Reduced triglyceride accumulation due to overactivation of farnesoid X receptor signaling contributes to impaired liver regeneration following 50% hepatectomy in extra‑cholestatic liver tissue

Jia,Wen‑Jun; Sun,Shi‑Quan; Huang,Luo‑Shun; Tang,Qiao‑Li; Qiu,Yu‑Dong; Mao,Liang

doi:10.3892/mmr.2017.8025

Reduced triglyceride accumulation due to overactivation of farnesoid X receptor signaling contributes to impaired liver regeneration following 50% hepatectomy in extra‑cholestatic liver tissue

Authors:
- Wen‑Jun Jia
- Shi‑Quan Sun
- Luo‑Shun Huang
- Qiao‑Li Tang
- Yu‑Dong Qiu
- Liang Mao
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Affiliations: Department of Hepatopancreatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China, Ministry of Education Key Laboratory of Model Animal for Disease Study, School of Medicine and Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210093, P.R. China
Published online on: November 10, 2017 https://doi.org/10.3892/mmr.2017.8025
Pages: 1545-1554
Copyright: © Jia et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to investigate the role of triglyceride metabolism in the effect of obstructive cholestasis on liver regeneration following 50% partial hepatectomy (PH). Obstructive cholestatic rat models were achieved via ligation of the common bile duct (BDL). Following comparisons between hepatic pathological alterations with patients with perihilar cholangiocarcinoma, rats in the 7 day post‑BDL group were selected as the BDL model for subsequent experiments. Liver weight restoration, proliferating cell nuclear antigen labeling index, cytokine and growth factor expression levels, and hepatic triglyceride content were evaluated to analyze liver regeneration post‑PH within BDL and control group rats. The results of the present study revealed that obstructive cholestasis impaired liver mass restoration, which occurred via inhibition of early stage hepatocyte proliferation. In addition, reduced triglyceride content and inhibited expression of fatty acid β‑oxidation‑associated genes, peroxisome proliferator activated receptor α and carnitine palmitoyltransferase, were associated with an insufficient energy supply within the BDL group post‑PH. Notably, the expression levels of fatty acid synthesis‑associated genes, including sterol‑regulatory element‑binding protein‑1c, acetyl‑coA carboxylase 1 and fatty acid synthase were also reduced within the BDL group, which accounted for the reduced triglyceride content and fatty acid utilization. Further investigation revealed that overactivated farnesoid X receptor (FXR) signaling may inhibit fatty acid synthesis within BDL group rats. Collectively, the role of triglycerides in liver regeneration following PH in extra‑cholestatic livers was identified in the present study. Additionally, the results indicated that overactivated FXR signaling‑induced triglyceride reduction is associated with insufficient energy supply and therefore contributes to the extent of impairment of liver regeneration following PH within extra‑cholestatic livers.

