Alan R Tall

Publications (101)1027.57 Total impact

• Article: Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis.

  Prabhakara R Nagareddy, Andrew J Murphy, Roslynn A Stirzaker, Yunying Hu, Shiquing Yu, Rachel G Miller, Bhama Ramkhelawon, Emilie Distel, Marit Westerterp, Li-Shin Huang, Ann Marie Schmidt, Trevor J Orchard, Edward A Fisher, Alan R Tall, Ira J Goldberg
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  ABSTRACT: Diabetes is a major risk factor for atherosclerosis. Although atherosclerosis is initiated by deposition of cholesterol-rich lipoproteins in the artery wall, the entry of inflammatory leukocytes into lesions fuels disease progression and impairs resolution. We show that diabetic mice have increased numbers of circulating neutrophils and Ly6-C(hi) monocytes, reflecting hyperglycemia-induced proliferation and expansion of bone marrow myeloid progenitors and release of monocytes into the circulation. Increased neutrophil production of S100A8/S100A9, and its subsequent interaction with the receptor for advanced glycation end products on common myeloid progenitor cells, leads to enhanced myelopoiesis. Treatment of hyperglycemia reduces monocytosis, entry of monocytes into atherosclerotic lesions, and promotes regression. In patients with type 1 diabetes, plasma S100A8/S100A9 levels correlate with leukocyte counts and coronary artery disease. Thus, hyperglycemia drives myelopoiesis and promotes atherogenesis in diabetes.
  Cell metabolism 05/2013; 17(5):695-708. · 17.35 Impact Factor
• Article: Pegylation of HDL Decreases Plasma Clearance and Enhances Anti-Atherogenic Activity.

  Andrew J Murphy, Samuel Funt, Darren J Gorman, Alan R Tall, Nan Wang
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  ABSTRACT: Rationale: Infusions of apoA-I, mimetic peptides or HDL remain a promising approach to treatment of atherosclerotic coronary disease. However, rapid clearance leads to a requirement for repeated administration of large amounts of material and limits effective plasma concentrations. Objective: Since pegylation of purified proteins is commonly used as a method to increase their half-life in the circulation, we determined whether pegylation of apoA-I or HDL would increase its plasma half-life and in turn its anti-atherogenic potential. Methods and Results:Initial pegylation attempts using lipid-poor apoA-I showed a marked tendency to form multi-pegylated (PEG) species with reduced ability to promote cholesterol efflux from macrophage foam cells. However, pegylation of human holo-HDL or reconstituted phospholipid/apoA-I particles (rHDL) led to selective N-terminal mono-pegylation of apoA-I with full preservation of cholesterol efflux activity. The plasma clearance of PEG-rHDL was estimated following injection into hypercholesterolemic Apoe(-/-) mice; the half-life of pegylated apoA-I following injection of PEG-rHDL was increased about 7-fold compared to apoA-I in non-pegylated rHDL. Compared to non-pegylated rHDL, infusion of PEG-rHDL (40 mg/kg) into hypercholesterolemic APOe(-/-) mice led to more pronounced suppression of bone marrow myeloid progenitor cell proliferation and monocytosis, as well as reduced atherosclerosis and a stable plaque phenotype. Conclusions: We describe a novel method for effective mono-pegylation of apoA-I in HDL particles, in which lipid binding appears to protect against pegylation of key functional residues. Pegylation of apoA-I in rHDL markedly increases its plasma half-life and enhances anti-atherogenic properties in vivo.
  Circulation Research 04/2013; · 9.49 Impact Factor
• Article: Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis.

