BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure. METHODS: 26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed. RESULTS: SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects. CONCLUSIONS: Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.

• Klíčová slova
• Adipose tissue, Ether lipids, Heart failure, Inflammation, Sodium-glucose cotransporter 2 inhibitors,
• MeSH
• antiflogistika terapeutické užití   farmakologie   MeSH
• biologické markery krev   MeSH
• diabetes mellitus 2. typu farmakoterapie   metabolismus   diagnóza   MeSH
• epikardiální adipózní tkáň MeSH
• funkce levé komory srdeční účinky léků   MeSH
• glifloziny * terapeutické užití   farmakologie   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mediátory zánětu * metabolismus   MeSH
• metabolomika MeSH
• perikard * metabolismus   účinky léků   MeSH
• srdeční selhání * metabolismus   patofyziologie   farmakoterapie   MeSH
• stupeň závažnosti nemoci * MeSH
• tepový objem účinky léků   MeSH
• tuková tkáň * účinky léků   metabolismus   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiflogistika MeSH
• biologické markery MeSH
• glifloziny * MeSH
• mediátory zánětu * MeSH

Fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous bioactive lipids known for their anti-inflammatory and anti-diabetic properties. Despite their therapeutic potential, little is known about the sex-specific variations in FAHFA metabolism. This study investigated the role of Androgen Dependent TFPI Regulating Protein (ADTRP), a FAHFA hydrolase. Additionally, tissue-specific differences in FAHFA levels, focusing on the perigonadal white adipose tissue (pgWAT), subcutaneous white adipose tissue (scWAT), brown adipose tissue (BAT), plasma, and liver, were evaluated using metabolomics and lipidomics. We found that female mice exhibited higher FAHFA levels in pgWAT, scWAT, and BAT compared to males. FAHFA levels were inversely related to Adtrp mRNA, which showed significantly lower expression in females compared with males in pgWAT and scWAT. However, no significant differences between the sexes were observed in plasma and liver FAHFA levels. Adtrp deletion had minimal impact on both sexes' metabolome and lipidome of pgWAT. However, we discovered higher endogenous levels of triacylglycerol estolides containing FAHFAs, a FAHFA metabolic reservoir, in the pgWAT of female mice. These findings suggest that sex-dependent differences in FAHFA levels occur primarily in specific WAT depots and may modulate local insulin sensitivity in adipocytes. However, further investigations are warranted to fully comprehend the underlying mechanisms and implications of sex effects on FAHFA metabolism in humans.

• Klíčová slova
• Adtrp, FAHFA, adipose tissue, female, lipokines, male,
• Publikační typ
• časopisecké články MeSH
• preprinty MeSH

With the increasing number of lipidomic studies, there is a need for an efficient and automated analysis of lipidomic data. One of the challenges faced by most existing approaches to lipidomic data analysis is lipid nomenclature. The systematic nomenclature of lipids contains all available information about the molecule, including its hierarchical representation, which can be used for statistical evaluation. The Lipid Over-Representation Analysis (LORA) web application (https://lora.metabolomics.fgu.cas.cz) analyzes this information using the Java-based Goslin framework, which translates lipid names into a standardized nomenclature. Goslin provides the level of lipid hierarchy, including information on headgroups, acyl chains, and their modifications, up to the "complete structure" level. LORA allows the user to upload the experimental query and reference data sets, select a grammar for lipid name normalization, and then process the data. The user can then interactively explore the results and perform lipid over-representation analysis based on selected criteria. The results are graphically visualized according to the lipidome hierarchy. The lipids present in the most over-represented terms (lipids with the highest number of enriched shared structural features) are defined as Very Important Lipids (VILs). For example, the main result of a demo data set is the information that the query is significantly enriched with "glycerophospholipids" containing "acyl 20:4" at the "sn-2 position". These terms define a set of VILs (e.g., PC 18:2/20:4;O and PE 16:0/20:4(5,8,10,14);OH). All results, graphs, and visualizations are summarized in a report. LORA is a tool focused on the smart mining of epilipidomics data sets to facilitate their interpretation at the molecular level.

