Jean E. Schaffer, MD
- Professor of Medicine, Cardiovascular Division
Lipotoxicity and cardiac endoplasmic reticulum stress.
Molecular mechanisms of lipotoxicity
Our lab has used cultured cells to gain an understanding of the molecular mechanisms underlying complications of metabolic diseases such as diabetes and the metabolic syndrome. Incubation of a wide range of cell types in high glucose media supplemented with pathophysiological levels of long-chain saturated fatty acids results in oxidative and endoplasmic reticulum stress and progression to cell death. We have used a variety of biochemical approaches to characterize pathways involved this lipotoxicity (Listenberger et al. 2001, Listenberger et al. 2003, Brookheart et al. 2010).
Pathophysiological models of lipotoxicity
To provide new insights into lipotoxicity in the pathophysiology of metabolic diseases, our cell biology approaches are complemented by studies in genetically modified mice. Given the strong association of altered cardiac lipid metabolism and heart failure in humans, efforts in our lab have focused on understanding the contributions of lipotoxicity to myocardial dysfunction. We have generated two transgenic mouse models in which excess lipid uptake, driven by overexpression of fatty acid transport proteins in the heart leads to cardiac dysfunction.
Human studies of lipotoxicity in diabetic cardiovascular complications
Given the high prevalence of metabolic disease and the significant morbidity and mortality which cardiovascular complications entail, we are motivated to translate our findings to human subjects. Ongoing work in the Schaffer laboratory is focusing on development of integrated measures of systemic lipid metabolism and identification of biomarkers for diabetic complications related to lipotoxicity.