  Andrew J Murphy, Nora Bijl, Laurent Yvan-Charvet, Carrie B Welch, Neha Bhagwat, Adili Reheman, Yiming Wang, James A Shaw, Ross L Levine, Heyu Ni, Alan R Tall, Nan Wang
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  ABSTRACT: Platelets have a key role in atherogenesis and its complications. Both hypercholesterolemia and increased platelet production promote atherothrombosis; however, a potential link between altered cholesterol homeostasis and platelet production has not been explored. Here we show that transplantation of bone marrow deficient in ABCG4, a transporter of unknown function, into Ldlr(-/-) mice resulted in thrombocytosis, accelerated thrombosis and atherosclerosis. Although not detected in atherosclerotic lesions, Abcg4 was highly expressed in bone marrow megakaryocyte progenitors (MkPs). Abcg4(-/-) MkPs had defective cholesterol efflux to high-density lipoprotein (HDL), increased cell surface expression of the thrombopoietin (TPO) receptor (c-MPL) and enhanced proliferation. These consequences of ABCG4 deficiency seemed to reflect disruption of negative feedback regulation of c-MPL signaling by the E3 ligase c-CBL and the cholesterol-sensing LYN kinase. HDL infusion reduced platelet counts in Ldlr(-/-) mice and in a mouse model of myeloproliferative neoplasm in an ABCG4-dependent fashion. HDL infusions may offer a new approach to reducing atherothrombotic events associated with increased platelet production.
  Nature medicine 04/2013; · 27.14 Impact Factor
• Article: Deficiency of ABCA1 and ABCG1 in Macrophages Increases Inflammation and Accelerates Atherosclerosis in Mice.

  Marit Westerterp, Andrew J Murphy, Mi Wang, Tamara A Pagler, Yuliya Vengrenyuk, Mojdeh S Kappus, Darren J Gorman, Prabhakara R Nagareddy, Xuewei Zhu, Sandra Abramowicz, John S Parks, Carrie L Welch, Edward A Fisher, Nan Wang, Laurent Yvan-Charvet, Alan R Tall
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  ABSTRACT: Rationale: Plasma HDL levels are inversely correlated with atherosclerosis. Although it is widely assumed that this is due to the ability of HDL to promote cholesterol efflux from macrophage foam cells, direct experimental support for this hypothesis is lacking. Objective: To assess the role of macrophage cholesterol efflux pathways in atherogenesis. Methods and Results: We developed MAC-ABC(DKO) mice with efficient deletion of the ATP Binding Cassette Transporters A1 and G1 (ABCA1 and ABCG1) in macrophages but not in hematopoietic stem or progenitor populations. MAC-ABC(DKO) bone marrow (BM) was transplanted into Ldlr(-/-) recipients. On the chow diet, these mice had similar plasma cholesterol and blood monocyte levels but increased atherosclerosis compared to controls. On the Western type diet (WTD), MAC-ABC(DKO) BM transplanted Ldlr(-/-) mice had disproportionate atherosclerosis, considering they also had lower VLDL/LDL cholesterol levels than controls. ABCA1/G1 deficient macrophages in lesions showed increased inflammatory gene expression. Unexpectedly, WTD-fed MAC-ABC(DKO) BM transplanted Ldlr(-/-) mice displayed monocytosis and neutrophilia in the absence of HSPC proliferation. Mechanistic studies revealed increased expression of M-CSF and G-CSF in splenic macrophage foam cells, driving BM monocyte and neutrophil production. Conclusions: These studies 1) show that macrophage deficiency of ABCA1/G1 is pro-atherogenic likely by promoting plaque inflammation and 2) uncover a novel positive feedback loop in which cholesterol-laden splenic macrophages signal BM progenitors to produce monocytes, with suppression by macrophage cholesterol efflux pathways.
  Circulation Research 04/2013; · 9.49 Impact Factor
• Article: Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice.

