Redox derived damage associated molecular patterns (DAMPs) as pro-inflammatory triggers in human obesity

Poster.-- 26th Annual Conference of the Society for Redox Biology and Medicine (SfRBM2019), November 20-23, 2019, Las Vegas, USAObesity and related complications including insulin resistance and type II diabetes are characterized by low level chronic inflammation and redox imbalance. Dysregulation of lipid metabolic pathways in the presence of increased amounts of reactive oxygen species result in a generation of lipid peroxidation products (LPPs). LPPs can play different roles in adipose tissue pathogenesis. They can act as a secondary messengers in signal transduction pathways and/or as damage associate molecular pattern (DAMPs) recognized by a natural antibodies and different pattern recognition receptors (PRRs) on immune cells. Furthermore, electrophilic LPPs can react with various cellular and extracellular proteins to form even more stable DAMPs thus increasing overall proinflammatory status of the affected tissue. To understand the role of lipid-derived protein modifications and especially there proinflammatory potential, we performed analysis of reactive LPPs protein targets in subcutaneous and visceral adipose tissue from insulin sensitive and resistant obese patients. Using combination of immunoprecipitation, Wertern blot, ELISA and LC-MS/MS analysis LPP-derived DAMPs in adipose tissue were identified and relatively quantified. Furthermore, significant differences between types of adipose tissue (subcutaneous vs visceral) and metabolic states (insulin sensitive vs insulin resistant) were demonstrated. Analysis of the complex interplay between oxidized lipid and their protein targets will assist the discovery of early disease biomarkers and key molecules for the design of targeted intervention strategiesPeer reviewe

Modified lipids and lipid-protein adducts as pro-inflammatory markers in obesity and related complications

1st International Lipidomics Society annual conference and 7th Lipidomics Forum, October 5th - 8th 2021, in Regensburg, GermanyN

From Oxidized Fatty Acids to Dimeric Species: In Vivo Relevance, Generation and Methods of Analysis

The occurrence of free fatty acids (FFAs) and the generation of reactive oxygen species (ROS) such as hydroxyl radicals (HO●) or hypochlorous acid (HOCl) is characteristic of inflammatory diseases, for instance, rheumatoid arthritis. Unsaturated fatty acids react with ROS yielding a variety of important products such as peroxides and chlorohydrins as primary and chain-shortened compounds (e.g., aldehydes and carboxylic acids) as secondary products. These modified fatty acids are either released from phospholipids by phospholipases or oxidatively modified subsequent to their release. There is increasing evidence that oligomeric products are also generated upon these processes. Fatty acid esters of hydroxy fatty acids (FAHFAs) are considered as very important products, but chlorinated compounds may be converted into dimeric and (with smaller yields) oligomeric products, as well. Our review is structured as follows: first, the different types of FFA oligomers known so far and the mechanisms of their putative generation are explained. Industrially relevant products as well as compounds generated from the frying of vegetable oils are also discussed. Second, the different opinions on whether dimeric fatty acids are considered as “friends” or “foes” are discussed

Mass spectrometric investigations of the action of hypochlorous acid on monomeric and oligomeric components of glycosaminoglycans

Hypochlorous acid (HOCl) is a strong non-radical oxidant, which is generated during inflammatory processes under the catalysis of the enzyme myeloperoxidase (MPO). HOCl reacts particularly with sulfhydryl and amino acid residues but affects also many other biomolecules. For instance, the glycosaminoglycans of articular cartilage and synovial fluids (such as hyaluronan) undergo degradation in the presence of HOCl at which the native polysaccharide is fragmented into oligosaccharides in a complex reaction.This is an initial mass spectrometry (MS)-based investigation dealing with the HOCl-induced degradation of glycosaminoglycans and the conversion of the related monosaccharides into chlorinated products. In particular, it will be shown that the reaction between HOCl and hyaluronan is slower than originally assumed and results in the generation of different products (particularly the hyaluronan monosaccharides) by the cleavage of the β-1,3/1,4-glycosidic linkages. The MS detection of chlorinated products is, however, only possible in the case of the monosaccharides. Potential reasons will be discussed

Phospholipid Scramblase 4 (PLSCR4) Regulates Adipocyte Differentiation via PIP3-Mediated AKT Activation

Phospholipid scramblase 4 (PLSCR4) is a member of a conserved enzyme family with high relevance for the remodeling of phospholipid distribution in the plasma membrane and the regulation of cellular signaling. While PLSCR1 and -3 are involved in the regulation of adipose-tissue expansion, the role of PLSCR4 is so far unknown. PLSCR4 is significantly downregulated in an adipose-progenitor-cell model of deficiency for phosphatase and tensin homolog (PTEN). PTEN acts as a tumor suppressor and antagonist of the growth and survival signaling phosphoinositide 3-kinase (PI3K)/AKT cascade by dephosphorylating phosphatidylinositol-3,4,5-trisphosphate (PIP3). Patients with PTEN germline deletion frequently develop lipomas. The underlying mechanism for this aberrant adipose-tissue growth is incompletely understood. PLSCR4 is most highly expressed in human adipose tissue, compared with other phospholipid scramblases, suggesting a specific role of PLSCR4 in adipose-tissue biology. In cell and mouse models of lipid accumulation, we found PLSCR4 to be downregulated. We observed increased adipogenesis in PLSCR4-knockdown adipose progenitor cells, while PLSCR4 overexpression attenuated lipid accumulation. PLSCR4 knockdown was associated with increased PIP3 levels and the activation of AKT. Our results indicated that PLSCR4 is a regulator of PI3K/AKT signaling and adipogenesis and may play a role in PTEN-associated adipose-tissue overgrowth and lipoma formation