Skip to main content

Advertisement

SpringerLink
Log in

Effects of Sleeve Gastrectomy on Nonalcoholic Fatty Liver Disease in an Obese Rat Model

  • Original Contributions
  • Published:
Obesity Surgery Aims and scope Submit manuscript

Abstract

Background/Aim

Laparoscopic sleeve gastrectomy (SG) is an increasingly used bariatric surgery, which is reported to be effective for nonalcoholic fatty liver disease (NAFLD). Recently, activation of farnesoid X receptor (FXR), which is a nuclear receptor of bile acid (BA), was reported to contribute to the resolution of NAFLD. However, it is unclear whether SG has an effect on expression of FXR in the liver. We aimed to investigate the expression of FXR and its related factors in the liver after SG and to clarify the relationship between changes in FXR expression and NAFLD in an obese rat model.

Methods

Thirty male Zucker fatty rats were divided into three groups: sham-operated (SO) control, pair-fed (PF) control, and SG. Eight weeks after the surgery, metabolic parameters, plasma levels of total BA and liver enzymes, liver triglyceride (TG) content, and mRNA expression of FXR and its related factors, such as small heterodimer partner (SHP) and peroxisome proliferator-activated receptor α (PPARα), were measured.

Results

Metabolic parameters in the SG group were significantly improved compared with the SO group. Liver enzymes and TG were significantly lower in the SG group than in the SO group. Plasma levels of BA were significantly higher in the SG group than in the SO and PF groups. mRNA expression of FXR, SHP, and PPARα in the liver was significantly higher in the SG group than in the SO group.

Conclusions

These results suggest that the effects of SG on NAFLD should be associated with the expression of the FXR pathway in the liver in a Zucker fatty rat model.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766–81. https://doi.org/10.1016/S0140-6736(14)60460-8.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Flegal KM, Kit BK, Orpana H, et al. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2013;309(1):71–82. https://doi.org/10.1001/jama.2012.113905.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Gloy VL, Briel M, Bhatt DL, Kashyap SR, Schauer PR, Mingrone G, Bucher HC, Nordmann AJ. Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomised controlled trials. BMJ. 2013; 22:347:f5934.

  4. Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes—3-year outcomes. N Engl J Med. 2014;370(21):2002–13. https://doi.org/10.1056/NEJMoa1401329.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Ohta M, Kai S, Iwashita Y, et al. Initial experience in laparoscopic sleeve gastrectomy for Japanese morbid obesity. Asian J Endosc Surg. 2009;2(3):68–72. https://doi.org/10.1111/j.1758-5910.2009.00007.x.

    Article  Google Scholar 

  6. Angrisani L, Santonicola A, Iovino P, et al. Bariatric surgery worldwide 2013. Obes Surg. 2015;25(10):1822–32. https://doi.org/10.1007/s11695-015-1657-z.

    Article  PubMed  CAS  Google Scholar 

  7. Masuda T, Ohta M, Hirashita T, et al. A comparative study of gastric banding and sleeve gastrectomy in an obese diabetic rat model. Obes Surg. 2011;21(11):1774–80. https://doi.org/10.1007/s11695-011-0512-0.

    Article  PubMed  Google Scholar 

  8. Kawano Y, Ohta M, Hirashita T, et al. Effects of sleeve gastrectomy on lipid metabolism in an obese diabetic rat model. Obes Surg. 2013;23(12):1947–56. https://doi.org/10.1007/s11695-013-1035-7.

    Article  PubMed  Google Scholar 

  9. Kawasaki T, Ohta M, Kawano Y, et al. Effects of sleeve gastrectomy and gastric banding on the hypothalamic feeding center in an obese rat model. Surg Today. 2015;45(12):1560–6. https://doi.org/10.1007/s00595-015-1135-1.

    Article  PubMed  CAS  Google Scholar 

  10. Talavera-Urquijo E, Rodríguez-Navarro S, Beisani M, et al. Morphofunctional changes after sleeve gastrectomy and very low calorie diet in an animal model of non-alcoholic fatty liver disease. Obes Surg. 2017 Jul 15. [Epub ahead of print]; https://doi.org/10.1007/s11695-017-2805-4.

  11. Chalasani N, Younossi Z, Lavine JE, et al. American Association for the Study of Liver Diseases; American College of Gastroenterology; American Gastroenterological Association. 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. Am J Gastroenterol. 2012;107(6):811–26. https://doi.org/10.1038/ajg.2012.128.

    Article  PubMed  Google Scholar 

  12. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34(3):274–85. https://doi.org/10.1111/j.1365-2036.2011.04724.x.

    Article  PubMed  CAS  Google Scholar 

  13. Fan JG, Saibara T, Chitturi S, et al. Asia-Pacific Working Party for NAFLD. What are the risk factors and settings for non-alcoholic fatty liver disease in Asia-Pacific? J Gastroenterol Hepatol. 2007;22(6):794–800. https://doi.org/10.1111/j.1440-1746.2007.04952.x.

    Article  PubMed  Google Scholar 

  14. Musso G, Gambino R, Cassader M, et al. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43(8):617–49. https://doi.org/10.3109/07853890.2010.518623.

    Article  PubMed  Google Scholar 

  15. Johnson NA, Sachinwalla T, Walton DW, et al. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology. 2009;50(4):1105–12. https://doi.org/10.1002/hep.23129.

    Article  PubMed  CAS  Google Scholar 

  16. Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51(1):121–9. https://doi.org/10.1002/hep.23276.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Boettcher E, Csako G, Pucino F, et al. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012;35(1):66–75. https://doi.org/10.1111/j.1365-2036.2011.04912.x.

    Article  PubMed  CAS  Google Scholar 

  18. Sato K, Gosho M, Yamamoto T, et al. Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Nutrition. 2015;31(7-8):923–30. https://doi.org/10.1016/j.nut.2014.11.018.

    Article  PubMed  CAS  Google Scholar 

  19. Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013;145(3):574–82. https://doi.org/10.1053/j.gastro.2013.05.042.

    Article  PubMed  CAS  Google Scholar 

  20. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956–65. https://doi.org/10.1016/S0140-6736(14)61933-4.

    Article  PubMed  CAS  Google Scholar 

  21. Bower G, Toma T, Harling L, et al. Bariatric surgery and non-alcoholic fatty liver disease: a systematic review of liver biochemistry and histology. Obes Surg. 2015;25(12):2280–9. https://doi.org/10.1007/s11695-015-1691-x.

    Article  PubMed  Google Scholar 

  22. Mummadi RR, Kasturi KS, Chennareddygari S, et al. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2008;6(12):1396–402. https://doi.org/10.1016/j.cgh.2008.08.012.

    Article  PubMed  Google Scholar 

  23. Forman BM, Goode E, Chen J, et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell. 1995;81(5):687–93. https://doi.org/10.1016/0092-8674(95)90530-8.

    Article  PubMed  CAS  Google Scholar 

  24. Wang H, Chen J, Hollister K, et al. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 1999;3(5):543–53. https://doi.org/10.1016/S1097-2765(00)80348-2.

    Article  PubMed  CAS  Google Scholar 

  25. Yang ZX, Shen W, Sun H. Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Hepatol Int. 2010;4(4):741–8. https://doi.org/10.1007/s12072-010-9202-6.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Watanabe M, Houten SM, Wang L, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. 2004;113(10):1408–18. https://doi.org/10.1172/JCI21025.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Nakatani H, Kasama K, Oshiro T, et al. Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery. Metabolism. 2009;58(10):1400–7. https://doi.org/10.1016/j.metabol.2009.05.006.

    Article  PubMed  CAS  Google Scholar 

  28. Myronovych A, Kirby M, Ryan KK, et al. Vertical sleeve gastrectomy reduces hepatic steatosis while increasing serum bile acids in a weight-loss-independent manner. Obesity. 2014;22(2):390–400. https://doi.org/10.1002/oby.20548.

    Article  PubMed  CAS  Google Scholar 

  29. Lopez PP, Nicholson SE, Burkhardt GE, et al. Development of a sleeve gastrectomy weight loss model in obese Zucker rats. J Surg Res. 2009;157(2):243–50. https://doi.org/10.1016/j.jss.2008.10.025.

    Article  PubMed  Google Scholar 

  30. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9. https://doi.org/10.1007/BF00280883.

