Digestive Diseases and Sciences

, Volume 64, Issue 2, pp 456–468 | Cite as

NAFLD Induction Delays Postoperative Liver Regeneration of ALPPS in Rats

  • Jinwei Zhao
  • Hongyue Xu
  • Yuan Li
  • Lulu Gong
  • Ge Zheng
  • Xuefei Wang
  • Wenjin Luan
  • Shulin Li
  • Fangxue Ma
  • Lihui Ni
  • Xudong Tang
  • Xueyan Wang
  • Lu YuEmail author
Original Article



Associating liver partition and portal vein ligation (ALPPS) is a promising two-step hepatectomy that is beneficial for accumulative regeneration of the future liver remnant (FLR) and avoids postoperative liver failure.


Our study aimed to evaluate whether nonalcoholic fatty liver disease affected the liver regeneration induced by ALPPS.


Sprague-Dawley rats fed a high-fat diet were used to construct the NAFLD model. ALPPS were performed, and blood and future liver remnant samples were collected at postoperative days 1 (POD1), POD3, and POD7.


The hepatic regeneration rate (HRR) of ALPPS was higher than that of portal vein ligation (PVL) at POD3 and POD7 (p < 0.05), and the number of Ki-67-positive hepatocytes (POD3) and CD68-positive Kupffer cells (POD7) per visual field was higher in the ALPPS group than in the PVL group (p < 0.05). The serum TNF-α, hepatocyte growth factor protein, and the serum IL-6 level were higher in the ALPPS group than in the PVL group at POD3 and POD7. Compared with those of the standard laboratory diet (SLD)-fed rats, the rats with NAFLD exhibited a decrease in the HRR, Ki-67-positive hepatocytes, and CD68-positive Kupffer cells in the FLR. The number of CD68-positive Kupffer cells was lower in rats with NAFLD than that in SLD-fed rats; noteworthily, the serum level of IL-6 and TNF-α changed dramatically after surgeries.


NAFLD induction delayed liver regeneration induced by the ALPPS procedure, which might be associated with hepatocyte proliferation and the number of Kupffer cells.


NAFLD ALPPS Liver regeneration Hepatocyte proliferation Kupffer cells 



Portal vein ligation


Standard laboratory diet


Hepatocyte growth factor


Left median lobe


Left lateral lobe


Postoperative liver failure


Portal branch embolization


Total cholesterol


Associating liver partition and portal vein ligation


Nonalcoholic fatty liver disease



This work was supported by the Fund for Science and Technology Development of Jilin Province (20160101060JC, 20150101108JC); the National Key R&D Program of China (2017YFD0502200, 2016YFD0501302); the Project of the Education Department of Jilin Province (No. 2016444).

Compliance with ethical standards

Conflict of interest

All authors declare no conflicts of interest.


