title: Potential role of ATM in hepatocyte endocytosis of ApoE-deficient, ApoB48-containing lipoprotein in ApoE-deficient mice.
abstract: Individuals carrying mutations at both ataxia telangiectasia mutated (ATM) gene alleles reportedly have increased plasma cholesterol and triglyceride levels. Previous studies have demonstrated that defective ATM function promotes atherosclerosis. We previously demonstrated that ATM facilitates the clearance of plasma apolipoprotein (Apo)E-deficient, ApoB48-containing (E(-)/B(48)) lipoproteins in ApoE-deficient mice (ApoE(-/-) mice). However, to date there is no exact explanation available as to the mechanism(s) through which ATM is involved in the removal of E(-)/B(48) lipoprotein in ApoE(-/-) mice. In this study, to our knowledge, we demonstrate for the first time that heterozygous ATM mutation reduces the hepatocyte uptake of E(-)/B(48) lipoproteins in ApoE(-/-) mice; however, heterozygous ATM mutation did not affect hepatocyte binding to E(-)/B(48) lipoproteins. Moreover, our results revealed that ATM proteins were localized in the nucleus, early endosomes and late endosomes, but not in the plasma membrane in the hepatocytes of ApoE(-/-) mice. In addition, following treatment with the ATM activator, chloroquine, and E(-)/B(48) lipoproteins, ATM interacted with class III phosphatidylinositol-3-kinases (PI3Ks) and the activated ATM protein enhanced class III PI3K activity. Furthermore, treatment with a class III PI3K inhibitor (LY290042 and 3-MA) attenuated the intracellular total cholesterol accumulation induced by ATM activation. These results provide insight into the mechanisms behind the involvment of ATM in the process of endocytosis of E(-)/B(48) lipoprotein in ApoE(-/-) mice, demonstrating the role of class III PI3K protein.
authors.affiliation: Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.
authors.forename: Juang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Biology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Osteology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.
authors.forename: San
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.
authors.forename: Shanrui
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.
authors.forename: Dongfang
authors.initials: D
authors.lastname: Wu
mesh_terms: D000483:Alleles; D000818:Animals; D053283:Apolipoprotein B-48 / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D002738:Chloroquine / Q000494:pharmacology; D004705:Endocytosis; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D053283:Apolipoprotein B-48; D001057:Apolipoproteins E; D002738:Chloroquine; D019869:Phosphatidylinositol 3-Kinases; D064007:Ataxia Telangiectasia Mutated Proteins