    Article  PubMed  CAS  Google Scholar 

  31. Matsumoto M, Ogawa W, Teshigawara K, et al. Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. Diabetes. 2002;51(6):1672–80. https://doi.org/10.2337/diabetes.51.6.1672.

    Article  PubMed  CAS  Google Scholar 

  32. Ding X, Saxena NK, Lin S, et al. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 2006;43(1):173–81. https://doi.org/10.1002/hep.21006.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Kamada Y, Matsumoto H, Tamura S, et al. Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. J Hepatol. 2007;47(4):556–64. https://doi.org/10.1016/j.jhep.2007.03.020.

    Article  PubMed  CAS  Google Scholar 

  34. Pineda Torra I, Claudel T, Duval C, et al. 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. https://doi.org/10.1210/me.2002-0120.

    Article  PubMed  CAS  Google Scholar 

  35. Algooneh A, Almazeedi S, Al-Sabah S, et al. Non-alcoholic fatty liver disease resolution following sleeve gastrectomy. Surg Endosc. 2016;30(5):1983–7. https://doi.org/10.1007/s00464-015-4426-0.

    Article  PubMed  Google Scholar 

  36. DUMMY

  37. Xiong X, Wang X, Lu Y, et al. Hepatic steatosis exacerbated by endoplasmic reticulum stress-mediated downregulation of FXR in aging mice. J Hepatol. 2014;60(4):847–54. https://doi.org/10.1016/j.jhep.2013.12.003.

    Article  PubMed  CAS  Google Scholar 

  38. Aguilar-Olivos NE, Carrillo-Córdova D, Oria-Hernández J, et al. The nuclear receptor FXR, but not LXR, up-regulates bile acid transporter expression in non-alcoholic fatty liver disease. Ann Hepatol. 2015;14(4):487–93.

    PubMed  CAS  Google Scholar 

  39. Ryan KK, Tremaroli V, Clemmensen C, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature. 2014;8(509):183–8.

    Article  CAS  Google Scholar 

  40. Belgaumkar AP, Vincent RP, Carswell KA, et al. Changes in bile acid profile after laparoscopic sleeve gastrectomy are associated with improvements in metabolic profile and fatty liver disease. Obes Surg. 2016;26(6):1195–202. https://doi.org/10.1007/s11695-015-1878-1.

    Article  PubMed  Google Scholar 

  41. Kucera O, Cervinkova Z. Experimental models of non-alcoholic fatty liver disease in rats. World J Gastroenterol. 2014;20(26):8364–76. https://doi.org/10.3748/wjg.v20.i26.8364.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Medina DA, Pedreros JP, Turiel D, Quezada N, Pimentel F, Escalona A, Garrido D. Distinct patterns in the gut microbiota after surgical or medical therapy in obese patients. PeerJ. 2017; 20;5:e3443.

  43. Sayin SI, Wahlström A, Felin J, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013;5(17):225–35.

    Article  CAS  Google Scholar 

  44. Zhang HM, Wang X, ZH W, et al. Beneficial effect of farnesoid X receptor activation on metabolism in a diabetic rat model. Mol Med Rep. 2016;13(3):2135–42. https://doi.org/10.3892/mmr.2016.4761.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Ms. Mayumi Takeda and Yuiko Aso for the technical assistance.x

Author information

Authors and Affiliations

  1. Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan

    Kiminori Watanabe, Masayuki Ohta, Hiroomi Takayama, Kazuhiro Tada, Yuki Shitomi, Takahide Kawasaki, Yuichiro Kawano, Yuichi Endo, Yukio Iwashita & Masafumi Inomata

Authors
  1. Kiminori Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masayuki Ohta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroomi Takayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazuhiro Tada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuki Shitomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takahide Kawasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuichiro Kawano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuichi Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yukio Iwashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masafumi Inomata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kiminori Watanabe.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Ethical Approval

All applicable institutional and/or national guidelines for the care and use of animals were followed.

Informed Consent

Does not apply.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Watanabe, K., Ohta, M., Takayama, H. et al. Effects of Sleeve Gastrectomy on Nonalcoholic Fatty Liver Disease in an Obese Rat Model. OBES SURG 28, 1532–1539 (2018). https://doi.org/10.1007/s11695-017-3052-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11695-017-3052-4

Keywords

Search

Navigation