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Text
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URL Address
<a href="http://doi.org/10.1016/j.jcmgh.2016.10.002" target="_blank" rel="noreferrer noopener">http://doi.org/10.1016/j.jcmgh.2016.10.002</a>
Pages
245–260
Issue
2
Volume
3
Dublin Core
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Title
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Targeting the Enterohepatic Bile Acid Signaling Induces Hepatic Autophagy via a
Publisher
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Cellular and molecular gastroenterology and hepatology
Date
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2017
2017-03
Subject
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4EBP-1; ACAT; acyl-CoA:cholesterol acyltransferase; CE; chloroquine; Cholesterol; cholesterol 7alpha-hydroxylase; cholesterol ester; cholestyramine; Cholestyramine; ChTM; CQ; CYP7A1; diet-induced obesity; DIO; endoplasmic reticulum; ER; eukaryotic translation initiation factor 4E-binding protein 1; Fatty Liver; FC; free cholesterol; glycogen synthase kinase 3beta; GSK3beta; HMG-CoA reductase; HMGCR; LC3; LDLR; LMP; low-density lipoprotein receptor; lysosome membrane permeabilization; messenger RNA; microtubule-associated protein 1A/1B-light chain 3; mRNA; mTOR; Nuclear Receptor; phosphatidylinositol; PI; plasma membrane; PM; S6; SREBP; sterol response element binding protein; the nutrient sensing mechanistic target of rapamycin; tibosomal protein S6
Creator
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Wang Yifeng; Ding Yifeng; Li Jibiao; Chavan Hemantkumar; Matye David; Ni Hong-Min; Chiang John Y L; Krishnamurthy Partha; Ding Wen-Xing; Li Tiangang
Description
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BACKGROUND & AIMS: Hepatic cholesterol accumulation and autophagy defects contribute to hepatocyte injury in fatty liver disease. Bile acid synthesis is a major pathway for cholesterol catabolism in the liver. This study aims to understand the molecular link between cholesterol and bile acid metabolism and hepatic autophagy activity. METHODS: The effects of cholesterol and cholesterol 7alpha-hydroxylase (CYP7A1) expression on autophagy and lysosome function were studied in cell models. The effects and mechanism of disrupting enterohepatic bile acid circulation on hepatic autophagy were studied in mice. RESULTS: The results first showed differential regulation of hepatic autophagy by free cholesterol and cholesterol ester, whereby a modest increase of cellular free cholesterol, but not cholesterol ester, impaired lysosome function and caused marked autolysosome accumulation. We found that CYP7A1 induction, either by cholestyramine feeding in mice or adenovirus-mediated CYP7A1 expression in hepatocytes, caused strong autophagy induction. Mechanistically, we showed that CYP7A1 expression markedly attenuated growth factor/AKT signaling activation of mechanistic target of rapamycin (mTOR), but not amino acid signaling to mTOR in vitro and in vivo. Metabolomics analysis further found that CYP7A1 induction not only decreased hepatic cholesterol but also altered phospholipid and sphingolipid compositions. Collectively, these results suggest that CYP7A1 induction interferes with growth factor activation of AKT/mTOR signaling possibly by altering membrane lipid composition. Finally, we showed that cholestyramine feeding restored impaired hepatic autophagy and improved metabolic homeostasis in Western diet-fed mice. CONCLUSIONS: This study identified a novel CYP7A1-AKT-mTOR signaling axis that selectively induces hepatic autophagy, which helps improve hepatocellular integrity and metabolic homeostasis.
Identifier
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<a href="http://doi.org/10.1016/j.jcmgh.2016.10.002" target="_blank" rel="noreferrer noopener">10.1016/j.jcmgh.2016.10.002</a>
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Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
2017
4EBP-1
ACAT
acyl-CoA:cholesterol acyltransferase
CE
Cellular and molecular gastroenterology and hepatology
Chavan Hemantkumar
Chiang John Y L
chloroquine
Cholesterol
cholesterol 7alpha-hydroxylase
cholesterol ester
Cholestyramine
ChTM
CQ
CYP7A1
Department of Integrative Medical Sciences
diet-induced obesity
Ding Wen-Xing
Ding Yifeng
DIO
endoplasmic reticulum
ER
eukaryotic translation initiation factor 4E-binding protein 1
Fatty Liver
FC
free cholesterol
glycogen synthase kinase 3beta
GSK3beta
HMG-CoA reductase
HMGCR
Krishnamurthy Partha
LC3
LDLR
Li Jibiao
Li Tiangang
LMP
low-density lipoprotein receptor
lysosome membrane permeabilization
Matye David
messenger RNA
microtubule-associated protein 1A/1B-light chain 3
mRNA
mTOR
NEOMED College of Medicine
Ni Hong-Min
Nuclear Receptor
phosphatidylinositol
PI
plasma membrane
PM
S6
SREBP
sterol response element binding protein
the nutrient sensing mechanistic target of rapamycin
tibosomal protein S6
Wang Yifeng