  Catherine Martel, Wenjun Li, Brian Fulp, Andrew M Platt, Emmanuel L Gautier, Marit Westerterp, Robert Bittman, Alan R Tall, Shu-Hsia Chen, Michael J Thomas, Daniel Kreisel, Melody A Swartz, Mary G Sorci-Thomas, Gwendalyn J Randolph
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  ABSTRACT: Reverse cholesterol transport (RCT) refers to the mobilization of cholesterol on HDL particles (HDL-C) from extravascular tissues to plasma, ultimately for fecal excretion. Little is known about how HDL-C leaves peripheral tissues to reach plasma. We first used 2 models of disrupted lymphatic drainage from skin - 1 surgical and the other genetic - to quantitatively track RCT following injection of [3H]-cholesterol-loaded macrophages upstream of blocked or absent lymphatic vessels. Macrophage RCT was markedly impaired in both models, even at sites with a leaky vasculature. Inhibited RCT was downstream of cholesterol efflux from macrophages, since macrophage efflux of a fluorescent cholesterol analog (BODIPY-cholesterol) was not altered by impaired lymphatic drainage. We next addressed whether RCT was mediated by lymphatic vessels from the aortic wall by loading the aortae of donor atherosclerotic Apoe-deficient mice with [2H]6-labeled cholesterol and surgically transplanting these aortae into recipient Apoe-deficient mice that were treated with anti-VEGFR3 antibody to block lymphatic regrowth or with control antibody to allow such regrowth. [2H]-Cholesterol was retained in aortae of anti-VEGFR3-treated mice. Thus, the lymphatic vessel route is critical for RCT from multiple tissues, including the aortic wall. These results suggest that supporting lymphatic transport function may facilitate cholesterol clearance in therapies aimed at reversing atherosclerosis.
  The Journal of clinical investigation 03/2013; · 15.39 Impact Factor
• Article: Expanded Granulocyte/Monocyte Compartment in Myeloid-Specific Triple Foxo Knockout Increases Oxidative Stress and Accelerates Atherosclerosis in Mice.

  Kyoichiro Tsuchiya, Marit Westerterp, Andrew J Murphy, Vidya Subramanian, Anthony Ferrante, Alan R Tall, Domenico Accili
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  ABSTRACT: Rationale: Increased neutrophil and monocyte counts are often associated with an increased risk of atherosclerosis, but their relationship to insulin sensitivity is unknown. Objective: To investigate the contribution of forkhead transcription factors (FoxO) in myeloid cells to neutrophil and monocyte counts, atherosclerosis, and systemic insulin sensitivity. Methods and Results: Genetic ablation of the three genes encoding FoxO isoforms 1, 3a, and 4, in myeloid cells resulted in an expansion of the granulocyte/monocyte progenitor compartment, and was associated with increased atherosclerotic lesion formation in Ldl receptor knockout mice. In vivo and ex vivo studies indicate that FoxO ablation in myeloid cells increased generation of reactive oxygen species. Accordingly, treatment with the antioxidant N-acetyl-L-cysteine reversed the phenotype, normalizing atherosclerosis. Conclusions: Our data indicate that myeloid cell proliferation and oxidative stress can be modulated via the FoxO branch of insulin receptor signaling, highlighting a heretofore-unknown link between insulin sensitivity and leukocytosis that can affect the predisposition to atherosclerosis.
  Circulation Research 02/2013; · 9.49 Impact Factor
• Article: Mild Renal Dysfunction and Metabolites Tied to Low HDL Cholesterol are Associated with Monocytosis and Atherosclerosis.

  Anjali Ganda, Martin Magnusson, Laurent Yvan-Charvet, Bo Hedblad, Gunnar Engström, Ding Ai, Thomas J Wang, Robert E Gerszten, Olle Melander, Alan R Tall
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  ABSTRACT: BACKGROUND: The number of circulating blood monocytes impacts atherosclerotic lesion size and in mouse models, elevated levels of high density lipoprotein-cholesterol (HDL-C) suppress blood monocyte counts and atherosclerosis. We hypothesized that individuals with mild renal dysfunction at increased cardiovascular risk would have reduced HDL levels, high blood monocyte counts, and accelerated atherosclerosis. METHODS AND RESULTS: To test whether mild renal dysfunction is associated with increase in a leukocyte subpopulation rich in monocytes that has a known association with future coronary events, we divided individuals from the Malmö Diet and Cancer study (MDC) into baseline cystatin C quintiles (N=4757). Lower levels of renal function were accompanied by higher monocyte counts, and monocytes were independently associated with carotid bulb intima-media thickness cross-sectionally (p= 0.02). Cystatin C levels were positively and plasma HDL-C levels negatively associated with monocyte counts at baseline, following adjustment for traditional risk factors. Several amino acid metabolites tied to low HDL-C and insulin resistance measured in a subset of individuals (N= 752) using liquid chromatography-mass spectrometry were independently associated with a 22-34% increased risk of being in the top quartile of monocytes (p<0.05). CONCLUSIONS: A low HDL-C, insulin resistance phenotype occurs in subjects with mild renal dysfunction and is associated with elevated monocytes and atherosclerosis. High blood monocytes may represent a previously unrecognized mechanism underlying the strong relationship between cystatin C and cardiovascular risk.
  Circulation 02/2013; · 14.74 Impact Factor
• Article: HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders.

