Greetings

Welcome to the Schlegel Laboratory. Located in the the Eccles Institute of Human Genetics on the University of Utah’s School of Medicine campus. We are a research enterprise focused on understanding metabolic diseases with particular attention to disorders marked by abnormal lipid synthesis, transport, and storage.

 

Image: An adult zebrafish stained with Oil Red O to reveal the subcutaneous adipose depots.

Mission Statement

The Schlegel Laboratory at the University of Utah School of Medicine is a research environment focused on metabolic diseases. We use zebrafish genetics and physiology to identify and characterize novel genes involved in lipid homeostasis. Our strategy involves positionally cloning the mutated genes and then characterizing their function. Reverse genetic methods (TALEN technology) are also used in select cases to address hypothesis-driven questions.

Molecular Genetics of Lipid Metabolism

 

 

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research4_wt and mut pair research2_adipose
research3_bodipy research1

 

Zebrafish late larvae and early juveniles remain sufficiently transparent to allow for inspection and staining of all the major organs for the presence of neutral lipids (image from Schlegel, 2012) with a variety of dyes. In the large panel to the lower left, a wildtype (upper) and mutant (with fatty liver) sibling pair are stained with with Oil Red O (ORO). The middle right, 3 part panel shows an older larva, its visceral adipose (VA), and vasculature (DA, dorsal aorta; PCV, posterior cardinal vein; ISV, intersegmental vessels) stained with ORO. The lower middle panels shows mutant hepatocytes (red background) stained with the fluorescent green dye BODIPY 493/503. The lower right panel is a transmission electron micrograph of the liver highlighting the architecture of lipid droplets.

 

Zebrafish as an Engine of Discovery for Metabolic Diseases

 

The post-World War II rise in obesity continues unabated, and it is clear that unanticipated and previously unrecognized players in regulating energy homeostasis must be discovered in order to combat the illnesses that follow from calorie excess (Olshansky et al., 2005). Indeed, the current pharmacologic armamentarium used in treating obesity’s attendant illnesses (e.g., type 2 diabetes mellitus, hypertension, dyslipidemia, atherosclerotic vascular disease) has seen some of its gains negated by increased adiposity (Stewart et al., 2009). Thus, there is pressing need for systematic and comprehensive strategies for identifying novel genes that participate in all aspects of energy homeostasis.

Special attention is needed for phenotypes of excessive and ectopic lipid accumulation because of the poorly understood reasons driving their development, and the toxic effects of ectopic lipid accumulation on the whole organism. More concretely, multiple lines of evidence indicate adipose tissue has a finite capacity to safely store neutral lipids. The spill-over of lipid metabolites from over-stuffed adipocytes into the circulation leads to a host of problems: insulin resistance, hepatic steatosis, intramyocellular liposis, accelerated atherosclerosis, hypertension, and beta cell dysfunction (Rosen and MacDougald, 2006). Conversely, absence of adipose tissue (discussed further below) is marked by striking accumulation of lipid metabolites in these other organs, with attendant morbidity (Garg, 2004). While metabolic syndrome and diabetes are the most prominent manifestations of deranged lipid storage, it has become widely recognized that obesity compounds or causes several other conditions including high output heart failure, restrictive lung disease, certain cancers, degenerative joint disease, and chronic kidney disease (Calle et al., 2003). Improved knowledge of adipocyte development and function holds the promise of showing us how to safely store or burn excess fat.

To meet the need for new diagnostic and therapeutic portals, we are performing large-scale forward genetic screens in zebrafish to identify novel mutants that have “metabolic phenotypes,” as defined by alterations in the abundance and location of neutral lipids (Schlegel and Stainier, 2007; Schlegel 2012). Particular attention will be given to adipose and liver phenotypes; however, the strategy is flexible and robust enough to detect and analyze lipids throughout the organism, and we may find phenotypes in other organs worth pursuing. This strategy arises from our previous, “reverse genetic” studies of embryos and larvae subjected to targeted knock-down of an evolutionarily central gene of lipid metabolism, mtp (Schlegel and Stainier, 2006).

Using our forward genetic approach, we identified and characterized of a novel liver transporter of ketone bodies whose mutation gives rise to nutritionally suppressible hepatic steaosis (Hugo et al., 2012). We continue to study the mechanisms of neutral lipid accumulation in mutant livers.

