In response to repeated and long-lasting food shortages during evolution, humans have evolved with an intricate metabolic control system that allows them to survive prolonged period of food deprivation. One hallmark of this adaptive system is the ability to store large amounts of energy in the form of fat in times of plenty and mobilize this energy under conditions of food shortage. My lab is interested in the molecular mechanisms that govern energy metabolism during fasting, concentrating on the role of two factors: the peroxisome proliferator activated receptor alpha, a ligand-activated transcription factor, and the Angiopoietin-like protein 4, a secreted protein mainly produced in adipose tissue. To study the function of these two proteins, a variety of tools are used including transgenics and micro-array technology

PPARa is one of three different PPAR isotypes that are known to date. The PPARs are members of the nuclear hormone receptor superfamily and therefore share the typical structure and molecular mode of action of these type of receptors. They can be activated by certain ligands and modulate DNA transcription by binding to specific nucleotide sequences in the promoter region of target genes. The PPARa isotype is mostly expressed in liver and is the cellular target of fibrate drugs. Fibrates, which include gemfibrozil, bezafibrate and fenofibrate, are potent hypolipidemic drugs widely used in the treatment of cardiovascular disease. It is now evident that one of the main functions of PPARa is to stimulate the expression of genes involved in fatty acid metabolism in liver, which includes fatty acid uptake through membranes, fatty acid binding in cells, fatty acid oxidation (mitochondrial, peroxisomal and microsomal), and lipoprotein assembly and transport. PPARa is also activated by fatty acids and likely accounts for the majority of the effects of dietary poly-unsaturated fatty acids on gene expression in liver. One of my current interests is to further elucidate the role of PPARa in energy homeostasis in liver and other organs. In this pursuit we extensively use transcriptomics as a global screening tool to map PPARa-dependent genes and pathways. By following this approach, we have been able to show that PPARa is directly involved in the regulation of glucose metabolism via stimulating the conversion of glycerol into glucose. Recently, we came up with an unique experimental design by feeding mice individual fatty acids in the form of synthetic triglycerides. Using microarray analysis we were able to show that the effect of dietary unsaturated fatty acids on gene expression in liver are almost entirely mediated by PPARa.

In the past few years it has become increasingly clear that adipose tissue not merely serves as a storage site for excess calories but also has an important endocrine function. The most widely known factor produced by adipose tissue is leptin, a 16 kD protein which regulates feeding behavior and influences energy expenditure. Other factors secreted by adipose tissue include Tumor Necrosis Factor alpha, which has been postulated to act as a link between obesity and insulin resistance, adipocyte complement related protein 30, adipoQ, angiotensin II, resistin, and the fasting induced adipose factor/Angiopoietin-like protein 4 (FIAF/Angptl4). Angptl4 is an about 50 kD protein that belongs to the family of angiopoietin-like proteins. The expression of Angptl4 is markedly increased during fasting in both liver and adipose tissue. It was discovered by screening for target genes of the peroxisome proliferators activated receptors alpha and gamma, which serve as the molecular targets of the hypolipidemic fibrate and the insulin sensitizing thiazolidinedione drugs, respectively. These data suggests that Angptl4 represents an endocrine factor involved in the regulation of energy homeostasis. Research in the lab is focused on further elucidating the function of Angptl4 in mammalian energy metabolism. Studies from our and other groups have indicated that Angptl4 plays a major role in the regulation of plasma lipoprotein metabolism. Indeed, upregulation of Angptl4 leads to markedly elevated plasma triglyceride concentrations. Rather than by affecting the production of very low density lipoproteins, Angptl4 raises plasma TG by impairing the LPL-mediated clearance of plasma triglycerides. These effects are likely achieved by physical association with plasma lipoproteins. Angptl4 thus represents a highly interesting candidate for therapeutic targeting of dyslipidemia.

List of publications

last updated April 30, 2009