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The Saez Laboratory


Nuclear receptors as nutrient sensors

Nuclear receptors are ligand transcription factors that modulate gene expression in response to a variety of endocrine and environmental signals. Members of the family that work as heterodimers with the Retinoid X Receptor (RXR) have emerged as sensors of various dietary components, including lipids, fatty acids, retinoids, vitamins, cholesterol, bile acids, and xenobiotics. The nuclear receptor Liver X Receptor (LXR) is a transcription factor that is activated by oxidized forms of cholesterol (oxysterols). It serves as a sensor of excessive intracellular accumulation of pathogenic forms of cholesterol, activating a program of gene expression aimed at promoting removal of harmful cholesterol. In addition to their role in regulation of cholesterol and lipid homeostasis, recent studies have demonstrated that the LXRs (α and β) also modulate expression of key genes in glucose metabolism. As a follow up to this work, we have recently made the surprising observation that glucose can bind and activate LXR target genes in vivo. This novel signal pathway appears to determine glucose fate in the liver: excess glucose is sensed by the same transcription factor responsible for control of fatty acid synthesis. LXR also behaves as a glucose sensor in the intestine, where LXR activation by glucose may impact cholesterol and fatty acid metabolism. Cardiovascular disease is the principal cause of death in patients with diabetes. Myocardial infarction, stroke, and peripheral vascular disease are more common and appear earlier in people with diabetes than in the general population. In spite of ample epidemiological data linking diabetes and cardiovascular disease, the molecular mechanisms that underlie how hyperglycemia promotes atherosclerosis, particularly the transcriptional events that link the two states, remain poorly understood. As the first described transcription factors that can bind both glucose and oxysterols, it is tempting to speculate that LXRs may represent a transcriptional link between hyperglycemia and atherosclerosis. This possibility is presently being explored. We are also using high-throughput cell based and biochemical screens as well as a variety of animal models to discover additional diet-derived physiological signaling pathways.

Genomic and chemical analysis of fat cell formation

Spread of the Western diet and a sedentary lifestyle has lead to a spectacular increase in the prevalence obesity, a major risk factor for insulin resistance, type 2 diabetes, and cardiovascular disease. Obesity is characterized by a massive expansion of white adipose tissue and increased recruitment of adipocyte precursor cells. The molecular mechanisms that regulate adipose cell determination and differentiation have been the subject of intense study. It has become evident that adipogenesis is a dynamic process under the control of multiple hormones and cytokines whose effects are mediated by several signaling cascades and transcription factors. Our view of adipose tissue has also evolved, from that of a simple storage depot, to that of an active endocrine organ that secretes molecules that regulate whole-body energy balance and insulin sensitivity. Transcription factors that act as positive regulators of adipogenesis include the C/EBP family, and PPARγ, a lipid-activated nuclear receptor essential for fat cell formation. PPARγ is also the target of thiazolidinedione drugs, compounds in clinical use for the treatment of type 2 diabetes. This fact highlights the therapeutic potential of modulation of adipose tissue differentiation. To broaden our understanding of the mechanisms that control adipogenesis, we are using novel genome analysis tools to carry out a functional genetic analysis of adipogenesis. In concert, we have identified small molecules to serve as chemical tools to probe signaling pathways that govern fat cell formation. This integrated approach may lead to the isolation of new genetic regulators of adipogenesis that may become therapeutic targets for obesity and diabetes.