Excess endoplasmic reticulum is degraded by p62‐mediated selective autophagy in mammals (151.6)

Abstract

Liver is the most vital and dynamic organ, and is the major site for the metabolism and detoxification of xenobiotics. The cytochrome P450 enzymes (CYPs), which are synthesized and localized in the endoplasmic reticulum (ER), are the most important enzymes responsible for the drug metabolism in the liver. It is known that there is increased ER proliferation and induction of CYPs to meet the needs of metabolism in response to several xenobiotics. Whether autophagy is essential for the removal of excess ER following xenobiotic‐induced ER proliferation and induction of CYPs, and whether an autophagy receptor is involved in this selective process in mammals remains elusive. In the present study, using GFP‐LC3 transgenic and liver‐specific Atg5 knockout mice, we show that autophagy is essential for the removal of excess ER after treatment with the hepatic mitogen TCPOBOP (t1, 4‐bis [2‐(3, 5‐dichloropyridyloxy)] benzene). In addition to regulating ER degradation, our results also suggest that autophagy plays a role in regulating the homeostasis of hepatic CYPs. Furthermore, we also show that p62/SQSTM1, an autophagy receptor that has been shown to be involved in many selective types of autophagy, may act as an autophagy receptor for selective erphagy. Taken together, our results indicate that autophagy is essential for selective removal of excess ER and hepatic CYP enzymes in mouse livers.Grant Funding Source: Supported by NIAAA R01 AA020518; 5P20RR021940‐07; 8 P20 GM103549‐07