  1. 1.
    Clavien PA, Oberkofler CE, Raptis DA, Lehmann K, Rickenbacher A, El-Badry AM. What is critical for liver surgery and partial liver transplantation: size or quality? Hepatology. 2010;52:715–729.CrossRefGoogle Scholar
  2. 2.
    Rahbari NN, Garden OJ, Padbury R, et al. Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery. 2011;149:713–724.CrossRefGoogle Scholar
  3. 3.
    Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg. 2012;255:405–414.CrossRefGoogle Scholar
  4. 4.
    Makuuchi M, Takayasu K, Takuma T, et al. Preoperative transcatheter embolization of the portal venous branch for patients receiving extended lobectomy due to the bile duct carcinoma. J Jpn Pract Surg Soc. 1984;45:1558–1564.Google Scholar
  5. 5.
    Budai A, Fulop A, Hahn O, et al. Animal models for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): achievements and future perspectives. Eur Surg Res. 2017;58:140–157.CrossRefGoogle Scholar
  6. 6.
    Bellentani S. The epidemiology of non-alcoholic fatty liver disease. Liver Int. 2017;37:81–84.CrossRefGoogle Scholar
  7. 7.
    Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol. 2012;56:1384–1391.CrossRefGoogle Scholar
  8. 8.
    White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10:1342–1359.CrossRefGoogle Scholar
  9. 9.
    Picard C, Lambotte L, Starkel P, et al. Steatosis is not sufficient to cause an impaired regenerative response after partial hepatectomy in rats. J Hepatol. 2002;36:645–652.CrossRefGoogle Scholar
  10. 10.
    Rao MS, Papreddy K, Abecassis M, Hashimoto T. Regeneration of liver with marked fatty change following partial hepatectomy in rats. Dig Dis Sci. 2001;46:1821–1826. Scholar
  11. 11.
    Garnol T, Kucera O, Stankova P, Lotkova H, Cervinkova Z. Does simple steatosis affect liver regeneration after partial hepatectomy in rats? Acta Med (Hradec Kralove). 2016;59:35–42.CrossRefGoogle Scholar
  12. 12.
    Yamauchi H, Uetsuka K, Okada T, Nakayama H, Doi K. Impaired liver regeneration after partial hepatectomy in db/db mice. Exp Toxicol Pathol. 2003;54:281–286.CrossRefGoogle Scholar
  13. 13.
    DeAngelis RA, Markiewski MM, Taub R, Lambris JD. A high-fat diet impairs liver regeneration in C57BL/6 mice through overexpression of the NF-kappaB inhibitor, IkappaBalpha. Hepatology. 2005;42:1148–1157.CrossRefGoogle Scholar
  14. 14.
    Murata H, Yagi T, Iwagaki H, et al. Mechanism of impaired regeneration of fatty liver in mouse partial hepatectomy model. J Gastroenterol Hepatol. 2007;22:2173–2180.CrossRefGoogle Scholar
  15. 15.
    Veteläinen RVVAV. Severe steatosis increases hepatocellular injury and impairs liver regeneration in a rat model of partial hepatectomy. Ann Surg. 2007;1:44–50.CrossRefGoogle Scholar
  16. 16.
    Hamano M, Ezaki H, Kiso S, et al. Lipid overloading during liver regeneration causes delayed hepatocyte DNA replication by increasing ER stress in mice with simple hepatic steatosis. J Gastroenterol. 2014;49:305–316.CrossRefGoogle Scholar
  17. 17.
    Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37:1202–1219.CrossRefGoogle Scholar
  18. 18.
    Schlegel A, Lesurtel M, Melloul E, et al. ALPPS: from human to mice highlighting accelerated and novel mechanisms of liver regeneration. Ann Surg. 2014;260:839–847.CrossRefGoogle Scholar
  19. 19.
    Yao L, Li C, Ge X, et al. Establishment of a rat model of portal vein ligation combined with in situ splitting. Plos One. 2014;9:e105511.CrossRefGoogle Scholar
  20. 20.
    Shi H, Yang G, Zheng T, et al. A preliminary study of ALPPS procedure in a rat model. Sci Rep. 2015;5:17567.CrossRefGoogle Scholar
  21. 21.
    Wei W, Zhang T, Zafarnia S, et al. Establishment of a rat model: associating liver partition with portal vein ligation for staged hepatectomy. Surgery. 2016;159:1299–1307.CrossRefGoogle Scholar
  22. 22.
    García-Pérez R, Revilla-Nuin B, Martínez CM, et al. Associated liver partition and portal vein ligation (ALPPS) versus selective portal vein ligation (PVL) for staged hepatectomy in a rat model Similar regenerative response? PLoS One. 2015;10:e144096.CrossRefGoogle Scholar
  23. 23.
    Almau TH, Moulin LE, Padin JM, Stringa P, Gondolesi GE, Barros SP. Development of an experimental model of portal vein ligation associated with parenchymal transection (ALPPS) in rats. Cir Esp. 2014;92:676–681.CrossRefGoogle Scholar
  24. 24.
    Dhar DK, Mohammad GH, Vyas S, et al. A novel rat model of liver regeneration: possible role of cytokine induced neutrophil chemoattractant-1 in augmented liver regeneration. Ann Surg Innov Res. 2015;9:11.CrossRefGoogle Scholar
  25. 25.
    Michalopoulos GK. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol. 2010;176:2–13.CrossRefGoogle Scholar
  26. 26.
    Moris D, Vernadakis S, Papalampros A, et al. Mechanistic insights of rapid liver regeneration after associating liver partition and portal vein ligation for stage hepatectomy. World J Gastroenterol. 2016;22:7613–7624.CrossRefGoogle Scholar
  27. 27.
    Nishiyama K, Nakashima H, Ikarashi M, et al. Mouse CD11b+ Kupffer cells recruited from bone marrow accelerate liver regeneration after partial hepatectomy. Plos One. 2015;10:e136774.Google Scholar
  28. 28.
    Shiratori Y, Hongo S, Hikiba Y, et al. Role of macrophages in regeneration of liver. Dig Dis Sci. 1996;41:1939–1946. Scholar
  29. 29.
    Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology. 2006;43:S45–S53.CrossRefGoogle Scholar
  30. 30.
    Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274:1379–1383.CrossRefGoogle Scholar
  31. 31.
    Aldeguer X, Debonera F, Shaked A, et al. Interleukin-6 from intrahepatic cells of bone marrow origin is required for normal murine liver regeneration. Hepatology. 2002;35:40–48.CrossRefGoogle Scholar
  32. 32.
    Wang J, Kubes P. A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell. 2016;165:668–678.CrossRefGoogle Scholar
  33. 33.
    Hsiao IT, Lin KJ, Chang SI, Yen TC, Chen TC, Yeh TS. Impaired liver regeneration of steatotic rats after portal vein ligation: a particular emphasis on (99 m)Tc-DISIDA scintigraphy and adiponectin signaling. J Hepatol. 2010;52:540–549.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Hepatopancreatobiliary Surgery of Second Hospital of Jilin University, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary MedicineJilin UniversityChangchunChina
  2. 2.Key Lab for New Drugs Research of TCM in ShenzhenResearch Institute of Tsinghua University in ShenzhenShenzhenChina

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