title: Targeting the Enterohepatic Bile Acid Signaling Induces Hepatic Autophagy via a CYP7A1-AKT-mTOR Axis in Mice.
abstract: OBJECTIVE
  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 7α-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.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Jibiao
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Hemantkumar
authors.initials: H
authors.lastname: Chavan
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: David
authors.initials: D
authors.lastname: Matye
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Ni
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio.
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chiang
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Partha
authors.initials: P
authors.lastname: Krishnamurthy
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Ding
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Tiangang
authors.initials: T
authors.lastname: Li
keywords: 4EBP-1, eukaryotic translation initiation factor 4E-binding protein 1; ACAT, acyl-CoA:cholesterol acyltransferase; CE, cholesterol ester; CQ, chloroquine; CYP7A1, cholesterol 7α-hydroxylase; ChTM, cholestyramine; Cholesterol; Cholestyramine; DIO, diet-induced obesity; ER, endoplasmic reticulum; FC, free cholesterol; Fatty Liver; GSK3β, glycogen synthase kinase 3β; HMGCR, HMG-CoA reductase; LC3, microtubule-associated protein 1A/1B-light chain 3; LDLR, low-density lipoprotein receptor; LMP, lysosome membrane permeabilization; Nuclear Receptor; PI, phosphatidylinositol; PM, plasma membrane; S6, tibosomal protein S6; SREBP, sterol response element binding protein; mRNA, messenger RNA; mTOR, the nutrient sensing mechanistic target of rapamycin