme M. Campos.

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Mazzini, G.S., Khoraki, J., Dozmorov, M. et al. Concomitant PPARα and FXR Activation as a Putative Mechanism of NASH Improvement after Gastric Bypass Surgery: a GEO Datasets Analysis. J Gastrointest Surg 23, 51–57 (2019). https://doi.org/10.1007/s11605-018-3938-z

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  • DOI: https://doi.org/10.1007/s11605-018-3938-z

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