 

Phenotypes Anticipated in our Screen

 

research5_larvae

Drawing Modified from Schlegel and Stainier (2007)

 

 

Phenotypes anticipated in our screen. This large scale-forward genetic screen will examine never-fed larvae that have exhausted their maternally deposited yolk supplies but have not been fed (on the 6th day post-fertilization, dpf), and larvae that have had adequate nutrition (marked by feeding between 5 and15 dpf). This double screening strategy will allow us to identify mutations that give rise to ectopic lipid accumulation before and after the development and normal lipid accumulation of adipose tissue. In the 6 dpf scenario (upper half), three potential phenotypes are presented that we envision being able to score readily and reliably with ORO: excessive liver lipid accumulation (hepatic steatosis), persisting vascular lipid staining (lipemia), and lipid accumulation in the heart, skeletal muscles, or both (intramyocellular liposis). In addition to these phenotypes, the animals that shall be fed for 10 days prior to screening will have a normal visceral adipose depots that are easily scored for increased or decreased neutral lipid accumulation. We define expanded adipocyte number, size, neutral lipid accumulation, or any combination of these three as obese for the initial isolation. Conversely, decreased numbers of adipocytes, neutral lipid accumulation, or both are referred qualitatively as lipodystrophy. These operational categories will necessarily be refined as the phenotypes are characterized fully.

 

 

References

 

Calle EE, Rodriguez C, Walker-Thurmond K, and Thun MJ. (2003). Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348, 1625-1638.

Garg A. (2004). Acquired and inherited lipodystrophies. N Engl J Med 350, 1220-1234.
Hugo SE, Cruz-Garcia L, Karanth S, Anderson RM, Stainier DYR, Schlegel A. (2012) A monocarboxylate transporter required for secretion of ketone bodies during fasting. Genes Dev. 26,282-293.
Olshansky SJ, Passaro DJ, Hershow RC, Layden J, Carnes BA, Brody J, Hayflick L, Butler RN, Allison DB., and Ludwig DS. (2005). A potential decline in life expectancy in the United States in the 21st century. N Engl J Med 352, 1138-1145.

Rosen ED, and MacDougald OA. (2006). Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 7, 885-896.

Schlegel A, and Stainier, DYR. (2006). Microsomal triglyceride transfer protein is required for yolk lipid utilization and absorption of dietary lipids in zebrafish larvae. Biochemistry 45, 15179-15187.

Schlegel, A., Stainier DYR. (2007). Lessons from “lower” organisms: what worms, flies, and zebrafish can teach us about human energy metabolism. PLoS Genet 3, e199.

Schlegel A. (2012) Studying non-alcoholic fatty liver disease with zebrafish: a confluence of optics, genetics and physiology. Cell Mol Life Sci. 69, 3953-3961.

Stewart, S.T., Cutler, D.M., and Rosen, A.B. (2009). Forecasting the effects of obesity and smoking on U.S. life expectancy. New Engl J Med 361, 2252-2260.

Group Leader

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Amnono Schlegel, MD, PH.D.

Principle Investigator

MD and PhD, Albert Einstein College of Medicine 2002

Dr. Schlegel was recruited to the University of Utah in 2010 as an Assistant Professor of Internal Medicine and an Investigator in the Molecular Medicine program. He was previously Assistant Adjunct Professor of Medicine and Member of the Liver Center at the University of California San Francisco. He was on the staff at San Francisco General Hospital and Trauma Center, where he attended on the in-patient consultative service and in the General Endocrine and Diabetes Clinics. Dr. Schlegel was a trainee in the Medical Scientist Training Program of the Albert Einstein College of Medicine where he received his M.D. and Ph.D. He was an intern and resident physician at Beth Israel Deaconess Medical Center in Boston, MA, and was a Fellow in Medicine at Harvard Medical School. He was a clinical fellow in the Diabetes, Endocrine, and Metabolism Training Program at the University of California San Francisco, where he was subsequently a post-doctoral associate in the laboratory of Professor Didier Y.R. Stainier, Ph.D., in the Department of Biochemistry and Biophysics. It was there that he established a zebrafish molecular genetic system for studying lipid metabolism.

Post-Doctoral Associates

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Tibiabin Benitez-Santana, Ph.D.

Post-Doctoral Associate

PhD in Aquaculture, 2011
University of Las Palmas de Gran Carnaria, Canary Islands, Spain.
tibiabinb [at] u2m2.utah.edu

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Santhosh Karanth, Ph.D.

Post-Doctoral Associate

PhD in Biology, 2010
Dalhousie University, Halifax, Canada
santhosh.karanth [at] u2m2.utah.edu

Technician

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Sarah E. Hugo, BS

Technician

BS in Molecular Biology and Biochemistry, 2005
University of California, Davis
shugo [at] genetics.utah.edu

Alumni

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Lourdes Cruz-Garcia, Ph.D.