  Emmanuel L Gautier, Marit Westerterp, Neha Bhagwat, Serge Cremers, Alan Shih, Omar Abdel-Wahab, Dieter Lütjohann, Gwendalyn J Randolph, Ross L Levine, Alan R Tall, Laurent Yvan-Charvet
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  ABSTRACT: A high metabolic rate in myeloproliferative disorders is a common complication of neoplasms, but the underlying mechanisms are incompletely understood. Using three different mouse models of myeloproliferative disorders, including mice with defective cholesterol efflux pathways and two models based on expression of human leukemia disease alleles, we uncovered a mechanism by which proliferating and inflammatory myeloid cells take up and oxidize glucose during the feeding period, contributing to energy dissipation and subsequent loss of adipose mass. In vivo, lentiviral inhibition of Glut1 by shRNA prevented myeloproliferation and adipose tissue loss in mice with defective cholesterol efflux pathway in leukocytes. Thus, Glut1 was necessary to sustain proliferation and potentially divert glucose from fat storage. We also showed that overexpression of the human ApoA-I transgene to raise high-density lipoprotein (HDL) levels decreased Glut1 expression, dampened myeloproliferation, and prevented fat loss. These experiments suggest that inhibition of Glut-1 and HDL cholesterol-raising therapies could provide novel therapeutic approaches to treat the energy imbalance observed in myeloproliferative disorders.
  Journal of Experimental Medicine 01/2013; · 13.85 Impact Factor
• Article: Cholesterol efflux: a novel regulator of myelopoiesis and atherogenesis.

  Alan R Tall, Laurent Yvan-Charvet, Marit Westerterp, Andrew J Murphy
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  ABSTRACT: Monocytosis and neutrophilia are well-established risk factors for atherosclerosis and seem to play a causative role in lesion development. Studies in mice with defects in cholesterol efflux pathways have identified novel roles for the ATP-binding cassette transporter A1, ATP-binding cassette transporter G1, and apolipoprotein E in suppressing hematopoietic stem cell proliferation, mobilization, and the production of monocytes and neutrophils in the bone marrow. In addition, stem cell mobilization to the spleen initiates extramedullary hematopoiesis, which acts as a monocytic reservoir. Increased monocyte and neutrophil levels drive atherogenesis and its complications. Increasing high-density lipoprotein levels and cholesterol efflux can reverse excessive myelopoiesis and stem cell mobilization, suggesting a novel antiatherogenic effect of some forms of high-density lipoprotein elevation. After a myocardial infarction, splenic Ly-6C(hi) monocyte populations are sustained by a second wave of stem cell mobilization from the bone marrow and continue to enter atheroma, accelerating atherogenesis. Because activation of cholesterol efflux pathways can inhibit stem cell proliferation, mobilization, and monocyte production, this may provide a rationale for boosting high-density lipoprotein levels after a myocardial infarction to prevent reocclusion.
  Arteriosclerosis Thrombosis and Vascular Biology 11/2012; 32(11):2547-52. · 6.37 Impact Factor
• Article: The not-so-simple HDL story: Is it time to revise the HDL cholesterol hypothesis?

