Suppression of Autophagic Flux by Bile Acids in Hepatocytes

Manley, Sharon; Ni, Hong-Min; Kong, Bo; Apte, Udayan; Guo, Grace; Ding, Wen-Xing
February 2014
Toxicological Sciences;Feb2014, Vol. 137 Issue 2, p478
Academic Journal
Retention of bile acids (BAs) in the liver during cholestasis plays an important role in the development of cholestatic liver injury. Several studies have reported that high concentrations of certain BAs induce cell death and inflammatory response in the liver, and BAs may promote liver tumorigenesis. Macroautophagy (hereafter referred to as autophagy) is a lysosomal degradation process that regulates organelle and protein homeostasis and serves as a cell survival mechanism under a variety of stress conditions. However, it is not known if BAs modulate autophagy in hepatocytes. In the present study, we determined autophagic flux in livers of farnesoid X receptor (FXR) knockout (KO) mice that have increased concentrations of hepatic BAs and in primary cultured mouse hepatocytes treated with BAs. The results showed that autophagic flux was impaired in livers of FXR KO mice and in BA-treated primary mouse hepatocytes. Mechanistically, BAs did not affect the activities of cathepsin or the proteasome, but impaired autophagosomal-lysosomal fusion likely due to reduction of Rab7 protein expression and targeting to autophagosomes. In conclusion, BAs suppress autophagic flux in hepatocytes by impairing autophagosomal-lysosomal fusion, which may be implicated in bile acid-induced liver tumor promotion observed in FXR KO mice.


Related Articles

  • p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 gene. He, Z; Liu, H; Agostini, M; Yousefi, S; Perren, A; Tschan, M P; Mak, T W; Melino, G; Simon, H U // Cell Death & Differentiation;Oct2013, Vol. 20 Issue 10, p1415 

    p73, a member of the p53 tumor suppressor family, is involved in neurogenesis, sensory pathways, immunity, inflammation, and tumorigenesis. How p73 is able to participate in such a broad spectrum of different biological processes is still largely unknown. Here, we report a novel role of p73 in...

  • TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. Sayaka Inokuchi-Shimizu; Eek Joong Park; Yoon Seok Roh; Ling Yang; Bi Zhang; Jingyi Song; Shuang Liang; Pimienta, Michael; Koji Taniguchi; Xuefeng Wu; Asahina, Kinji; Lagakos, William; Mackey, Mason R.; Shizuo Akira; Ellisman, Mark H.; Sears, Dorothy D.; Olefsky, Jerrold M.; Karin, Michael; Brenner, David A.; Ekihiro Seki // Journal of Clinical Investigation;Aug2014, Vol. 124 Issue 8, p3566 

    The MAP kinase kinase kinase TGFβ-activated kinase 1 (TAK1) is activated by TLRs, IL-1, TNF, and TGFβ and in turn activates IKK-NF-kB and JNK, which regulate cell survival, growth, tumorigenesis, and metabolism. TAK1 signaling also upregulates AMPK activity and autophagy. Here, we...

  • Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis. Cazanave, S C; Wang, X; Zhou, H; Rahmani, M; Grant, S; Durrant, D E; Klaassen, C D; Yamamoto, M; Sanyal, A J // Cell Death & Differentiation;Aug2014, Vol. 21 Issue 8, p1303 

    Non-alcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA) and hepatocyte lipoapoptosis. This lipoapoptosis requires increased JNK phosphorylation and activation of the pro-apoptotic BH3-only proteins Bim and PUMA. Kelch-like...

  • Eupatilin attenuates bile acid-induced hepatocyte apoptosis. Park, Su Cheol; Yoon, Jung-Hwan; Kim, Won; Gwak, Geum-Youn; Kim, Kang Mo; Lee, Sung-Hee; Lee, Soo-Mi; Lee, Hyo-Suk // Journal of Gastroenterology;Aug2006, Vol. 41 Issue 8, p772 

    In cases of cholestasis, bile acids induce hepatocyte apoptosis by activating death receptor-mediated apoptotic signaling cascades. Eupatilin (5,7-dihydroxy-3,4,6-trimethoxyflavone) is a pharmacologically active ingredient found in Artemisia asiatica and exhibits cytoprotective effects against...

  • Bile Acids Affect Liver Mitochondrial Bioenergetics: Possible Relevance for Cholestasis Therapy. Rolo, Anabela P.; Oliveira, Paulo J.; Moreno, António J. M.; Palmeira, Carlos M. // Toxicological Sciences;Sep2000, Vol. 57 Issue 1, p177 

    It has been pointed out that intracellular accumulation of bile acids cause hepatocyte injury in cholestatic disease process. This study was aimed to test if cytotoxicity of these compounds is mediated through mitochondria dysfunction. Bile acids effects on isolated rat liver mitochondrial were...

  • IFNg-induced Irgm1 promotes tumorigenesis of melanoma via dual regulation of apoptosis and Bif-1-dependent autophagy. Dong, H; Tian, L; Li, R; Pei, C; Fu, Y; Dong, X; Xia, F; Wang, C; Li, W; Guo, X; Gu, C; Li, B; Liu, A; Ren, H; Xu, H // Oncogene;10/15/2015, Vol. 34 Issue 42, p5363 

    Interferon gamma (IFNg) has been known as the regulator for both tumor immune surveillance and tumorgenesis. However, mechanisms underlying the resistance of tumor cell to IFNg have yet been fully understood. In the current study, we showed that immunity-related GTPase family member 1 (mouse:...

  • Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex. McKnight, Nicole C.; Zhong, Yun; Wold, Mitchell S.; Gong, Shiaoching; Phillips, Greg R.; Dou, Zhixun; Zhao, Yanxiang; Heintz, Nathaniel; Zong, Wei-Xing; Yue, Zhenyu // PLoS Genetics;Oct2014, Vol. 10 Issue 10, p1 

    Deficiency of autophagy protein beclin 1 is implicated in tumorigenesis and neurodegenerative diseases, but the molecular mechanism remains elusive. Previous studies showed that Beclin 1 coordinates the assembly of multiple VPS34 complexes whose distinct phosphatidylinositol 3-kinase III...

  • Autophagic cell death RIPs into tumors. Oberst, A // Cell Death & Differentiation;Sep2013, Vol. 20 Issue 9, p1131 

    An introduction to the journal is presented in which the editor discusses the autophagy-driven cell death mediated by interaction.

  • Sepsis induces extensive autophagic vacuolization in hepatocytes: a clinical and laboratory-based study. Watanabe, Eizo; Muenzer, Jared T.; Hawkins, William G.; Davis, Christopher G.; Dixon, David J.; McDunn, Jonathan E; Brackett, Daniel J.; Lerner, Megan R.; Swanson, Paul E.; Hotchkiss, Richard S. // Laboratory Investigation (00236837);May2009, Vol. 89 Issue 5, p549 

    Autophagy is the regulated process cells use to recycle nonessential, redundant, or inefficient components and is an adaptive response during times of stress. In addition to its function in enabling the cell to gain vital nutrients in times of stress, autophagy can also be involved in...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics