Premium
Modulation of autophagy by bile acids in hepatocytes and liver
Author(s) -
Manley Sharon Jessica,
Guo Grace,
Apte Udayan,
Ding Wen-Xing
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.396.4
Subject(s) - autophagy , farnesoid x receptor , microbiology and biotechnology , flux (metallurgy) , chemistry , carcinogenesis , organelle , homeostasis , biochemistry , biology , nuclear receptor , apoptosis , gene , transcription factor , organic chemistry
Autophagy is a lysosomal degradation process that regulates the homeostasis of organelles and proteins in cells. Mice with liver‐specific loss of autophagy develop spontaneous liver tumors possibly caused by p62 protein accumulation. Farnesoid X receptor (FXR) −/− mice exhibit higher hepatic bile acids (BAs) levels and develop spontaneous liver tumors. However, the mechanisms by which BAs promote liver tumors are not known. From the finding that FXR−/− mice have increased hepatic p62 proteins compared to wild type mice, which suggests that FXR−/− mice may have decreased liver autophagy, we hypothesized that BAs modulate autophagy and promote liver tumorigenesis. Using a series of autophagic flux assays, we found that hydrophobic and hydrophilic BAs differentially regulate autophagy, where hydrophobic BAs increase while hydrophilic BAs decrease autophagic flux in primary mouse hepatocytes. Interestingly, both hydrophobic and hydrophilic BAs increase p62 protein levels without significant changes to p62 mRNA expression. These results suggest that BAs‐induced accumulation of hepatic p62 proteins could be mediated by their differential modulation on autophagy, and current experiments are being conducted to determine these mechanisms. In conclusion, we found that hydrophobic and hydrophilic BAs differentially modulate autophagy, leading to the accumulation of p62 and LC3‐II proteins in hepatocytes.