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1	Nagino M, Ebata T, Yokoyama Y, Igami T, Sugawara G, Takahashi Y and Nimura Y: Evolution of surgical treatment for perihilar cholangiocarcinoma: A single-center 34-year review of 574 consecutive resections. Ann Surg. 258:129–140. 2013. View Article : Google Scholar
2	DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, Choti MA, Yeo CJ and Schulick RD: Cholangiocarcinoma-Thirty-one-year experience with 564 patients at a single institution. Ann Surg. 245:755–762. 2007. View Article : Google Scholar :
3	Zhang Y, Hong JY, Rockwell CE, Copple BL, Jaeschke H and Klaassen CD: Effect of bile duct ligation on bile acid composition in mouse serum and liver. Liver Int. 32:58–69. 2012. View Article : Google Scholar
4	Marin JJ, Macias RI, Briz O, Banales JM and Monte MJ: Bile acids in physiology, pathology and pharmacology. Curr Drug Metab. 17:4–29. 2015. View Article : Google Scholar
5	Kennedy TJ, Yopp A, Qin Y, Zhao B, Guo P, Liu F, Schwartz LH, Allen P, D'Angelica M, Fong Y, et al: Role of preoperative biliary drainage of liver remnant prior to extended liver resection for hilar cholangiocarcinoma. HPB (Oxford). 11:445–451. 2009. View Article : Google Scholar :
6	Yokoyama Y, Nagino M and Nimura Y: Mechanism of impaired hepatic regeneration in cholestatic liver. J Hepatobiliary Pancreat Surg. 14:159–166. 2007. View Article : Google Scholar
7	Xiong JJ, Nunes QM, Huang W, Pathak S, Wei AL, Tan CL and Liu XB: Preoperative biliary drainage in patients with hilar cholangiocarcinoma undergoing major hepatectomy. World J Gastroenterol. 19:8731–8739. 2013. View Article : Google Scholar :
8	Iacono C, Ruzzenente A, Campagnaro T, Bortolasi L, Valdegamberi A and Guglielmi A: Role of preoperative biliary drainage in jaundiced patients who are candidates for pancreatoduodenectomy or hepatic resection: Highlights and drawbacks. Ann Surg. 257:191–204. 2013. View Article : Google Scholar
9	Maguchi H, Takahashi K, Katanuma A, Osanai M, Nakahara K, Matuzaki S, Urata T and Iwano H: Preoperative biliary drainage for hilar cholangiocarcinoma. J Hepatobiliary Pancreat Surg. 14:441–446. 2007. View Article : Google Scholar
10	Takahashi Y, Nagino M, Nishio H, Ebata T, Igami T and Nimura Y: Percutaneous transhepatic biliary drainage catheter tract recurrence in cholangiocarcinoma. Br J Surg. 97:1860–1866. 2010. View Article : Google Scholar
11	Liu F, Li Y, Wei Y and Li B: Preoperative biliary drainage before resection for hilar cholangiocarcinoma: Whether or not? A systematic review. Dig Dis Sci. 56:663–672. 2011. View Article : Google Scholar
12	Bird MA, Lange PA, Schrum LW, Grisham JW, Rippe RA and Behrns KE: Cholestasis induces murine hepatocyte apoptosis and DNA synthesis with preservation of the immediate-early gene response. Surgery. 131:556–563. 2002. View Article : Google Scholar
13	Tracy TF Jr, Bailey PV, Goerke ME, Sotelo-Avila C and Weber TR: Cholestasis without cirrhosis alters regulatory liver gene expression and inhibits hepatic regeneration. Surgery. 110:176–783. 1991.
14	Foss A, Andersson R, Ding JW, Hochbergs P, Paulsen JE, Bengmark S and Ahrén B: Effect of bile obstruction on liver regeneration following major hepatectomy: an experimental study in the rat. Eur Surg Res. 27:127–133. 1995. View Article : Google Scholar
15	Makino H, Shimizu H, Ito H, Kimura F, Ambiru S, Togawa A, Ohtsuka M, Yoshidome H, Kato A, Yoshitomi H, et al: Changes in growth factor and cytokine expression in biliary obstructed rat liver and their relationship with delayed liver regeneration after partial hepatectomy. World J Gastroenterol. 12:2053–2059. 2006. View Article : Google Scholar :
16	García-Arcos I, González-Kother P, Aspichueta P, Rueda Y, Ochoa B and Fresnedo O: Lipid analysis reveals quiescent and regenerating liver-specific populations of lipid droplets. Lipids. 45:1101–1108. 2010. View Article : Google Scholar
17	Brasaemle DL: Cell biology. A metabolic push to proliferate. Science. 313:1581–1582. 2006. View Article : Google Scholar
18	Komura M, Chijiiwa K, Naito T, Kameoka N, Yamashita H, Yamaguchi K, Kuroki S and Tanaka M: Sequential changes of energy charge, lipoperoxide level, and DNA synthesis rate of the liver following biliary obstruction in rats. J Surg Res. 61:503–508. 1996. View Article : Google Scholar
19	Moustafa T, Fickert P, Magnes C, Guelly C, Thueringer A, Frank S, Kratky D, Sattler W, Reicher H, Sinner F, et al: Alterations in lipid metabolism mediate inflammation, fibrosis and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology. 142:140–151.e12. 2012. View Article : Google Scholar
20	Nagai K, Yagi S, Uemoto S and Tolba RH: Surgical procedures for a rat model of partial orthotopic liver transplantation with hepatic arterial reconstruction. J Vis Exp. e43762013.
21	Jia WJ, Jiang S, Tang QL, Shen D, Xue B, Ning W and Li CJ: Geranylgeranyl diphosphate synthase modulates fetal lung branching morphogenesis possibly through controlling K-Ras prenylation. Am J Pathol. 186:1454–1465. 2016. View Article : Google Scholar
22	Jiang S, Shen D, Jia WJ, Han X, Shen N, Tao W, Gao X, Xue B and Li CJ: GGPPS mediated Rab27A geranylgeranylation regulates beta-cell dysfunction during type 2 diabetes development via affecting insulin granule docked pool formation. J Pathol. 2015.
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
24	Chen WB, Lai SS, Yu DC, Liu J, Jiang S, Zhao DD, Ding YT, Li CJ and Xue B: GGPPS deficiency aggravates CCl4-induced liver injury by inducing hepatocyte apoptosis. FEBS Lett. 589:1119–1126. 2015. View Article : Google Scholar
25	Fausto N, Campbell JS and Riehle KJ: Liver regeneration. Hepatology. 43 2 Suppl 1:S45–S53. 2006. View Article : Google Scholar
26	Stedman C, Liddle C, Coulter S, Sonoda J, Alvarez JG, Evans RM and Downes M: Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Proc Natl Acad Sci USA. 103:11323–11328. 2006. View Article : Google Scholar :
27	Halilbasic E, Baghdasaryan A and Trauner M: Nuclear receptors as drug targets in cholestatic liver diseases. Clin Liver Dis. 17:161–189. 2013. View Article : Google Scholar :
28	Soares KC, Kamel I, Cosgrove DP, Herman JM and Pawlik TM: Hilar cholangiocarcinoma: Diagnosis, treatment options, and management. Hepatobiliary Surg Nutr. 3:18–34. 2014.
29	Paik WH, Loganathan N and Hwang JH: Preoperative biliary drainage in hilar cholangiocarcinoma: When and how? World J Gastrointest Endosc. 6:68–73. 2014. View Article : Google Scholar :
30	Farges O, Regimbeau JM, Fuks D, Le Treut YP, Cherqui D, Bachellier P, Mabrut JY, Adham M, Pruvot FR and Gigot JF: Multicentre European study of preoperative biliary drainage for hilar cholangiocarcinoma. Br J Surg. 100:274–283. 2013. View Article : Google Scholar
31	Yazgan Y, Oncu K, Kaplan M, Tanoglu A, Kucuk I, Dιnc M and Demιrturk L: Malignant biliary obstruction significantly increases serum lipid levels: A novel biochemical tumor marker? Hepatogastroenterology. 59:2079–2082. 2012.
32	Fuchs C, Claudel T and Trauner M: Bile acid-mediated control of liver triglycerides. Semin Liver Dis. 33:330–342. 2013. View Article : Google Scholar
33	Yan XP, Wang S, Yang Y and Qiu YD: Effects of n-3 polyunsaturated fatty acids on rat livers after partial hepatectomy via LKB1-AMPK signaling pathway. Transplant Proc. 43:3604–3612. 2011. View Article : Google Scholar