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−/B48) 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−/B48 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−/B48 lipoproteins in ApoE−/− mice; however, heterozygous ATM mutation did not affect hepatocyte binding to E−/B48 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−/B48 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−/B48 lipoprotein in ApoE−/− mice, demonstrating the role of class III PI3K protein.

Multifaceted roles of ATM in autophagy: From nonselective autophagy to selective autophagy

“…[2][3][4][5][6] ATM autophosphorylates Ser 1981, resulting in the dissociation of its inactivate dimer and the formation of an active monomer, 7 which coordinates the activation of cell cycle checkpoints and DDR and further maintains gene stability. 9,12,13 In the cytoplasm, however, ATM was shown to be located in peroxisomes, mitochondria, and endosomes, [14][15][16][17][18][19] and it participates in regulating oxidative stress, cell metabolism, and autophagy. The nuclear function of ATM is tightly associated with DNA damage, such as DDR and cell cycle checkpoints, through the ATM-Chk2 and ATM-ATR-Chk1 pathways, 11 as well as the MRN (Mre11-Rad590-Nb1) complex and MDC1.…”

“…The nuclear function of ATM is tightly associated with DNA damage, such as DDR and cell cycle checkpoints, through the ATM-Chk2 and ATM-ATR-Chk1 pathways, 11 as well as the MRN (Mre11-Rad590-Nb1) complex and MDC1. 9,12,13 In the cytoplasm, however, ATM was shown to be located in peroxisomes, mitochondria, and endosomes, [14][15][16][17][18][19] and it participates in regulating oxidative stress, cell metabolism, and autophagy. 20,21 PACS-2 is required for the IR-induced cytoplasmic localization of nuclear ATM.…”

Overexpression of the key metabolic protein CPT1A defines mantle cell lymphoma patients with poor response to standard high-dose chemotherapy independent of MIPI and complement established highrisk factors

“…Of interest, individuals with germline mutations in the AT M gene are known to have increased plasma cholesterol and triglyceride levels, and AT M has been demonstrated to facilitate clearance of apolipoproteins in plasma. 49 Thus, AT M mutations may contribute to altered lipid metabolism and steroid biosynthesis.…”

Weighted gene coexpression network analysis identifies specific transcriptional modules and hub genes related to intramuscular fat traits in chicken breast muscle

“…The CACTIN , EGFR , ERBB2 , CYR61 , and TNFRSF1B genes are also thought to be associated with cell proliferation, differentiation, and apoptosis . On the regulation of the cell cycle, the protein encoded by the ATM gene is an important cell cycle checkpoint kinase and is thought to be a master controller in cell cycle checkpoint signaling pathways . The RB1 gene is a negative regulator of the cell cycle and is able to promote adipogenesis .…”

“…[31][32][33] On the regulation of the cell cycle, the protein encoded by the ATM gene is an important cell cycle checkpoint kinase and is thought to be a master controller in cell cycle checkpoint signaling pathways. 34 The RB1 gene is a negative regulator of the cell cycle and is able to promote adipogenesis. 35,36 These results suggest that IMF deposition is mainly linked to the regulation of various adipocyte events, such as cell proliferation, differentiation, apoptosis, and cell cycle in chicken.…”