At the crossroads of inflammation and lipid metabolism : modulation of macrophage functionality by long-chain metabolites of Vitamin E and related compounds

Aim: Extend and distribute the knowledge on the effects of long-chain metabolites of vitamin E (LCM) on lipid metabolism and the inflammatory response. Virtually all non-communicable diseases (NCD) are accompanied by a minor inflammation, often caused by a metabolic dysfunction. Consequently, LCM could mediate the effect of vitamin E in these disease patterns at least in part and potentially serve as possible therapeutic approaches in the future. Understanding the molecular effects of LCM is essential to establish plausibility between the observations from studies with vitamin E and the potential effects of LCM. Strategy: 1) The current state of knowledge on LCM and similar structures was regularly summarized to provide the knowledge and hypotheses to a broad (professional) audience. 2) Methods and models for research on LCM (useful in the general context of NCD) were developed, refined, characterized and validated. 3) Properties of LCM and similar structures with respect to the beneficial influence on lipid metabolism and the inflammatory response were investigated. Contribution to the research field: 1) Suggestion of a direction for future LCM research with respect to the physiological function as a metabolically activated form of vitamin E. 2) Demonstration of the unsuitability of GW9662 as tool for examination of PPARγ in macrophages and highlighting the predominance of PPARδ in macrophages, thus generating a significant impact on the investigation of the effects of LCM in this model. 3) Characterization of the adaptive response of macrophages and the identification of CCL2 as a major target of LCM provide new promising starting points for future studies. 4) Demonstration of LCM-mediated protection against the harmful effects of lipid overload suggests positive effects in corresponding disease patterns. 5) Highlighting the LCM-like δ-garcinoic acid as an interesting pharmacological lead substance for future research in the context of inflammatory diseases.