The involvement of endoplasmic reticulum stress in bile acid-induced hepatocellular injury

被引:50
作者
Adachi, Tetsuo [1 ]
Kaminaga, Tomoyuki [1 ]
Yasuda, Hiroyuki [1 ]
Kamiya, Tetsuro [1 ]
Hara, Hirokazu [1 ]
机构
[1] Gifu Pharmaceut Univ, Lab Clin Pharmaceut, Gifu 5011196, Japan
基金
日本学术振兴会;
关键词
bile acid; endoplasmic reticulum stress; apoptosis; transforming growth factor-beta; hydrophobicity; VASCULAR ENDOTHELIAL-CELLS; NITRIC-OXIDE PRODUCTION; ER STRESS; OXIDATIVE STRESS; COBALT CHLORIDE; LIVER FIBROSIS; APOPTOSIS; DISEASES; DEATH; CHOLESTASIS;
D O I
10.3164/jcbn.13-46
中图分类号
R15 [营养卫生、食品卫生]; TS201 [基础科学];
学科分类号
100403 ;
摘要
Secondary bile acids produced by enteric bacteria accumulate to high levels in the enterohepatic circulation and may contribute to the pathogenesis of hepatocellular injury. Relative hydrophobicity has been suggested to be an important determinant of the biological properties of these compounds, although the mechanism by which bile acids induce pathogenesis is not fully understood. On the other hand, endoplasmic reticulum stress has been shown to be involved in the induction and development of various pathogenic conditions. In this report, we demonstrated that the intensities of cytotoxicity and endoplasmic reticulum stress in HepG2 cells triggered by the bile acids tested were largely dependent on their hydrophobicity. The activation of caspase-3 and DNA fragmentation by treatment with chenodeoxycholic acid showed the contribution of apoptosis to cytotoxicity. Increases in intracellular calcium levels and the generation of reactive oxygen species stimulated by treatment with chenodeoxycholic acid contributed to endoplasmic reticulum stress. Bile acids also induced transforming growth factor-beta, a potent profibrogenic factor, which is known to induce hepatocyte apoptosis and ultimately liver fibrosis. In conclusion, our study demonstrated that bile acids induced endoplasmic reticulum stress, which in turn stimulated apoptosis in HepG2 cells, in a hydrophobicity-dependent manner.
引用
收藏
页码:129 / 135
页数:7
相关论文
共 34 条
  • [21] Bile Acid-Induced Elevated Oxidative Stress in the Absence of Farnesoid X Receptor
    Nomoto, Masahiro
    Miyata, Masaaki
    Yin, Shanai
    Kurata, Yasushi
    Shimada, Miki
    Yoshinari, Kouichi
    Gonzalez, Frank J.
    Suzuki, Kokichi
    Shibasaki, Shigeki
    Kurosawa, Tohru
    Yamazoe, Yasushi
    [J]. BIOLOGICAL & PHARMACEUTICAL BULLETIN, 2009, 32 (02) : 172 - 178
  • [22] TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death
    Ohoka, N
    Yoshii, S
    Hattori, T
    Onozaki, K
    Hayashi, H
    [J]. EMBO JOURNAL, 2005, 24 (06) : 1243 - 1255
  • [23] NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells
    Pedruzzi, E
    Guichard, C
    Ollivier, W
    Driss, F
    Fay, M
    Prunet, C
    Marie, JC
    Pouzet, C
    Samadi, M
    Elbim, C
    O'Dowd, Y
    Bens, M
    Vandewalle, A
    Gougerot-Pocidalo, MA
    Lizard, G
    Ogier-Denis, E
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (24) : 10703 - 10717
  • [24] Bile-acid-induced cell injury and protection
    Perez, Maria J.
    Briz, Oscar
    [J]. WORLD JOURNAL OF GASTROENTEROLOGY, 2009, 15 (14) : 1677 - 1689
  • [25] Bile acid hydrophobicity is correlated with induction of apoptosis and/or growth arrest in HCT116 cells
    Powell, AA
    LaRue, JM
    Batta, AK
    Martinez, JD
    [J]. BIOCHEMICAL JOURNAL, 2001, 356 (02) : 481 - 486
  • [26] Portal tract fibrogenesis in the liver
    Ramadori, G
    Saile, B
    [J]. LABORATORY INVESTIGATION, 2004, 84 (02) : 153 - 159
  • [27] Bile salt biotransformations by human intestinal bacteria
    Ridlon, JM
    Kang, DJ
    Hylemon, PB
    [J]. JOURNAL OF LIPID RESEARCH, 2006, 47 (02) : 241 - 259
  • [28] PROTECTION AGAINST HYDROPHOBIC BILE SALT-INDUCED CELL-MEMBRANE DAMAGE BY LIPOSOMES AND HYDROPHILIC BILE-SALTS
    SAGAWA, H
    TAZUMA, S
    KAJIYAMA, G
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1993, 264 (05): : G835 - G839
  • [29] Bile acid toxicity structure-activity relationships: Correlations between cell viability and lipophilicity in a panel of new and known bile acids using an oesophageal cell line (HET-1A)
    Sharma, Ruchika
    Majer, Ferenc
    Peta, Vijaya Kumar
    Wang, Jun
    Keaveney, Ray
    Kelleher, Dermot
    Long, Aideen
    Gilmer, John F.
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2010, 18 (18) : 6886 - 6895
  • [30] CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury
    Tamaki, Nobuyuki
    Hatano, Etsuro
    Taura, Kojiro
    Tada, Masaharu
    Kodama, Yuzo
    Nitta, Takashi
    Iwaisako, Keiko
    Seo, Satoru
    Nakajima, Akio
    Ikai, Iwao
    Uemoto, Shinji
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2008, 294 (02): : G498 - G505