Professor, Interim Chief, Basic Reproductive Sciences
Department of Obstetrics and Gynecology, Department of Physiology and Biophysics
University of Colorado Denver
Regulation of Cellular TRIGLYCERIDE METABOLISM
Grants: 1) NIH 2 R01 HD045965, "Mechanism of Milk Lipid Secretion"
2) NIH 5P01HD038129. “Developmental Regulation of Cytoplasmic Lipid Droplet Synthesis”
3) March of Dimes, “Identification of Biomarkers of Preterm Birth”
Description of Research
The primary focus of research in my laboratory is regulation of cellular triglyceride metabolism. We are interested in the molecular and cellular mechanisms regulating storage and secretion of triglycerides by mammary epithelial cells and hepatocytes, and in the physiological mechanisms regulating triglyceride metabolism during pregnancy and lactation and how diet and ethanol impacts these processes.
Regulation of triglyceride storage, trafficking and secretion: Triglycerides are stored the cytoplasm of most eukaryotic cells in organelle-like structures called cytoplasm lipid droplets (CLD) that in addition to storage also function in triglyceride trafficking and secretion. The biological functions of CLD are hypothesized to be regulated by specific surface associated proteins. A major protein component of CLD in mammalian cells is adipophilin (ADPH), a member of the perilipin family of CLD associated proteins. We utilize targeted mutagenesis of adipophilin and other perilipin family members in conjunction with expression of the mutated proteins in cell culture and mouse transgenic models to study the molecular physiology of their actions.
Mechanisms of diet and ethanol induced liver toxicity: Hepatic triglyceride accumulation (steatosis), induced by a combination of diet or alcohol consumption, is thought to promote cellular damage through production of cytotoxic lipid peroxidation products. Using normal and transgenic mice that lack ADPH we are investigating functional relationships between CLD surface proteins, steatosis, lipid peroxide formation, hepatic cell damage in mice fed diets high in fat and/or ethanol.
Effects of Obesity on lactation: Obesity is known to affect the ability of women to initiate and sustain lactation. We use a mouse model of obesity-induced lactation impairment that was developed in our laboratory to investigate how obesity affects lactation at the physiological and molecular levels. Our studies focus on the effects of diet and obesity on lactation, mammary gland development and maternal and neonatal nutrient utilization.
1-2 Most Significant Publications
1) Orlicky et al., Multiple functions encoded by the N-terminal PAT domain of adipophilin J. Cell Science, 121: 2921, 2008
2) McManaman, J.L. Formation of milk lipids: molecular perspective, Clinical Lipidology, 4: 391, 2009 .
Primary Focus Area (if part of the obesity initiative)
· Obesity Cell Biology
Secondary Focus Areas (if part of the obesity initiative)
· Obesity Pathophysiology and Disease: Applied Mechanisms.
· Developmental Aspects of Obesity
Benefit of CNRU
The major benefit of the CNRU for me has been the enhanced interaction and collaboration with other CNRU investigators. Additionally, the core laboratories of the CNRU are critical to my research success. These laboratories provide services in a cost-effective manner than I could not develop in my own laboratory. CNRU
Metabolism, Proteomics Mass Spectrometry