Semenkovich Lab

We are interested in lipid metabolism and how it promotes atherosclerosis in the setting of obesity, insulin resistance and diabetes. Our work is translational, spanning cultured cells, animal models and humans.

Fats are partitioned to tissues in highly regulated ways. Excess lipids directed to adipose tissue are stored and lead to obesity, a disorder associated with diabetes, insulin resistance, and heart disease. We engineered mice with ectopic and inducible expression of uncoupling protein-1 (UCP-1) in specific tissues. UCP-1 is an inner mitochondrial anion transporter that uncouples respiration and oxidative phosphorylation. These animals are being used to study the role of metabolism in age-related diseases such as atherosclerosis and hypertension.

Fatty acid metabolism is controlled in part by the nuclear receptor perioxisome proliferator-activated receptor alpha (PPARalpha). We have demonstrated a role for this receptor in atherosclerosis, diabetes and hypertension in animal models. Using tissue-specific inactivation of the rate-limiting enzyme in atherosclerosis, fatty acid synthase (FAS), we have also shown that FAS generates an endogenous ligand responsible for PPARalpha activation. Ongoing studies are defining how FAS and PPARalpha interact to affect metabolism.

Up to a quarter of Americans have some combination of abnormal lipids, high blood pressure, elevated blood sugar, and excess abdominal fat. Collectively, these conditions constitute the metabolic syndrome, which confers considerable risk for frank diabetes and cardiovascular disease. We have shown that a mutation in the kinase ATM, known to be responsible for the cancer-prone disease ataxia telangiectasia, contributes to features of the metabolic syndrome in mice. Low dose, intermittent administration of the anti-malarial drug chloroquine activates ATM and improves metabolic abnormalities in mice. Mechanistic studies in animal models and clinical trials in humans are testing the hypothesis that ATM activation ameliorates the metabolic syndrome.

People

Principal Investigator

Clay F. Semenkovich, MD

Chief, Division of Endocrinology, Metabolism and Lipid Research

Irene E. and Michael M. Karl Professor
Director, Diabetes Research Center
Professor of Medicine and of Cell Biology and Physiology

Faculty

Support Scientists

Publications

Skeletal muscle lipid flux: running water carries no poison.
Funai K, Semenkovich CF.
AJP – Endo. 2011 August.
PMCID: PMC3275151
Link to Publication

De Novo lipogenesis maintains vascular homeostasis through endothelial nitric-oxide synthase (eNOS) palmitoylation.
Wei X, Schneider JG, Shenouda SM, Lee A, Towler DA, Chakravarthy MV, Vita JA, Semenkovich CF.
J Biol Chem. 2010 Nov 23.
PMID: 21098489

Lipoexpediency: de novo lipogenesis as a metabolic signal transmitter.
Lodhi IJ, Wei X, Semenkovich CF.
Trends Endocrinol Metab. 2010 Oct 1.
PMID: 20889351

Deletion of Tis7 protects mice from high-fat diet-induced weight gain and blunts the intestinal adaptive response postresection.
Yu C, Jiang S, Lu J, Coughlin CC, Wang Y, Swietlicki EA, Wang L, Vietor I, Huber LA, Cikes D, Coleman T, Xie Y, Semenkovich CF, Davidson NO, Levin MS, Rubin DC.
J Nutr. 2010 Nov;140(11):1907-14. Epub 2010 Sep 22.
PMID: 20861213

Genetic, epigenetic, and gene-by-diet interaction effects underlie variation in serum lipids in a LG/JxSM/J murine model.
Lawson HA, Zelle KM, Fawcett GL, Wang B, Pletscher LS, Maxwell TJ, Ehrich TH, Kenney-Hunt JP, Wolf JB, Semenkovich CF, Cheverud JM.
J Lipid Res. 2010 Oct;51(10):2976-84. Epub 2010 Jul 2.
PMID: 20601649

Diet-Dependent Genetic and Genomic Imprinting Effects on Obesity in Mice.
Cheverud JM, Lawson HA, Fawcett GL, Wang B, Pletscher LS, R Fox A, Maxwell TJ, Ehrich TH, Kenney-Hunt JP, Wolf JB, Semenkovich CF.
Obesity (Silver Spring). 2010 Jun 10.
PMID: 20539295