Alumni

PhD in Biology, 2010
University of Barcelona, Barcelona, Spain
lourdescruz.garcia [at] utah.edu
Post-doctoral associate 2011-2014

Original Work

 

Schlegel, A. Stainier DYR. Microsomal triglyceride transfer protein is required for yolk lipid utilization and absorption of dietary lipids. Biochemistry. 2006. 45:15179-87. (http://pubs.acs.org/doi/abs/10.1021/bi0619268).

Anderson RM, Bosch JA, Goll MG, Hesselson D, Dong PD, Shin D, Chi NC, Shin CH, Schlegel A, Halpern M, Stainier DY. Loss of Dnmt1 catalytic activity reveals multiple roles for DNA methylation during pancreas development. Dev Biol. 2009. 334:213-23. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759669/)

Hugo SE, Cruz-Garcia L, Karanth S, Anderson RM, Stainier DYR, and Schlegel A. A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting. Genes Dev. 2012. 26:282-293. (http://genesdev.cshlp.org/content/26/3/282.long)

Karanth S, Tran VM, Kuberan B, Schlegel A. Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis. Dis Model Mech. 2013. 6:1365-77. (http://dmm.biologists.org/content/early/2013/09/18/dmm.013425.long)

Cruz-Garcia L, Schlegel A. Lxr-driven enterocyte lipid droplet formation delays transport of ingested lipids.  J Lipid Res. 2014. 55:1944-58. (http://www.jlr.org/content/55/9/1944.long)

Safavi-Hemami H, Gajewiak J, Karanth S, Robinson SD, Ueberheide B, Douglass AD, Schlegel A, Imperial JS, Watkins M, Bandyopadhyay PK, Yandell M, Li Q, Purcell AW, Norton RS, Ellgaard L, Olivera BM. Specialized insulin is used for chemical warfare by fish-hunting cone snails. Proc Natl Acad Sci USA. 2015 112,1743-8. (http://www.pnas.org/content/112/6/1743.long)

Karanth S, Zinkhan EK, Hill JT, Yost HJ, Schlegel A . FOXN3 regulates hepatic glucose utilization. Cell Rep. 2016. 15, 2745-2755. (http://www.cell.com/cell-reports/fulltext/S2211-1247(16)30654-4)

Hugo SE, Schlegel A. A genetic screen for zebrafish mutants with hepatic steatosis identifies a locus required for larval growth. 2016. Dec 15. J Anat,  DOI:  10.1111/joa.12570. (http://onlinelibrary.wiley.com/doi/10.1111/joa.12570/abstract).

Review Articles

Schlegel, A, Stainier DYR. Lessons from “lower” organisms: what worms, flies, and zebrafish can teach us about human energy metabolism. PLoS Genet. 2007. 3:e199. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2098794/)

Schlegel A.  Studying non-alcoholic fatty liver disease with zebrafish: a confluence of optics, genetics and physiology. Cell Mol Life Sci. 2012. 69, 3953-3961. (http://www.springerlink.com/content/712k81680x902248/)

Schlegel A, Gut P. Metabolic insights from zebrafish genetics, physiology, and chemical biology. Cell Mol Life Sci. 2015. 72,2249-60. (http://link.springer.com/article/10.1007%2Fs00018-014-1816-8).

Schlegel A. Zebrafish models for dyslipidemia and atherosclerosis research. Front Endocrinol. 2016. 7,159. (http://journal.frontiersin.org/article/10.3389/fendo.2016.00159/full)

Editorials

Schlegel A, Studying lipoprotein trafficking in zebrafish, the case of chylomicron retention disease. J Mol Med. 2015 93, 115-118.
(http://link.springer.com/article/10.1007/s00109-014-1248-9)

Letters to the Editor

Schlegel A, Monocarboxylate transporter 1 deficiency and ketone utilization. N Engl J Med 2015. 372,578.
(http://www.nejm.org/doi/full/10.1056/NEJMc1415111)

Graduate Programs and Interest Groups

 

We Participate in two Ph-D. granting programs and accept rotation Students:

University of Utah Molecular Biology Program
University of Utah Biological Chemistry Program
15 North 2030 East, Room 1400
Salt Lake City, UT 84112-5330

 

Office: (801) 585-5207
Fax: (801) 585-2465

 

http://www.bioscience.utah.edu/

We are not soliciting post-doctoral fellowship applications right now. Please check back for postings.
We are members of the following Interest Groups:

1. Metabolism (Seminars In Metabolism), which meets Thursdays at 4 pm (HSEB 6200).

2. Zebrafish Interest Group, which meets two Mondays per month at 12 pm (HSEB 1730 or 1750)

3. Membrane Biology Interest Group, which meets the first Tuesday of the month at 9 am (as scheduled).

4. Department of Biochemistry Research In Progress, which meets at 1 pm on Thursdays (Kjeldsberg Conference Room, JMRB 1200)

 

 

Members of the laboratory must attend all interest group meetings, and trainees are expected to present in one or more forum annually.

Living in Utah

Moving to Utah

Apartment Searching

 

ForRent.com | Apartments.com
Craig’s List | KSL Classifieds
University Housing

 

Inexpensive Hotels

 

University Guest House
The Avenues Hostel

 

Housing/Real Estate

 

Chamber of Commerce Salt Lake City
Zip code map for Salt Lake City
Wasatch Front Regional
Realtors.com

 

Commuting

Univ of Utah Commuter Services
UTA (Utah Transit Authority)
Utah Dept of Motor Vehicles

 

Parks and Recreation

Parks

 

Arches, Bryce, Zion, Capitol Reef, Canyonlands, and nearby Yellowstoneand Grand Tetons
Recreation:  utah.com

 

Outdoor Destinations

Antelope Island
Little Cottonwood Canyon
Big Cottonwood Canyon
Uinta National Forest
American Fork Canyon (Pictures)
Bear River Migratory Bird Refuge

 

Everything Snow

Ski*Utah

 

Families with Kids

Child Care

 

Children’s Service Society of Utah
Child care Coordinating Office (University of Utah)

I.J. and Jeanné Wagner Jewish community center

 

Activities

Lagoon Water Park
Outdoor Swimming Pools for Kids
Snowbird Summer Activities
Red Butte Gardens – Kids
Wheeler Historic Farms
Hogle Zoo

Discovery gateway

 

Schools

Salt Lake City School District
Granite School District
Murray School District

Favorite Restaurants

settebello pizzeria napoletana
Red Iguana
Aristo’s

Mazza

Brew Pubs and Taverns

Desert Edge Brewery
Squatters
Red Rock Brewing Company
The Bayou

Upscale Restaurants

Bambara
Cafe Molise

CUcina toscana
Em’s Restaurant
Fresco Italian Cafe

Garden café
Log Haven
Martine’s
Michelangelo Ristorante
Shogun (sushi)

Takashi (sushi)

Kyoto

Beer

Epic Brewing

Moab Brewery

Utah beer festival

 

Salt Lake City Culture

Live Music
Twilight Concert Series (free)
Red Butte Concert Series
The Depot
The Urban Lounge
Shaggy’s Velvet Room
Club Suede (Park City)
Kingsbury Hall (music & theatre)
Kilby Court
Jazz in Salt Lake City
Zanzibar for Live Jazz

 

Art

 

Gallery Stroll
Pioneer Theatre Company
U of U Theatre Productions
Kingsbury Hall
Utah Museum of Fine Arts
Utah Museum of Natural History
Temple Square

 

Farmers Market

directory

 

Miscellaneous

Craig’s list

Downtown Alliance
KSL Classifieds
Salt Lake City Public Library
City Weekly’s “Best of Utah”

Contact Information

 

Amnon Schlegel, MD, PhD
Assistant Professor of Internal Medicine
Adjunct Assistant Professor of Biochemistry
Investigator, University of Utah Molecular Medicine (U2M2) Program

 

Office Address

University of Utah School of Medicine
Division of Endocrinology
15 N 2030 East, EIHG Room 3240B
Salt Lake City, UT 84112

 

Phone: (801) 585-0730
Fax: (801) 585-0701
Email: amnons [at] u2m2.utah.edu

 

Laboratory (FEDEX) Address

15 N 2030 East, EIHG Room 3420
Salt Lake City, UT 84112

 

Phone: (801) 585-0733

 

Clinical Address

(for appointments, questions, and prescriptions)

 

Utah Diabetes and Endocrinology Center
615 Arapeen Dr., Suite 100
Salt Lake City, UT 84108

 

Office: (801) 585-7761
Fax: (801) 585-5906
Appointments: (801) 587-3913

 

http://healthcare.utah.edu/fad
University of Utah Molecular Medicine (U2M2) Program
University of Utah Department of Biochemistry