Concomitant PPARα and FXR Activation as a Putative Mechanism of NASH Improvement after Gastric Bypass Surgery: a GEO Datasets Analysis
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.
KeywordsBariatric surgery Gastric bypass NASH NAFLD Bile acids FXR PPRAα
The authors would like to thank CAPES (88887.145322/2017-00).
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.
- 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
- 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
- 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.GEO. GEO Documentation - GEO - NCBI 2018 [updated 10-17-2018; cited 2018 05–12]. Available from: https://www.ncbi.nlm.nih.gov/geo/info/.
- 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.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
- 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.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.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
- 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
- 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.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