Pathology & Laboratory Medicine

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Laboratory of Cell Metabolism

Ann-Hwee Lee, PhD, Principal Investigator

Dr. Lee’s laboratory focuses on metabolic functions of unfolded protein response, a signaling pathway that governs protein folding homeostasis in the endoplasmic reticulum. He also studies the physiological functions and action mechanisms of a group of transcription factors that are anchored in the ER membrane and activated by proteolytic cleavage.

Active Projects

  • Regulation of Triglyceride Metabolism by the transcription factor CREB-H
  • Metabolic functions of the Unfolded Protein Response
  • Role of Unfolded Protein Response in insulin secretory function of beta cells

Active Grants

  • IRE1a and XBP1 dependent microRNAs and their role in hepatic lipid metabolism
    PI: Ann-Hwee Lee, PhD
    Qatar National Research Fund (QNRF) Research Grant
  • Regulation of Triglyceride Metabolism by the transcription factor CREB-H
    PI: Ann-Hwee Lee, PhD
    NIDDK

Selected Publications

Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP

Ann-Hwee Lee, PhD

Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP

Semin Liver Dis. 2013 Nov;33(4):301-11.

Xu X, So JS, Park JG, Lee AH.

PMID: 24222088; PMCID: PMC4035704

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Regulated IRE1-dependent decay participates in curtailing immunoglobulin secretion from plasma cells

Ann-Hwee Lee, PhD

Regulated IRE1-dependent decay participates in curtailing immunoglobulin secretion from plasma cells

Eur J Immunol. 2014 Mar;44(3):867-76.

Benhamron S, Hadar R, Iwawaky T, So JS, Lee AH, Tirosh B.

PMID: 24242955

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Heteroclitic XBP1 peptides evoke tumor-specific memory cytotoxic T lymphocytes against breast cancer, colon cancer, and pancreatic cancer cells

Ann-Hwee Lee, PhD

Heteroclitic XBP1 peptides evoke tumor-specific memory cytotoxic T lymphocytes against breast cancer, colon cancer, and pancreatic cancer cells

Oncoimmunology. 2014 Dec 2;3(12):e970914.

Bae J, Samur M, Munshi A, Hideshima T, Keskin D, Kimmelman A, Lee AH, Dranoff G, Anderson KC, Munshi NC.

PMID: 25941601; PMCID: PMC4356023

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Transcriptional regulation of apolipoprotein A-IV by the transcription factor CREBH

Ann-Hwee Lee, PhD

Transcriptional regulation of apolipoprotein A-IV by the transcription factor CREBH

J Lipid Res. 2014 May;55(5):850-9.

Xu X, Park JG, So JS, Hur KY, Lee AH.

PMID: 24598141; PMCID: PMC3995463.

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Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway

Ann-Hwee Lee, PhD

Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway

Cell. 2014 Mar 13;156(6):1179-92.

Wang ZV, Deng Y, Gao N, Pedrozo Z, Li DL, Morales CR, Criollo A, Luo X, Tan W, Jiang N, Lehrman MA, Rothermel BA, Lee AH, Lavandero S, Mammen PP, Ferdous A, Gillette TG, Scherer PE, Hill JA.

PMID: 24630721; PMCID: PMC3959665.

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Transcriptional activation of Fsp27 by the liver-enriched transcription factor CREBH promotes lipid droplet growth and hepatic steatosis

Ann-Hwee Lee, PhD

Transcriptional activation of Fsp27 by the liver-enriched transcription factor CREBH promotes lipid droplet growth and hepatic steatosis

Hepatology. 2015 Mar;61(3):857-69.

Xu X, Park JG, So JS, Lee AH.

PMID: 25125366; PMCID: PMC4329115

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X-box binding protein 1 is a novel key regulator of peroxisome proliferator-activated receptor γ2

Ann-Hwee Lee, PhD

X-box binding protein 1 is a novel key regulator of peroxisome proliferator-activated receptor γ2

FEBS J. 2014 Nov;281(22):5132-46.

Cho YM, Kwak SN, Joo NS, Kim DH, Lee AH, Kim KS, Seo JB, Jeong SW, Kwon OJ.

PMID: 25223794

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Altered trafficking and stability of polycystins underlie polycystic kidney disease

Ann-Hwee Lee, PhD

Altered trafficking and stability of polycystins underlie polycystic kidney disease

J Clin Invest. 2014 Dec;124(12):5129-44.

Cai Y, Fedeles SV, Dong K, Anyatonwu G, Onoe T, Mitobe M, Gao JD, Okuhara D, Tian X, Gallagher AR, Tang Z, Xie X, Lalioti MD, Lee AH, Ehrlich BE, Somlo S.

PMID: 25365220; PMCID: PMC4348948

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Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity

Ann-Hwee Lee, PhD

Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity

J Clin Invest. 2015 May;125(5):1955-67.

Fedeles SV, So JS, Shrikhande A, Lee SH, Gallagher AR, Barkauskas CE, Somlo S, Lee AH.

PMID: 25844898; PMCID: PMC4463201.

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IRE1α-Dependent Decay of CReP/Ppp1r15b mRNA Increases Eukaryotic Initiation Factor 2α Phosphorylation and Suppresses Protein Synthesis

Ann-Hwee Lee, PhD

IRE1α-Dependent Decay of CReP/Ppp1r15b mRNA Increases Eukaryotic Initiation Factor 2α Phosphorylation and Suppresses Protein Synthesis

Mol Cell Biol. 2015 Aug;35(16):2761-70.

So JS, Cho S, Min SH, Kimball SR, Lee AH.

PMID: 26031337; PMCID: PMC4508316

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ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis

Ann-Hwee Lee, PhD

ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis

Cell. 2015 Jun 18;161(7):1527-38.

Cubillos-Ruiz JR, Silberman PC, Rutkowski MR, Chopra S, Perales-Puchalt A, Song M, Zhang S, Bettigole SE, Gupta D, Holcomb K, Ellenson LH, Caputo T, Lee AH, Conejo-Garcia JR, Glimcher LH.

PMID: 26073941; PMCID: PMC4580135

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The transcription factor XBP1 is selectively required for eosinophil differentiation

Ann-Hwee Lee, PhD

The transcription factor XBP1 is selectively required for eosinophil differentiation

Nat Immunol. 2015 Aug;16(8):829-37.

Bettigole SE, Lis R, Adoro S, Lee AH, Spencer LA, Weller PF, Glimcher LH.

PMID: 26147683; PMCID: PMC4577297

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Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes

Ann-Hwee Lee, PhD

Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes

J Am Soc Nephrol. 2015 Aug 24.

Hassan H, Tian X, Inoue K, Chai N, Liu C, Soda K, Moeckel G, Tufro A, Lee AH, Somlo S, Fedeles S, Ishibe S.

PMID: 26303067

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Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion.

Ann-Hwee Lee, PhD

Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion.

Proc Natl Acad Sci U S A. 2011 May 24;108(21):8885-90.

Lee AH, Heidtman K, Hotamisligil GS, Glimcher LH.

PMID: 21555585

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The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism.

Ann-Hwee Lee, PhD

The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism.

Nat Med. 2011 Jun 12;17(7):812-5.

Lee JH, Giannikopoulos P, Duncan SA, Wang J, Johansen CT, Brown JD, Plutzky J, Hegele RA, Glimcher LH, Lee AH.

PMID: 21666694

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Dissociation of inositol-requiring enzyme (IRE1α)-mediated c-Jun N-terminal kinase activation from hepatic insulin resistance in conditional X-box-binding protein-1 (XBP1) knock-out mice.

Ann-Hwee Lee, PhD

Dissociation of inositol-requiring enzyme (IRE1α)-mediated c-Jun N-terminal kinase activation from hepatic insulin resistance in conditional X-box-binding protein-1 (XBP1) knock-out mice.

J Biol Chem. 2012 Jan 20;287(4):2558-67. 

Jurczak MJ, Lee AH, Jornayvaz FR, Lee HY, Birkenfeld AL, Guigni BA, Kahn M, Samuel VT, Glimcher LH, Shulman GI.

PMID: 22128176

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Extensive pancreas regeneration following acinar-specific disruption of Xbp1 in mice.

Ann-Hwee Lee, PhD

Extensive pancreas regeneration following acinar-specific disruption of Xbp1 in mice.

Gastroenterology. 2011 Oct;141(4):1463-72.

Hess DA, Humphrey SE, Ishibashi J, Damsz B, Lee AH, Glimcher LH, Konieczny SF.

PMID: 21704586

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Excess of rare variants in non-genome-wide association study candidate genes in patients with hypertriglyceridemia.

Ann-Hwee Lee, PhD

Excess of rare variants in non-genome-wide association study candidate genes in patients with hypertriglyceridemia.

Circ Cardiovasc Genet. 2012 Feb 1;5(1):66-72.

Johansen CT, Wang J, McIntyre AD, Martins RA, Ban MR, Lanktree MB, Huff MW, Péterfy M, Mehrabian M, Lusis AJ, Kathiresan S, Anand SS, Yusuf S, Lee AH, Glimcher LH, Cao H, Hegele RA.

PMID: 22135386

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Assurance of mitochondrial integrity and mammalian longevity by the p62-Keap1-Nrf2-Nqo1 cascade.

Ann-Hwee Lee, PhD

Assurance of mitochondrial integrity and mammalian longevity by the p62-Keap1-Nrf2-Nqo1 cascade.

EMBO Rep. 2012 Feb 1;13(2):150-6.

Kwon J, Han E, Bui CB, Shin W, Lee J, Lee S, Choi YB, Lee AH, Lee KH, Park C, Obin MS, Park SK, Seo YJ, Oh GT, Lee HW, Shin J.

PMID: 22222206

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Differential effects of unfolded protein response pathways on axon injury-induced death of retinal ganglion cells.

Ann-Hwee Lee, PhD

Differential effects of unfolded protein response pathways on axon injury-induced death of retinal ganglion cells.

Neuron. 2012 Feb 9;73(3):445-52.

Hu Y, Park KK, Yang L, Wei X, Yang Q, Cho KS, Thielen P, Lee AH, Cartoni R, Glimcher LH, Chen DF, He Z.

PMID: 22325198

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IRE1α activation protects mice against acetaminophen-induced hepatotoxicity.

Ann-Hwee Lee, PhD

IRE1α activation protects mice against acetaminophen-induced hepatotoxicity.

J Exp Med. 2012 Feb 13;209(2):307-18. 

Hur KY, So JS, Ruda V, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Iwawaki T, Glimcher LH, Lee AH.

PMID: 22291093

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The role of CREB-H transcription factor in triglyceride metabolism.

Ann-Hwee Lee, PhD

The role of CREB-H transcription factor in triglyceride metabolism.

Curr Opin Lipidol. 2012 Apr;23(2):141-6. 

Lee AH.

PMID: 22262056

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Silencing of lipid metabolism genes through IRE1α-mediated mRNA decay lowers plasma lipids in mice.

Ann-Hwee Lee, PhD

Silencing of lipid metabolism genes through IRE1α-mediated mRNA decay lowers plasma lipids in mice.

Cell Metab. 2012 Oct 3;16(4):487-99. 

So JS, Hur KY, Tarrio M, Ruda V, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Lichtman AH, Iwawaki T, Glimcher LH, Lee AH.

PMID: 23040070

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The unfolded protein response element IRE1α senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling.

Ann-Hwee Lee, PhD

The unfolded protein response element IRE1α senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling.

Cell Host Microbe. 2013 May 15;13(5):558-69. 

Cho JA, Lee AH, Platzer B, Cross BC, Gardner BM, De Luca H, Luong P, Harding HP, Glimcher LH, Walter P, Fiebiger E, Ron D, Kagan JC, Lencer WI.

PMID: 23684307

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The role of adipocyte XBP1 in metabolic regulation during lactation.

Ann-Hwee Lee, PhD

The role of adipocyte XBP1 in metabolic regulation during lactation.

Cell Rep. 2013 May 30;3(5):1430-9.

Gregor MF, Misch ES, Yang L, Hummasti S, Inouye KE, Lee AH, Bierie B, Hotamisligil GS.

PMID: 23623498

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XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands

Ann-Hwee Lee, PhD

XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands

EMBO J. 2005 Dec 21;24(24):4368-80.

Lee AH, Chu GC, Iwakoshi NN, Glimcher LH.

PMID: 16362047; PMCID: PMC1356340

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Human cytomegalovirus protein US11 provokes an unfolded protein response that may facilitate the degradation of class I major histocompatibility complex products

Ann-Hwee Lee, PhD

Human cytomegalovirus protein US11 provokes an unfolded protein response that may facilitate the degradation of class I major histocompatibility complex products

J Virol. 2005 Mar;79(5):2768-79.

Tirosh B, Iwakoshi NN, Lilley BN, Lee AH, Glimcher LH, Ploegh HL.

PMID: 15708995; PMCID: PMC548438

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Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha.

Ann-Hwee Lee, PhD

Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha.

Science. 2006 Apr 28;312(5773):572-6.

Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Antonsson B, Brandt GS, Iwakoshi NN, Schinzel A, Glimcher LH, Korsmeyer SJ.

PMID: 16645094

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Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis.

Ann-Hwee Lee, PhD

Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis.

Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):757-62.

Hetz C, Lee AH, Gonzalez-Romero D, Thielen P, Castilla J, Soto C, Glimcher LH.

PMID: 18178615; PMCID: PMC2206609

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XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease

Ann-Hwee Lee, PhD

XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease

Cell. 2008 Sep 5;134(5):743-56.

Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS.

PMID: 18775308; PMCID: PMC2586148

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Regulation of hepatic lipogenesis by the transcription factor XBP1

Ann-Hwee Lee, PhD

Regulation of hepatic lipogenesis by the transcription factor XBP1

Science. 2008 Jun 13;320(5882):1492-6.

Lee AH, Scapa EF, Cohen DE, Glimcher LH.

PMID: 18556558; PMCID: PMC3620093

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The endoplasmic reticulum stress response in immunity and autoimmunity

Ann-Hwee Lee, PhD

The endoplasmic reticulum stress response in immunity and autoimmunity

Nat Rev Immunol. 2008 Sep;8(9):663-74.

Todd DJ, Lee AH, Glimcher LH.

PMID: 18670423

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From sugar to fat: How the transcription factor XBP1 regulates hepatic lipogenesis

Ann-Hwee Lee, PhD

From sugar to fat: How the transcription factor XBP1 regulates hepatic lipogenesis

Ann N Y Acad Sci. 2009 Sep;1173 Suppl 1:E2-9.

Glimcher LH, Lee AH.

PMID: 19751410; PMCID: PMC3096021

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Intersection of the unfolded protein response and hepatic lipid metabolism

Ann-Hwee Lee, PhD

Intersection of the unfolded protein response and hepatic lipid metabolism

Cell Mol Life Sci. 2009 Sep;66(17):2835-50.

Lee AH, Glimcher LH.

PMID: 19468685; PMCID: PMC3096022

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XBP1 governs late events in plasma cell differentiation and is not required for antigen-specific memory B cell development

Ann-Hwee Lee, PhD

XBP1 governs late events in plasma cell differentiation and is not required for antigen-specific memory B cell development

J Exp Med. 2009 Sep 28;206(10):2151-9.

Todd DJ, McHeyzer-Williams LJ, Kowal C, Lee AH, Volpe BT, Diamond B, McHeyzer-Williams MG, Glimcher LH.

PMID: 19752183; PMCID: PMC2757870

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XBP1 controls maturation of gastric zymogenic cells by induction of MIST1 and expansion of the rough endoplasmic reticulum

Ann-Hwee Lee, PhD

XBP1 controls maturation of gastric zymogenic cells by induction of MIST1 and expansion of the rough endoplasmic reticulum

Gastroenterology. 2010 Dec;139(6):2038-49.

Huh WJ, Esen E, Geahlen JH, Bredemeyer AJ, Lee AH, Shi G, Konieczny SF, Glimcher LH, Mills JC.

PMID: 20816838; PMCID: PMC2997137

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TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages.

Ann-Hwee Lee, PhD

TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages.

Nat Immunol. 2010 May;11(5):411-8.

Martinon F, Chen X, Lee AH, Glimcher LH.

PMID: 20351694; PMCID: PMC3113706

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Identification of novel myeloma-specific XBP1 peptides able to generate cytotoxic T lymphocytes: a potential therapeutic application in multiple myeloma.

Ann-Hwee Lee, PhD

Identification of novel myeloma-specific XBP1 peptides able to generate cytotoxic T lymphocytes: a potential therapeutic application in multiple myeloma.

Leukemia. 2011 Oct;25(10):1610-9.

Bae J, Carrasco R, Lee AH, Prabhala R, Tai YT, Anderson KC, Munshi NC.

PMID: 21660045; PMCID: PMC3483794

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