Dysregulated Autophagy in Hepatocytes Promotes Bisphenol A-Induced Hepatic Lipid Accumulation in Male Mice.
Accumulating evidence suggests that bisphenol A (BPA) exposure is associated with nonalcoholic fatty liver disease. Disruption of autophagy causes lipid accumulation in hepatocytes. Whether and how BPA regulates autophagy remains to be explored. We investigated the effect of BPA on autophagy in hepatocytes and examined the influence of BPA-regulated autophagy on hepatic lipid accumulation. Male CD1 mice were treated with BPA for 8 weeks, followed by histological and biochemical evaluation of liver lipids and autophagy. Also, the effects of BPA on autophagy and hepatic lipid accumulation were examined in primary hepatocytes and HepG2 cells. Lipid content in HepG2 cells and/or primary hepatocytes was increased obviously after BPA exposure. In addition, BPA exposure caused accumulation of autophagosomes in HepG2 cells and enhanced colocalization of Bodipy 493/503 with microtubule associated protein light-chain 3. These changes were accompanied with increased expression levels of p-mammalian target of rapamycin, p-p70S6 kinase, p-ULK1 and decreased expression levels of Atg5. BPA exposure also downregulated the expression of cathepsin L and decreased cytoplasmic retention of acridine orange in HepG2 cells. The impaired autophagic degradation was further evidenced by increased levels of p62 in BPA-treated HepG2 cells. At the whole animal level, BPA treatment induced lipid accumulation in livers of male CD1 mice, which was accompanied with changes in hepatic autophagy-related proteins. Moreover, induction of autophagy by Torin1 protected against BPA-induced lipid accumulation whereas suppression of autophagy by chloroquine exacerbated BPA-induced lipid accumulation in HepG2 cells. BPA dysregulates autophagy in hepatocytes, which is linked to BPA-induced hepatic lipid accumulation.
Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Shumin
S
Yang
Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Aipin
A
Zhang
Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.|Department of Endocrinology, the First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China.
Ting
T
Li
Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.|School of Public Health and Management, Chongqing Medical University, Chongqing 400016, China.
Rufei
R
Gao
Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.|Laboratory of Lipids and Glucose Metabolism, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Chuan
C
Peng
Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Lulu
L
Liu
Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Qingfeng
Q
Cheng
Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Mei
M
Mei
Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Ying
Y
Song
Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Xiaojiao
X
Xiang
Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843.
Chaodong
C
Wu
Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.|Laboratory of Lipids and Glucose Metabolism, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Xiaoqiu
X
Xiao
Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Qifu
Q
Li
D000818:Animals; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects