1. Fatty Acid 2-Hydroxylase and Regulation of Lipid Metabolism.
Mammalian fatty acid 2-hydroxylase (FA2H) was recently identified and characterized. 2-Hydroxy fatty acids (2-OHFA) generated by FA2H are utilized for synthesis of 2-hydroxysphingolipids, which are components of membrane rafts. Alternatively, 2-OHFA can be alpha oxidized in peroxisomes to generate odd chain length fatty acids. Our recent study demonstrated a role of FA2H in adipocyte differentiation and lipogenesis in mature adipocytes by modulation of raft fluidity and levels of GLUT4. We hypothesize that FA2H represents a novel determinant of metabolism in adipocytes. The potential functions of FA2H in pathophysiology of obesity and insulin resistance are under investigation using recently available FA2H null mice and other mouse models of obesity. Correlations of FA2H activities with obesity and insulin resistance in human subjects are also studied.
2. Membrane Remodeling and Trafficking of Nutrient Transporters:
GLUT4 is the major glucose transporter of muscle and adipocytes, where it is responsible for insulin–stimulated glucose uptake. Intensive research on signals regulating trafficking of GLUT4 between the insulin responsive compartment and the plasma membrane (PM) has been performed over the last two decades. In contrast, only a few studies have been carried out to understand the regulatory molecular mechanisms on the trafficking of GLUT4 to lysosomes for degradation. Recent studies identified membrane mobility as a regulator of GLUT4 trafficking and degradation. We will further study molecular mechanisms leading to altered GLUT4 trafficking and degradation.
Fatty acid translocase (FAT)/CD36 has been implicated in the etiology of the metabolic syndrome and of atherosclerosis. Dysfunction of CD36 cycling is reported in muscle and hearts from obese and diabetic subjects resulting in persistently high sarcolemmal CD36 levels. This abnormality is thought to contribute to high fatty acid utilization at the expense of glucose. The mechanisms underlying CD36 trafficking and its dysfunction in diabetes and obesity are unknown. A major pathway important in the regulation of membrane protein trafficking and degradation is ubiquitination. We have made the novel observation that CD36 is ubiquitinated and identified K469 and K472 in the C-terminal cytoplasmic tail of CD36 as the major ubiquitination sites. Our current research is to understand the molecular mechanisms by which palmitoylation and ubiquitination modulate CD36 levels, cellular distribution and lipid metabolism in adipose, muscle and heart and to examine the potential alteration in chemical modifications of CD36 in animal models of insulin resistance and obesity.