Journal of Gastrointestinal Surgery

, Volume 23, Issue 1, pp 51–57 | Cite as

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

  • Guilherme S. Mazzini
  • Jad Khoraki
  • Mikhail Dozmorov
  • Matthew G. Browning
  • Dayanjan Wijesinghe
  • Luke Wolfe
  • Richard R. Gurski
  • Guilherme M. CamposEmail author
2018 SSAT Plenary Presentation



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.


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.


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).


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.


Bariatric surgery Gastric bypass NASH NAFLD Bile acids FXR PPRAα 



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

Author 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.


  1. 1.
    Machado M, Cortez-Pinto H. Non-alcoholic steatohepatitis and metabolic syndrome. Curr Opin Clin Nutr Metab Care. 2006;9(5):637–42.CrossRefGoogle Scholar
  2. 2.
    Rabl C, Campos GM. The impact of bariatric surgery on nonalcoholic steatohepatitis. Semin Liver Dis. 2012;32(1):80–91.CrossRefGoogle Scholar
  3. 3.
    Angulo P. NAFLD, obesity, and bariatric surgery. Gastroenterology. 2006;130(6):1848–52.CrossRefGoogle Scholar
  4. 4.
    NCD-RisC. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet. 2016;387(10026):1377–96.CrossRefGoogle Scholar
  5. 5.
    Penney NC, Kinross J, Newton RC, Purkayastha S. The role of bile acids in reducing the metabolic complications of obesity after bariatric surgery: a systematic review. Int J Obes (Lond). 2015;39(11):1565–74.CrossRefGoogle Scholar
  6. 6.
    Kohli R, Myronovych A, Tan BK, Salazar-Gonzalez RM, Miles L, Zhang W, et al. Bile Acid Signaling: Mechanism for Bariatric Surgery, Cure for NASH? Dig Dis. 2015;33(3):440–6.CrossRefGoogle Scholar
  7. 7.
    Jahansouz C, Xu H, Hertzel AV, Serrot FJ, Kvalheim N, Cole A, et al. Bile Acids Increase Independently From Hypocaloric Restriction After Bariatric Surgery. Ann Surg. 2016;264(6):1022–8.CrossRefGoogle Scholar
  8. 8.
    Risstad H, Kristinsson JA, Fagerland MW, le Roux CW, Birkeland KI, Gulseth HL, et al. Bile acid profiles over 5 years after gastric bypass and duodenal switch: results from a randomized clinical trial. Surg Obes Relat Dis. 2017;13(9):1544–1553.Google Scholar
  9. 9.
    Chavez-Talavera O, Tailleux A, Lefebvre P, Staels B. Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease. Gastroenterology. 2017;152(7):1679–94.e3.CrossRefGoogle Scholar
  10. 10.
    Steinert RE, Peterli R, Keller S, Meyer-Gerspach AC, Drewe J, Peters T, et al. Bile acids and gut peptide secretion after bariatric surgery: a 1-year prospective randomized pilot trial. Obesity (Silver Spring). 2013;21(12):E660–8.CrossRefGoogle Scholar
  11. 11.
    Fouladi F, Mitchell JE, Wonderlich JA, Steffen KJ. The Contributing Role of Bile Acids to Metabolic Improvements After Obesity and Metabolic Surgery. Obes Surg. 2016;26(10):2492–502.CrossRefGoogle Scholar
  12. 12.
    Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature. 2014;509(7499):183–8.CrossRefGoogle Scholar
  13. 13.
    Kaska L, Sledzinski T, Chomiczewska A, Dettlaff-Pokora A, Swierczynski J. Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome. World J Gastroenterol. 2016;22(39):8698–719.CrossRefGoogle Scholar
  14. 14.
    Han CY, Kim TH, Koo JH, Kim SG. Farnesoid X receptor as a regulator of fuel consumption and mitochondrial function. Arch Pharm Res. 2016;39(8):1062–74.CrossRefGoogle Scholar
  15. 15.
    Hue L, Taegtmeyer H. The Randle cycle revisited: a new head for an old hat. Am J Physiol Endocrinol Metab. 2009;297(3):E578–91.CrossRefGoogle Scholar
  16. 16.
    Kersten S. Integrated physiology and systems biology of PPARalpha. Mol Metab. 2014;3(4):354–71.CrossRefGoogle Scholar
  17. 17.
    Francque S, Verrijken A, Caron S, Prawitt J, Paumelle R, Derudas B, et al. PPARalpha gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J Hepatol. 2015;63(1):164–73.CrossRefGoogle Scholar
  18. 18.
    Li T, Chiang JY. Regulation of bile acid and cholesterol metabolism by PPARs. PPAR Res. 2009;2009:501739.CrossRefGoogle Scholar
  19. 19.
    Pineda Torra I, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B. Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol. 2003;17(2):259–72.CrossRefGoogle Scholar
  20. 20.
    Mazzini GS, Khoraki J, Browning MG, Campos GM. Concurrent miR-21 suppression and FXR activation as a mechanism of improvement in nonalcoholic fatty liver disease. Cell Death Dis. 2018;9(3):354.CrossRefGoogle Scholar
  21. 21.
    Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, et al. NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Res. 2013;41(Database issue):D991–5.Google Scholar
  22. 22.
    GEO. GEO Documentation - GEO - NCBI 2018 [updated 10-17-2018; cited 2018 05–12]. Available from:
  23. 23.
    Lefebvre P, Lalloyer F, Bauge E, Pawlak M, Gheeraert C, Dehondt H, et al. Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARalpha-regulated dermatopontin. JCI Insight. 2017;2(13):e92264.Google Scholar
  24. 24.
    Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005–23.CrossRefGoogle Scholar
  25. 25.
    Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015;149(2):367–78.e5; quiz e14–5.CrossRefGoogle Scholar
  26. 26.
    Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients. Gastroenterology. 2015;149(2):379–88; quiz e15–6.CrossRefGoogle Scholar
  27. 27.
    Browning MG, Campos GM. Bile acid physiology as the potential driver for the sustained metabolic improvements with bariatric surgery. Surg Obes Relat Dis. 2017;13(9):1553–4.CrossRefGoogle Scholar
  28. 28.
    Tsuchiya T, Naitoh T, Nagao M, Tanaka N, Watanabe K, Imoto H, et al. Increased Bile Acid Signals After Duodenal-Jejunal Bypass Improve Non-alcoholic Steatohepatitis (NASH) in a Rodent Model of Diet-Induced NASH. Obes Surg. 2018;28(6):1643–1652.Google Scholar
  29. 29.
    Yoshikawa T, Ide T, Shimano H, Yahagi N, Amemiya-Kudo M, Matsuzaka T, et al. Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling. Mol Endocrinol. 2003;17(7):1240–54.CrossRefGoogle Scholar
  30. 30.
    Ide T, Shimano H, Yoshikawa T, Yahagi N, Amemiya-Kudo M, Matsuzaka T, et al. Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling. Mol Endocrinol. 2003;17(7):1255–67.CrossRefGoogle Scholar
  31. 31.
    Kim KH, Moore DD. Regulation of Liver Energy Balance by the Nuclear Receptors Farnesoid X Receptor and Peroxisome Proliferator Activated Receptor alpha. Dig Dis. 2017;35(3):203–9.CrossRefGoogle Scholar
  32. 32.
    Kassam A, Capone JP, Rachubinski RA. The short heterodimer partner receptor differentially modulates peroxisome proliferator-activated receptor alpha-mediated transcription from the peroxisome proliferator-response elements of the genes encoding the peroxisomal beta-oxidation enzymes acyl-CoA oxidase and hydratase-dehydrogenase. Mol Cell Endocrinol. 2001;176(1–2):49–56.CrossRefGoogle Scholar
  33. 33.
    Rodrigues PM, Afonso MB, Simao AL, Carvalho CC, Trindade A, Duarte A, et al. miR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice. Cell Death Dis. 2017;8(4):e2748.CrossRefGoogle Scholar
  34. 34.
    Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest. 1999;103(11):1489–98.CrossRefGoogle Scholar
  35. 35.
    Videla LA, Pettinelli P. Misregulation of PPAR Functioning and Its Pathogenic Consequences Associated with Nonalcoholic Fatty Liver Disease in Human Obesity. PPAR Res. 2012;2012:107434.CrossRefGoogle Scholar
  36. 36.
    Veiga FMS, Graus-Nunes F, Rachid TL, Barreto AB, Mandarim-de-Lacerda CA, Souza-Mello V. Anti-obesogenic effects of WY14643 (PPAR-alpha agonist): Hepatic mitochondrial enhancement and suppressed lipogenic pathway in diet-induced obese mice. Biochimie. 2017;140:106–16.CrossRefGoogle Scholar
  37. 37.
    Pawlak M, Bauge E, Bourguet W, De Bosscher K, Lalloyer F, Tailleux A, et al. The transrepressive activity of peroxisome proliferator-activated receptor alpha is necessary and sufficient to prevent liver fibrosis in mice. Hepatology. 2014;60(5):1593–606.CrossRefGoogle Scholar
  38. 38.
    Loyer X, Paradis V, Henique C, Vion AC, Colnot N, Guerin CL, et al. Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARalpha expression. Gut. 2016;65(11):1882–94.CrossRefGoogle Scholar
  39. 39.
    Younossi ZM, Loomba R, Rinella ME, Bugianesi E, Marchesini G, Neuschwander-Tetri BA, et al. Current and Future Therapeutic Regimens for Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis. Hepatology. 2018;68(1):361–371.Google Scholar
  40. 40.
    Tanaka N, Aoyama T, Kimura S, Gonzalez FJ. Targeting nuclear receptors for the treatment of fatty liver disease. Pharmacol Ther. 2017;179:142–157.Google Scholar
  41. 41.
    ClinicalTrials. Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment - Full Text View - 2018 [updated 01-24-2018; cited 2018 05–26]. Available from:
  42. 42.
    Biemann R, Penner M, Borucki K, Westphal S, Luley C, Ronicke R, et al. Serum bile acids and GLP-1 decrease following telemetric induced weight loss: results of a randomized controlled trial. Sci Rep. 2016;6:30173.CrossRefGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2018

Authors and Affiliations

  1. 1.Division of Bariatric and Gastrointestinal Surgery, Department of SurgeryVirginia Commonwealth UniversityRichmondUSA
  2. 2.Postgraduate Program in Medicine: Surgical SciencesFederal University of Rio Grande do SulPorto AlegreBrazil
  3. 3.Department of BiostatisticsVirginia Commonwealth UniversityRichmondUSA
  4. 4.Department of Pharmacotherapy and Outcomes ScienceVirginia Commonwealth UniversityRichmondUSA

Personalised recommendations