  Daniel J Rader, Alan R Tall
  Nature medicine 09/2012; 18(9):1344-6. · 27.14 Impact Factor
• Source

  Available from: Tanya M Teslovich

  Dataset: Supplementary Material (nature09270-s1)

  Tanya M Teslovich, Kiran Musunuru, Albert V Smith, Andrew C Edmondson, Ioannis M Stylianou, Masahiro Koseki, James P Pirruccello, Samuli Ripatti, Daniel I Chasman, Cristen J Willer, [......], Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, Cornelia M van Duijn, Leena Peltonen, Gonçalo R Abecasis, Michael Boehnke, Sekar Kathiresan
• Source

  Available from: Tanya M Teslovich

  Dataset: Supplementary Material (nature09270-s1)

  Tanya M Teslovich, Kiran Musunuru, Albert V Smith, Andrew C Edmondson, Ioannis M Stylianou, Masahiro Koseki, James P Pirruccello, Samuli Ripatti, Daniel I Chasman, Cristen J Willer, [......], Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, Cornelia M van Duijn, Leena Peltonen, Gonçalo R Abecasis, Michael Boehnke, Sekar Kathiresan
• Article: Regulation of hematopoietic stem and progenitor cell mobilization by cholesterol efflux pathways.

  Marit Westerterp, Samuel Gourion-Arsiquaud, Andrew J Murphy, Alan Shih, Serge Cremers, Ross L Levine, Alan R Tall, Laurent Yvan-Charvet
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  ABSTRACT: Intact cholesterol homeostasis helps to maintain hematopoietic stem and multipotential progenitor cell (HSPC) quiescence. Mice with defects in cholesterol efflux pathways due to deficiencies of the ATP binding cassette transporters ABCA1 and ABCG1 displayed a dramatic increase in HSPC mobilization and extramedullary hematopoiesis. Increased extramedullary hematopoiesis was associated with elevated serum levels of G-CSF due to generation of IL-23 by splenic macrophages and dendritic cells. This favored hematopoietic lineage decisions toward granulocytes rather than macrophages in the bone marrow leading to impaired support for osteoblasts and decreased Cxcl12/SDF-1 production by mesenchymal progenitors. Greater HSPC mobilization and extramedullary hematopoiesis were reversed by raising HDL levels in Abca1(-/-)Abcg1(-/-) and Apoe(-/-) mice or in a mouse model of myeloproliferative neoplasm mediated by Flt3-ITD mutation. Our data identify a role of cholesterol efflux pathways in the control of HSPC mobilization. This may translate into therapeutic strategies for atherosclerosis and hematologic malignancies.
  Cell stem cell 08/2012; 11(2):195-206. · 23.56 Impact Factor
• Article: Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism.

  Alanna Strong, Qiurong Ding, Andrew C Edmondson, John S Millar, Katherine V Sachs, Xiaoyu Li, Arthi Kumaravel, Margaret Ye Wang, Ding Ai, Liang Guo, Eric T Alexander, David Nguyen, Sissel Lund-Katz, Michael C Phillips, Carlos R Morales, Alan R Tall, Sekar Kathiresan, Edward A Fisher, Kiran Musunuru, Daniel J Rader
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  ABSTRACT: Genome-wide association studies (GWAS) have identified a genetic variant at a locus on chromosome 1p13 that is associated with reduced risk of myocardial infarction, reduced plasma levels of LDL cholesterol (LDL-C), and markedly increased expression of the gene sortilin-1 (SORT1) in liver. Sortilin is a lysosomal sorting protein that binds ligands both in the Golgi apparatus and at the plasma membrane and traffics them to the lysosome. We previously reported that increased hepatic sortilin expression in mice reduced plasma LDL-C levels. Here we show that increased hepatic sortilin not only reduced hepatic apolipoprotein B (APOB) secretion, but also increased LDL catabolism, and that both effects were dependent on intact lysosomal targeting. Loss-of-function studies demonstrated that sortilin serves as a bona fide receptor for LDL in vivo in mice. Our data are consistent with a model in which increased hepatic sortilin binds intracellular APOB-containing particles in the Golgi apparatus as well as extracellular LDL at the plasma membrane and traffics them to the lysosome for degradation. We thus provide functional evidence that genetically increased hepatic sortilin expression both reduces hepatic APOB secretion and increases LDL catabolism, providing dual mechanisms for the very strong association between increased hepatic sortilin expression and reduced plasma LDL-C levels in humans.
  The Journal of clinical investigation 07/2012; 122(8):2807-16. · 15.39 Impact Factor
• Article: Impaired MEK Signaling and SERCA Expression Promote ER Stress and Apoptosis in Insulin-Resistant Macrophages and Are Reversed by Exenatide Treatment.

