Washington University
School of Medicine

Dept. of Medicine
Div. of Cardiovascular Diseases
Box 8086
660 S. Euclid Ave.
St. Louis, MO 63110

tel: (314) 362-8717
fax: (314) 362-0186
email: jschaff@wustl.edu
web: Personal Weblink

Studies of long-chain fatty acid uptake in mammalian cells support the existence of a high affinity protein-mediated transport mechanism at the cell surface that facilitates uptake at physiologic fatty acid concentrations. The plasma membrane-the fatty acid transport protein (FATP1) and long chain fatty acyl Coenzyme A synthetase (ACS1) function coordinately to couple fatty acid import to initial esterification at the plasma membrane of adipocytes and myocytes. Ongoing studies in the lab are aimed at understanding structure-function correlates and regulation of FATP1 and ACS1.

While fatty acids are critical for many cellular functions, accumulation of excess fatty acids in non-adipose tissues leads to cell dysfunction and/or cell death. This lipotoxicity plays an important role in the pathogenesis of diabetes and heart failure. We are using genetic approaches to identify molecules that are important for channeling imported long chain fatty acids to specific cell fates, and to identify lipid metabolic and signaling pathways critical for fatty acid-induced apoptosis. Specifically, we have used a promoter trapping strategy to isolate mutant cell lines resistant to fatty acid-induced apoptosis. We are presently characterizing the disrupted gene that confers resistance in each mutant. We have also created transgenic mouse lines with tissue-restricted overexpression of FATP1 and ACS1 to understand the physiology of lipotoxicity. Our studies may provide insight to the pathogenesis of human disorders such as obesity, diabetes, and heart failure, in which fatty acid homeostasis is perturbed.

Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, Herrero P, Saffitz JE, Schaffer JE. A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest. 2001;107:813-22.