Macrophage fatty-acid synthase deficiency decreases diet-induced atherosclerosis.
Schneider JG, Yang Z, Chakravarthy MV, Lodhi IJ, Wei X, Turk J, Semenkovich CF.
J Biol Chem. 2010 Jul 23;285(30):23398-409. Epub 2010 May 17.
PMID: 20479009

Calpain-10 is a component of the obesity-related quantitative trait locus Adip1.
Cheverud JM, Fawcett GL, Jarvis JP, Norgard EA, Pavlicev M, Pletscher LS, Polonsky KS, Ye H, Bell GI, Semenkovich CF.
J Lipid Res. 2010 May;51(5):907-13.
PMID: 20388922

p53 is required for chloroquine-induced atheroprotection but not insulin sensitization.
Razani B, Feng C, Semenkovich CF.
J Lipid Res. 2010 Jul;51(7):1738-46. Epub 2010 Mar 5.
PMID: 20208057

Mice deficient in group VIB phospholipase A2 (iPLA2gamma) exhibit relative resistance to obesity and metabolic abnormalities induced by a Western diet.
Song H, Wohltmann M, Bao S, Ladenson JH, Semenkovich CF, Turk J.
Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1097-114. Epub 2010 Feb 23.
PMID: 20179248

Identification of a physiologically relevant endogenous ligand for PPARalpha in liver.
Chakravarthy MV, Lodhi IJ, Yin L, Malapaka RR, Xu HE, Turk J, Semenkovich CF.
Cell. 2009 Aug 7;138(3):476-88. Epub 2009 Jul 30.
PMID: 19646743

Calpain-10 is a component of the obesity-related quantitative trait locus, Adip1.
Cheverud JM, Fawcett GL, Jarvis JP, Norgard EA, Pavlicev M, Pletscher LS, Polonsky KS, Ye H, Bell GI, Semenkovich CF.
J Lipid Res. 2009 May 12.
PMID: 19436065

Getting away from glucose: stop sugarcoating diabetes.
Razani B, Semenkovich CF.
Nat Med. 2009 Apr;15(4):372-3. No abstract available.
PMID: 19350008

Why we should put clothes on mice.
Lodhi IJ, Semenkovich CF.
Cell Metab. 2009 Feb;9(2):111-2.
PMID: 19187768

Inactivation of hypothalamic FAS protects mice from diet-induced obesity and inflammation.
Chakravarthy MV, Zhu Y, Yin L, Coleman T, Pappan KL, Marshall CA, McDaniel ML, Semenkovich CF.
J Lipid Res. 2009 Apr;50(4):630-40. Epub 2008 Nov 22.
PMID: 19029118

Insulin resistance and atherosclerosis.
Razani B, Chakravarthy MV, Semenkovich CF.
Endocrinol Metab Clin North Am. 2008 Sep;37(3):603-21, viii. Review.
PMID: 18775354

Altered hepatic triglyceride content after partial hepatectomy without impaired liver regeneration in multiple murine genetic models.
Newberry EP, Kennedy SM, Xie Y, Luo J, Stanley SE, Semenkovich CF, Crooke RM, Graham MJ, Davidson NO.
Hepatology. 2008 Oct;48(4):1097-105.
PMID: 18697204

Requirement for p38 mitogen-activated protein kinase activity in neointima formation after vascular injury.
Proctor BM, Jin X, Lupu TS, Muglia LJ, Semenkovich CF, Muslin AJ.
Circulation. 2008 Aug 5;118(6):658-66. Epub 2008 Jul 21.
PMID: 18645058

Contact

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Lab Contact Information

Clay F. Semenkovich, M.D.
Irene E. and Michael M. Karl Professor
Chief, Division of Endocrinology, Metabolism & Lipid Research
Professor of Medicine and of Cell Biology and Physiology

Email

csemenko@wustl.edu

Mailing Address

660 S. Euclid Ave
Campus Box 8127
St. Louis, MO 63110

Phones & Faxes

Office: (314) 362-7617
Laboratory: (314) 747-8282
Fax: (314) 362-7641
Office Location: 842 SW Tower

Patients

See contact information at the Washington University Physicians website.

Resources
Center for Advanced Medicine (CAM)
Center for Advanced Medicine (CAM)