  Chien-Ping Liang, Seongah Han, Gang Li, Ira Tabas, Alan R Tall
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  ABSTRACT: Accumulation of toxic lipids evokes the unfolded protein response (UPR) and apoptotic death of macrophages and vascular cells in atherosclerotic plaques. Primary macrophages from insulin-resistant ob/ob and insulin receptor (Insr)(-/-) mice display increased apoptosis in response to loading with free cholesterol or oxysterol, but underlying mechanisms have not been elucidated. We show increased activation of all three major branches of the UPR in response to free cholesterol or oxysterol loading in insulin-resistant macrophages. Inhibition and rescue experiments revealed that defective MEK/extracellular signal\x{2013}related kinase (ERK)/cAMP-responsive element-binding protein (CREBP) signaling in insulin-resistant macrophages leads to decreased expression of sarcoplasmic endoplasmic reticulum (ER) Ca(2+)-ATPase, depletion of ER calcium stores, PKR-like ER kinase activation, and ER stress-associated apoptosis. Activation of macrophage glucagon-like peptide 1 (GLP-1) receptor via the antidiabetic drug exenatide led to improvements in both ERK and AKT signaling and reversed the increase in UPR and apoptosis of insulin-resistant macrophages in atherosclerotic lesions of ob/ob.Ldlr(-/-) and Insr(-/-).Ldlr(-/-) mice. Increased signaling via GLP-1 receptor or the CREBP activator protein kinase A thus offers a way to rescue insulin-resistant macrophages from excessive ER stress responses and apoptosis in insulin resistance and type 2 diabetes.
  Diabetes 06/2012; 61(10):2609-20. · 8.29 Impact Factor
• Article: Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport.

  Robert S Rosenson, H Bryan Brewer, W Sean Davidson, Zahi A Fayad, Valentin Fuster, James Goldstein, Marc Hellerstein, Xian-Cheng Jiang, Michael C Phillips, Daniel J Rader, Alan T Remaley, George H Rothblat, Alan R Tall, Laurent Yvan-Charvet
  Circulation 04/2012; 125(15):1905-19. · 14.74 Impact Factor
• Article: Activation of ER stress and mTORC1 suppresses hepatic sortilin-1 levels in obese mice.

  Ding Ai, Juan M Baez, Hongfeng Jiang, Donna M Conlon, Antonio Hernandez-Ono, Maria Frank-Kamenetsky, Stuart Milstein, Kevin Fitzgerald, Andrew J Murphy, Connie W Woo, Alanna Strong, Henry N Ginsberg, Ira Tabas, Daniel J Rader, Alan R Tall
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  ABSTRACT: Recent GWAS have identified SNPs at a human chromosom1 locus associated with coronary artery disease risk and LDL cholesterol levels. The SNPs are also associated with altered expression of hepatic sortilin-1 (SORT1), which encodes a protein thought to be involved in apoB trafficking and degradation. Here, we investigated the regulation of Sort1 expression in mouse models of obesity. Sort1 expression was markedly repressed in both genetic (ob/ob) and high-fat diet models of obesity; restoration of hepatic sortilin-1 levels resulted in reduced triglyceride and apoB secretion. Mouse models of obesity also exhibit increased hepatic activity of mammalian target of rapamycin complex 1 (mTORC1) and ER stress, and we found that administration of the mTOR inhibitor rapamycin to ob/ob mice reduced ER stress and increased hepatic sortilin-1 levels. Conversely, genetically increased hepatic mTORC1 activity was associated with repressed Sort1 and increased apoB secretion. Treating WT mice with the ER stressor tunicamycin led to marked repression of hepatic sortilin-1 expression, while administration of the chemical chaperone PBA to ob/ob mice led to amelioration of ER stress, increased sortilin-1 expression, and reduced apoB and triglyceride secretion. Moreover, the ER stress target Atf3 acted at the SORT1 promoter region as a transcriptional repressor, whereas knockdown of Atf3 mRNA in ob/ob mice led to increased hepatic sortilin-1 levels and decreased apoB and triglyceride secretion. Thus, in mouse models of obesity, induction of mTORC1 and ER stress led to repression of hepatic Sort1 and increased VLDL secretion via Atf3. This pathway may contribute to dyslipidemia in metabolic disease.
  The Journal of clinical investigation 04/2012; 122(5):1677-87. · 15.39 Impact Factor
• Article: Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice.

  Ding Ai, Chiyuan Chen, Seongah Han, Anjali Ganda, Andrew J Murphy, Rebecca Haeusler, Edward Thorp, Domenico Accili, Jay D Horton, Alan R Tall
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  ABSTRACT: Individuals with type 2 diabetes have an increased risk of atherosclerosis. One factor underlying this is dyslipidemia, which in hyperinsulinemic subjects with early type 2 diabetes is typically characterized by increased VLDL secretion but normal LDL cholesterol levels, possibly reflecting enhanced catabolism of LDL via hepatic LDLRs. Recent studies have also suggested that hepatic insulin signaling sustains LDLR levels. We therefore sought to elucidate the mechanisms linking hepatic insulin signaling to regulation of LDLR levels. In WT mice, insulin receptor knockdown by shRNA resulted in decreased hepatic mTORC1 signaling and LDLR protein levels. It also led to increased expression of PCSK9, a known post-transcriptional regulator of LDLR expression. Administration of the mTORC1 inhibitor rapamycin caused increased expression of PCSK9, decreased levels of hepatic LDLR protein, and increased levels of VLDL/LDL cholesterol in WT but not Pcsk9-/- mice. Conversely, mice with increased hepatic mTORC1 activity exhibited decreased expression of PCSK9 and increased levels of hepatic LDLR protein levels. Pcsk9 is regulated by the transcription factor HNF1α, and our further detailed analyses suggest that increased mTORC1 activity leads to activation of PKCδ, reduced activity of HNF4α and HNF1α, decreased PCSK9 expression, and ultimately increased hepatic LDLR protein levels, which result in decreased circulating LDL levels. We therefore suggest that PCSK9 inhibition could be an effective way to reduce the adverse side effect of increased LDL levels that is observed in transplant patients taking rapamycin as immunosuppressive therapy.
  The Journal of clinical investigation 03/2012; 122(4):1262-70. · 15.39 Impact Factor
• Article: FoxOs integrate pleiotropic actions of insulin in vascular endothelium to protect mice from atherosclerosis.

  Kyoichiro Tsuchiya, Jun Tanaka, Yu Shuiqing, Carrie L Welch, Ronald A DePinho, Ira Tabas, Alan R Tall, Ira J Goldberg, Domenico Accili
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  ABSTRACT: Atherosclerotic cardiovascular disease is the leading cause of death in insulin-resistant (type 2) diabetes. Vascular endothelial dysfunction paves the way for atherosclerosis through impaired nitric oxide availability, inflammation, and generation of superoxide. Surprisingly, we show that ablation of the three genes encoding isoforms of transcription factor FoxO in endothelial cells prevents atherosclerosis in low-density lipoprotein receptor knockout mice by reversing these subphenotypes. Paradoxically, the atheroprotective effect of FoxO deletion is associated with a marked decrease of insulin-dependent Akt phosphorylation in endothelial cells, owing to reduced FoxO-dependent expression of the insulin receptor adaptor proteins Irs1 and Irs2. These findings support a model in which FoxO is the shared effector of multiple atherogenic pathways in endothelial cells. FoxO ablation lowers the threshold of Akt activity required for protection from atherosclerosis. The data demonstrate that FoxO inhibition in endothelial cells has the potential to mediate wide-ranging therapeutic benefits for diabetes-associated cardiovascular disease.
  Cell metabolism 03/2012; 15(3):372-81. · 17.35 Impact Factor
• Source

  Available from: Sarah G Buxbaum

  Article: Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

  Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R B Perry, Xin Yuan, Robert A Scott, Peter Henneman, Iris M Heid, Jorge R Kizer, Leo-Pekka Lyytikäinen, [......], Eric E Schadt, David P Strachan, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, Sekar Kathiresan
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  ABSTRACT: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
  PLoS Genetics 03/2012; 8(3):e1002607. · 8.69 Impact Factor