Research

Current Research Projects

PPARs and LXRs are central regulators of gene expression linked to lipid metabolism. We have provided in vivo evidence that the nuclear receptor signaling pathways have important roles in physiologic lipid homeostasis as well as in the pathobiology of atherosclerosis, dyslipidemia, and diabetes. This work has highlighted nuclear receptors as potential therapeutic targets for metabolic disease.

We are interested how the phospholipid and cholesterol composition of biological membranes impacts their function. Recent work has highlighted that phospholipid remodeling is used as a regulatory strategy to control biological processes such as lipoprotein production and cell proliferation. Furthermore, altered membrane composition affects inflammatory signaling pathways in macrophages and other immune cells.

We have shown that nuclear receptors such as the LXRs and PPARs coordinate lipid metabolism and modulate immunity and inflammation. They also control the transcription of genes directly linked to lipid uptake, efflux, and transport and genes involved in inflammatory responses. Our studies have revealed mechanisms through which cholesterol and triglyceride metabolism affect immune responses.

Our group has a longstanding interest in adipocyte biology, stemming from the discovery of PPARg as the master adipocyte transcription factor. In recent years we have elucidated pathways underlying adipocyte differentiation and function, provided insight into how differential gene expression programs are established in white and brown adipose tissue. We have used high-throughput screening approaches to identify new genes and small molecules that modulate adipocyte development and function.

We have defined the E3 ubiquitin ligase IDOL as an LXR-dependent mechanism for feedback regulation of the LDLR pathway by sterols. We elucidated the structural basis for the IDOL–LDLR interaction and cellular pathways involved in LDLR degradation. We also defined the contribution of the LXR-LDLR pathway in controlling sterol homeostasis in mice and primates and uncovered links to central nervous system biology. IDOL is a major regulator of LDLR expression in the brain and a major determinant of susceptibility to Alzheimer’s-like disease in mice. Recent work has shown that control of brain ApoER2 levels by IDOL is critical for synaptic plasticity and learning and memory in mice.