Walter Wahli, Professor
|Walter Wahli received his PhD from the University of Bern. He was a postdoc at the Carnegie Institution of Washington in Baltimore, and a visiting associate at the National Cancer Institute, NIH, Bethesda. He became Professor and Director of the Institute of Animal Biology of the UNIL in 1980 and was Vice-rector. He founded the CIG, which he directed until 2005. He has been a member of the SNSF’s research council and presided over the Biology and Medicine Division. He became a member of the Swiss Science and Technology Council in 2008. He is an elected member of the EMBO and of the Institut Jurassien des Sciences, des Lettres et des Arts. Since 2007, he is an elected individual member of the Swiss National Academy of Medical Sciences. He received the Otto-Naegeli Prize (2002), the European Federation of Lipid Research Award (2002) and the Hartmann Müller Prize (2008).
Peroxisome proliferator-activated receptors, energy homeostasis, wound healing, inflammation, cell survival and migration.
The multifaceted roles of PPARs
The three Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear receptors that act as lipid sensors to modulate gene expression. They are implicated in major metabolic and inflammatory regulations with far-reaching medical consequences, and in important mechanisms controlling cellular fate. PPARs exhibit a broad but isotype-specific tissue expression pattern, which can account for the variety of cellular functions they regulate. This diversity of functions is also reflected by the broad range of ligands that can be accommodated within their ligand binding pocket. These ligands are naturally occurring lipids, which include diverse fatty acids, leukotrienes and prostaglandins. Recently, his group has analyzed functions of the three PPAR isotypes, PPARbeta (also called PPARdelta) in wound-healing, muscle energy metabolism and early development of Xenopus, PPARgamma in adipogenesis, and PPARalpha in liver sexual dimorphism.
Healing of cutaneous wounds proceeds via a pattern of events including inflammation, re-epithelialization, and tissue remodeling. We have shown that the inflammation that immediately follows injury increases the expression of PPARbeta and triggers the production of endogenous PPARbeta ligands. PPARbeta then activates a major cellular survival pathway, which protects keratinocytes from death at the site of injury. We have also demonstrated that transforming growth factor beta (TGFbeta1) down regulates the action of inflammation-induced PPARbeta, thereby participating in the coordination of re-epithelialization. This latter event depends on directional sensing and migration of keratinocytes. We found that the activation of PPARbeta amplifies intracellular signals required for cellular directional sensing, cell polarization and pseudopodia extension. These processes are delayed and reduced in PPARbeta-null keratinocytes. Consistently, early wound biopsies of PPARbeta-null mice reveal uncoordinated migratory fronts at the wound edge demonstrating a defect in directional sensing. Together, these observations reveal the molecular mechanisms by which PPARbeta and its ligands contribute to wound closure. In addition, PPARbeta contributes to the homeostatic control of keratinocyte proliferation and differentiation mediated via its regulation, in dermal fibroblasts, of IL-1 signaling.
We have undertaken an in depth analysis of the role of PPARs in Xenopus laevis development. Down regulation of PPARbeta has dramatic effects on both gastrulation and early organogenesis. PPARbeta controls gastrulation movements. At the molecular level, it regulates the Nodal pathway by controlling the transcription of the 6 Nodal ligands (Xenopus nodal related genes 1-6; Xnr 1-6). Interestingly, PPARbeta behaves as a positive regulator of Xnr genes immediately prior to gastrulation but functions as a repressor during gastrulation. All together, our data pinpoint PPARbeta as a key factor in early embryo patterning.
PPARgamma is involved in adipocyte differentiation and insulin sensitivity. Synthetic ligands, the thiazolidinediones (TZD), are used as insulin sensitizers in the treatment of type 2 diabetes. PPARgamma serves as an essential regulator of adipocyte differentiation and lipid storage, and is required for maintenance and survival of mature adult adipocytes. Deregulations of its functions are thought to account for diseases such as obesity and diabetes. We found recently that deletion of one PPARgamma allele not only affects lipid synthesis, pentose phosphate shunt, lipolysis, and glycerol export, but also, more surprisingly, networks of genes involved in IR/IGF-1 signaling, cellular integrity, detoxification, and inflammation/immunity. These results unveil novel roles of PPARgamma in the adipose tissue and underscore the multifaceted action of this receptor in the fine-tuned functioning of this major tissue in the healthy and diseased organism.
Most metabolic studies are conducted in male animals and, consequently, the molecular mechanism controlling gender-specific pathways has been neglected. Our recent work showed that PPARalpha has broad female-dependent repressive actions on hepatic genes involved in steroid metabolism and inflammation. Using the steroid oxysterol hydroxylase gene Cyp7b1 as a model, we elucidated the molecular mechanism of this PPARalpha-dependent repression. Physiologically, this repression confers protection against estrogen-induced intrahepatic cholestasis, suggesting a novel therapy against the most common hepatic disease during pregnancy.
N. Leuenberger, S. Pradervand, Wahli W. (2009). Sumoylated PPARalpha mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice. J. Clin. Invest., 119, 3138–3148.
Brawand D, *Wahli W, *Kaessmann H. (2008). Loss of egg yolk genes in mammals and the origin of lactation and placentation. PLoS Biol, 6:e63. *Joint corresponding authors.
Michalik L, Wahli W. (2006). Involvement of PPAR nuclear receptors in tissue injury and wound repair. J Clin Invest, 116:598-606.
Di-Poi N, Ng CY, Tan NS, Yang Z, Hemmings BA, Desvergne B, Michalik L, Wahli W. (2005). Epithelium-mesenchyme interactions control the activity of peroxisome proliferator-activated receptor beta/delta during hair follicle development. Molecular and Cellular Biology, 25(5):1696-712.
Tan NS, Michalik L, Di-Poi N, Ng CY, Mermod N, Roberts AB, Desvergne B, Wahli W. (2004). Essential role of Smad3 in the inhibition of inflammation-induced PPARbeta/delta expression. EMBO Journal, 23(21):4211-21.
Michalik L, Desvergne B, Wahli W. (2004). Peroxisome proliferator-activated receptors and cancers: complex stories. Nature Reviews Cancer, 4:61-70.