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Gastric Bypass Increases Circulating Bile Acids and Activates Hepatic Farnesoid X Receptor (FXR) but Requires Intact Peroxisome Proliferator Activator Receptor Alpha (PPARα) Signaling to Significantly Reduce Liver Fat Content

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Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background

We interrogate effects of gastric bypass (RYGB), compared with a low-calorie diet, on bile acid (BA), liver fat, and FXR, PPARα, and targets in rats with obesity and non-alcoholic fatty liver disease (NAFLD).

Methods

Male Wistar rats received a high-fat diet (obese/NAFLD, n=24) or standard chow (lean, n=8) for 12 weeks. Obese/NAFLD rats had RYGB (n=11), sham operation pair-fed to RYGB (pair-fed sham, n=8), or sham operation (sham, n=5). Lean rats had sham operation (lean sham, n=8). Post-operatively, five RYGB rats received PPARα antagonist GW6417. Sacrifice occurred at 7 weeks. We measured weight changes, fasting total plasma BA, and liver % steatosis, triglycerides, and mRNA expression of the nuclear receptors FXR, PPARα, and their targets SHP and CPT-I.

Results

At sacrifice, obese sham was heavier (p<0.01) than all other groups that had lost similar weight loss. Obese sham had lower BA levels and lower hepatic FXR, SHP, and CPT-I mRNA expression than lean sham (P<0.05, for all comparisons). RYGB had increased BA levels compared with obese and pair-fed sham (P<0.05, for both), while pair-fed sham had BA levels, similar to obese sham. Compared with pair-fed sham, RYGB animals had increased liver FXR and PPARα expression and signaling (P<0.05). Percentage of steatosis was lower in RYGB and lean sham, relative to obese and pair-fed sham (P<0.05, for all comparisons). PPARα inhibition after RYGB resulted in similar weight loss but higher liver triglyceride content (P=0.01) compared with RYGB alone.

Conclusions

RYGB led to greater liver fat loss than low-calorie diet, an effect associated to increased fasting BA levels and increased expression of modulators of liver fat oxidation, FXR, and PPARα. However, intact PPARα signaling was necessary for resolution of NAFLD after RYGB.

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Authors and Affiliations

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

    Guilherme S. Mazzini, Jad Khoraki, Matthew G. Browning, Jilin Wu, Luke G. Wolfe, Martin J. Mangino & Guilherme M. Campos

  2. Division of Gastrointestinal Surgery, Hospital de Clínicas de Porto Alegre, 2350 Ramiro Barcelos Street, Porto Alegre, RS, Brazil

    Guilherme S. Mazzini

  3. Central Virginia Veterans Affairs Health Care System, Department of Microbiology and Immunology, Virginia Commonwealth University, 1220 E. Broad Street, Richmond, VA, USA

    Huiping Zhou

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

    Elvin T. Price

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  1. Guilherme S. Mazzini
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  2. Jad Khoraki
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  3. Matthew G. Browning
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  4. Jilin Wu
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Correspondence to Guilherme M. Campos.

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Mazzini, G.S., Khoraki, J., Browning, M.G. et al. Gastric Bypass Increases Circulating Bile Acids and Activates Hepatic Farnesoid X Receptor (FXR) but Requires Intact Peroxisome Proliferator Activator Receptor Alpha (PPARα) Signaling to Significantly Reduce Liver Fat Content. J Gastrointest Surg 25, 871–879 (2021). https://doi.org/10.1007/s11605-021-04908-3

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