Our primary research interests revolve around the mechanisms, pathways, and functional implications of dietary fatty acid sensing. Fatty acid sensing can be interpreted as the property of fatty acids to influence biological processes by serving as signaling molecules. In the past two decades, a molecular framework underlying fatty acid sensing has slowly evolved. It is well established that one of the mechanisms by which fatty acids alter gene transcription is by serving as agonists for a group of receptors called peroxisome proliferactors-activated receptors (PPARs). PPARs are ligand-activated transcription factors that are members of the nuclear hormone receptor superfamily. Three different PPARs are known: PPARα, PPARβ/δ and PPARγ. Most of our work has been on PPARα. Partly using transcriptomics we have been able to provide a comprehensive picture of the diverse role of PPARα in hepatic metabolism. We have also come up with an unique experimental design by feeding mice individual fatty acids in the form of synthetic triglycerides. Via the use of transcriptomics we showed that the effects of dietary unsaturated fatty acids on gene expression in liver are almost entirely mediated by PPARα. In recent years, our research focus has progressively shifted to specific target genes of PPARs and fatty acids.
One of the genes that is very sensitive to stimulation by fatty acids encodes Angiopoietin-like protein 4 (Angptl4). Angptl4 is a pro-hormone released by a variety of different organs and cells types. Depending on the cell type, expression of Angptl4 is under control of PPARα, PPARβ/δ or PPARγ. Upon secretion Angptl4 is cleaved into at least two fragments. One fragment blocks lipoprotein lipase, the enzyme that catalyzes uptake of circulating lipids into tissues. Through this mechanism, Angptl4 raises serum triglycerides and protects against cellular lipotoxicity. In macrophages inhibition of lipoprotein lipase by Angptl4 protects against lipid-induced macrophage activation. Failure of this mechanism in mesenteric lymph nodes leads to excessive lipolytic release of fatty acids from lymph chylomicrons, macrophage foam cell formation, ER stress, and marked inflammation that becomes systemic. The other Angptl4 fragment interacts with integrins, a family of cell surface receptors that mediate cell-to-cell and cell-to–extracellular matrix interactions, to modulate wound healing and tumor cell behavior. Currently, we are trying to better characterize the role of Angptl4 in a variety of tissues. In addition, we are exploring the regulation of circulating Angptl4 levels in humans. Finally, our research addresses the communication between metabolically active organs in the context of metabolic diseases such as obesity, diabetes and atherosclerosis. Particular attention goes to the role of specific components of the immune system. To meet these research objectives, a functional genomics type of approach is followed that combines detailed in vitro studies in cell lines and primary cells with experiments in (transgenic) animal models and humans.