Sequestosome 1/p62 Protein Is Associated with Autophagic Removal of Excess Hepatic Endoplasmic Reticulum in Mice.
Xenobiotics exposure increases endoplasmic reticulum (ER) proliferation and cytochrome P-450 (CYP) induction to sustain metabolic requirements. Whether autophagy is essential for the removal of excess ER and CYP and whether an autophagy receptor is involved in this process in mammals remains elusive. In this study, we show that autophagy is induced in mouse livers after withdrawal of the hepatic mitogen 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP). Although isolated autophagosomes, autolysosomes, and lysosomes from mouse livers after withdrawal of TCPOBOP contained ER proteins, those in control mouse livers did not. Liver-specific Atg5 knockout mice had higher basal hepatic ER content that was further increased and sustained after withdrawal of TCPOBOP compared with wild-type mice. In addition to regulating ER degradation, our results also suggest that autophagy plays a role in regulating the homeostasis of hepatic CYP because blocking autophagy led to increased CYP2B10 accumulation either at the basal level or following TCPOBOP withdrawal. Furthermore, we found that the autophagy receptor protein sequestosome 1 (SQSTM1)/p62 is associated with the ER. After withdrawal of TCPOBOP, p62 knockout mice had increased ER content in the liver compared with wild-type mice. These results suggest that p62 may act as an autophagy receptor for the autophagic removal of excess ER in the mouse liver. Taken together, our results indicate that autophagy is important for the removal of excess ER and hepatic CYP enzymes in mouse livers, a process associated with the autophagy receptor protein p62.
From the Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 20032, China, the Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160.
Hua
H
Yang
the Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160.
Hong-Min
HM
Ni
the Stowers Institute for Medical Research, Kansas City, Missouri 64110.
Fengli
F
Guo
the Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160.
Yifeng
Y
Ding
From the Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 20032, China.
Ying-Hong
YH
Shi
the Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria.
Pooja
P
Lahiri
the Department of Cranio-Maxillofacial Surgery, University of Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
Leopold F
LF
Fröhlich
the Institute of Laboratory Animal Science and Biomodels Austria, University of Veterinary Medicine, 1210 Vienna, Austria.
Thomas
T
Rülicke
the Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria.
Claudia
C
Smole
the Institute of Laboratory Animal Science and Biomodels Austria, University of Veterinary Medicine, 1210 Vienna, Austria.
Volker C
VC
Schmidt
the Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria.
Kurt
K
Zatloukal
the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98159, and.
Yue
Y
Cui
the Department of Biochemistry, School of Medicine, Niigata University, Chuo-ku, Niigata 951-8510, Japan.
Masaaki
M
Komatsu
From the Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 20032, China, fan.jia@zs-hospital.sh.cn.
Jia
J
Fan
the Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, wxding@kumc.edu.
Wen-Xing
WX
Ding
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000071187:Autophagy-Related Protein 5 / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2 / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D011725:Pyridines; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D000072467:Cytochrome P450 Family 2
autophagy; cytochrome P-450; endoplasmic reticulum (ER); liver; p62 (sequestosome 1 (SQSTM1))