Category: Lipids/CV Health

Monitor: 17

17 - TFEB-MEDIATED INHIBITION OF ENDOPLASMIC RETICULUM STRESS IN HUMAN CORONARY ARTERY ENDOTHELIAL CELLS

Saturday, Apr 27
10:00 AM – 10:30 AM

Objective : The transcription factor TFEB is involved in regulating expression of genes involved in autophagy as well as carbohydrate and lipid metabolism. It has also been shown to inhibit atherosclerosis, presumably by inducing expression of free-radical scavenging enzymes. Since TFEB is expressed in endothelial cells and is anti-atherogenic, we wished to examine whether or not TFEB inhibits endoplasmic reticulum (ER) stress in human coronary artery endothelial cells.


Methods : TFEB, inositol-requiring enzyme 1a (IRE1a), phospho-IRE1a, protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), phospho-PERK, and ATF6 expression were measured by Western blot. The effect of TFEB gain-of-function and loss-of–function on ER stress were assessed by transient transfection with a plasmid expressing a constitutively active form of TFEB or via siRNA-mediated silencing, respectively. ER stress was measured using the ER stress secreted alkaline phosphatase (ES-TRAP) assay.


Results : TFEB expression increased 2.8-fold, 3.2-fold, and 2.1-fold in HCAEC treated with the ER stress inducers tunicamycin (TM) (1 mM), thapsigargin (TG) (0.1 mM), and high-dextrose (Dex) (27.5 mM). In HCAEC transfected with the TFEB siRNA and treated with either solvent, TM, TG, or Dex, IRE1a and PERK phosphorylation and ATF6 levels were significantly higher relative to cells transfected with the control siRNA. In contrast, transfection with the TFEB expression plasmid decreased IRE1a and PERK phosphorylation and decreased ATF6 levels relative to cells transfected with the empty vector. TFEB knockout or over-expression had no effect on IRE1a and PERK expression.


Discussion : TFEB inhibited ER stress in HCAEC induced by TM, TG, and high-dextrose as measured by the ES-TRAP assay. Likewise, decreased TFEB expression increased the degree of ER stress experienced by cells treated with all three compounds, while exogenous TFEB expression protected cells from ER stress.


Conclusion : TFEB-mediated ER stress reduction may contribute to its anti-atherogenic effects in HCAEC and may be a novel target for drug development.

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Marie Angelica Landicho

Endocrinology Fellow
University of Florida College of Medicine - Jacksonville
Jacksonville, Florida

Ateneo de Manila University (Quezon City, Philippines), B. S., Completion in 2007
University of Santo Tomas (Manila, Philippines), M. D., Completion in 2011
2011-2012 Postgraduate Internship Training, University of Santo Tomas Hospital (Manila, Philippines)
2014-2017 Internal Medicine Residency, Monmouth Medical Center (Long Branch, New Jersey)
2017-present Endocrinology Fellowship, University of Florida College of Medicine – Jacksonville (Jacksonville, Florida)

Priyanka Bikkina

Fellow
University of Florida Jacksonville
Jacksonville, Florida

University of Michigan B.S Completion in 2009. American University of Antigua MD completion in 2014. 2006-2008: Research assistant, Department of Pathology at University of Michigan. 2008-2009: Research assistant, The Molecular and Behavioral Neuroscience Institute, University of Michigan. 2009- Research assistant , Department of psychology at University of Michigan. Dean's Grant for study of Effect of Vitamin D Deficiency on ER/Oxidative stress in Type 2 Diabetes: Inhibition by statins.

Victoria Feng

Endocrinology Fellow
University of Florida College of Medicine - Jacksonville

B. A. University of California Berkeley, Completion 2001
M. D. Boston University, Completion 2007
M.P.H. Bostone University, Completion 2007
2012-2015 Internal Medicine Residency, Stony Brook University Hospital (Stony Brook, New York)
2016-2018 Endocrinology Fellowship, University of Florida College of Medicine – Jacksonville (Jacksonville, Florida)

Krista Gonzales

Endocrinology Fellow
University of Florida College of Medicine - Jacksonville

M.D., Ross University School of Medicine, Completion 2012
2013-2016 Internal Medicine Residency, Memorial Health University Medical Center (Savannah, Georgia)
2016-2018 Endocrinology Fellowship, University of Florida College of Medicine – Jacksonville (Jacksonville, Florida)

Luisa Onstead-Haas

Research Assistant
Mayo Clinic, Florida

Department of Health Sciences Research at Mayo Clinic. Regulation of apolipoprotein A-I gene expression by the histamine H1 receptor: Requirement for NF-κB. Article Jul 2018. Inhibition of hepatic apolipoprotein A-I gene expression by histamine
Article Jan 2018. The Effects of Known Cardioprotective Drugs on Proinflammatory Cytokine Secretion From Human Coronary Artery Endothelial Cells Article Nov 2017

Michael J. Haas

Research Associate Professor of Medicine
University of Florida Jacksonville

B.S. from University of Missouri 1995. Ph.D. from University of Nebraska Medical Center, Omaha. Postdoctoral from University of Wisconsin-Madison. 1991-1995, Post-doctoral research, McArdle Cancer Research Laboratory, University of Wisoconsin - Madison.
1995-1998, Research Associate, McArdle Cancer Research Laboratory, University of Wisconsin – Madison.
1998-2004, Assistant Research Professor, Saint Louis University, Department of Internal Medicine, Division of Endocrinology.
2004-2007, Associate Research Professor, Saint Louis University, Department of Internal Medicine, Division of Endocrinology.
2007-present, Associate Research Professor, University of Florida – Jacksonville, Department of Medicine, Division of Endocrinology.

Arshag Mooradian

Chair, Department of Medicine
University of Florida College of Medicine - Jacksonville

Medical Education: American University of Beirut, New York, NY, USA
Residency: Internal Medicine, American University of Beirut, New York, NY, USA
Fellowship: Endocrinology, Diabetes and Metabolism, University of Minnesota Medical School, Minneapolis, MN, USA