• MeSH
• glycerofosfolipidy * chemie   MeSH
• lipidomika MeSH
• lipidy * analýza   MeSH
• software MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• glycerofosfolipidy * MeSH
• lipidy * MeSH

Branched esters of palmitic acid and hydroxy stearic acid are antiinflammatory and antidiabetic lipokines that belong to a family of fatty acid (FA) esters of hydroxy fatty acids (HFAs) called FAHFAs. FAHFAs themselves belong to oligomeric FA esters, known as estolides. Glycerol-bound FAHFAs in triacylglycerols (TAGs), named TAG estolides, serve as metabolite reservoir of FAHFAs mobilized by lipases upon demand. Here, we characterized the involvement of two major metabolic lipases, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in TAG estolide and FAHFA degradation. We synthesized a library of 20 TAG estolide isomers with FAHFAs varying in branching position, chain length, saturation grade, and position on the glycerol backbone and developed an in silico mass spectra library of all predicted catabolic intermediates. We found that ATGL alone or coactivated by comparative gene identification-58 efficiently liberated FAHFAs from TAG estolides with a preference for more compact substrates where the estolide branching point is located near the glycerol ester bond. ATGL was further involved in transesterification and remodeling reactions leading to the formation of TAG estolides with alternative acyl compositions. HSL represented a much more potent estolide bond hydrolase for both TAG estolides and free FAHFAs. FAHFA and TAG estolide accumulation in white adipose tissue of mice lacking HSL argued for a functional role of HSL in estolide catabolism in vivo. Our data show that ATGL and HSL participate in the metabolism of estolides and TAG estolides in distinct manners and are likely to affect the lipokine function of FAHFAs.

• Klíčová slova
• ATGL, FAHFA, HSL, lipokine,
• MeSH
• bílá tuková tkáň metabolismus   MeSH
• estery chemie   MeSH
• HEK293 buňky MeSH
• kyselina palmitová metabolismus   MeSH
• kyseliny stearové metabolismus   MeSH
• lidé MeSH
• lipasa metabolismus   MeSH
• lipolýza fyziologie   MeSH
• mastné kyseliny metabolismus   MeSH
• metabolismus fyziologie   MeSH
• myši knockoutované MeSH
• myši MeSH
• sterolesterasa metabolismus   MeSH
• triglyceridy metabolismus   MeSH
• tuková tkáň metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• estery MeSH
• kyselina palmitová MeSH
• kyseliny stearové MeSH
• lipasa MeSH
• mastné kyseliny MeSH
• stearic acid MeSH Prohlížeč
• sterolesterasa MeSH
• triglyceridy MeSH

Branched esters of palmitic acid and hydroxystearic acid (PAHSA) are anti-inflammatory and antidiabetic lipokines that connect glucose and lipid metabolism. We aimed to characterize involvement of the 5-PAHSA regioisomer in the adaptive metabolic response of white adipose tissue (WAT) to cold exposure (CE) in mice, exploring the cross talk between glucose utilization and lipid metabolism. CE promoted local production of 5- and 9-PAHSAs in WAT. Metabolic labeling of de novo lipogenesis (DNL) using 2H2O revealed that 5-PAHSA potentiated the effects of CE and stimulated triacylglycerol (TAG)/fatty acid (FA) cycling in WAT through impacting lipogenesis and lipolysis. Adipocyte lipolytic products were altered by 5-PAHSA through selective FA re-esterification. The impaired lipolysis in global adipose triglyceride lipase (ATGL) knockout mice reduced free PAHSA levels and uncovered a metabolite reservoir of TAG-bound PAHSAs (TAG estolides) in WAT. Utilization of 13C isotope tracers and dynamic metabolomics documented that 5-PAHSA primes adipocytes for glucose metabolism in a different way from insulin, promoting DNL and impeding TAG synthesis. In summary, our data reveal new cellular and physiological mechanisms underlying the beneficial effects of 5-PAHSA and its relation to insulin action in adipocytes and independently confirm a PAHSA metabolite reservoir linked to ATGL-mediated lipolysis.

• MeSH
• bílá tuková tkáň metabolismus   MeSH
• glukosa metabolismus   MeSH
• izotopy uhlíku MeSH
• kyselina palmitová metabolismus   MeSH
• kyseliny stearové metabolismus   MeSH
• lipasa genetika   metabolismus   MeSH
• lipogeneze genetika   MeSH
• lipolýza MeSH
• mastné kyseliny metabolismus   MeSH
• metabolomika MeSH
• myši knockoutované MeSH
• myši MeSH
• nízká teplota MeSH
• oxid deuteria MeSH
• triglyceridy metabolismus   MeSH
• tukové buňky metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 5-PAHSA MeSH Prohlížeč
• 9-PAHSA MeSH Prohlížeč
• glukosa MeSH
• izotopy uhlíku MeSH
• kyselina palmitová MeSH
• kyseliny stearové MeSH
• lipasa MeSH
• mastné kyseliny MeSH
• oxid deuteria MeSH
• PNPLA2 protein, mouse MeSH Prohlížeč
• triglyceridy MeSH

Fatty acid esters of hydroxy fatty acids (FAHFAs) are lipid mediators with promising antidiabetic and anti-inflammatory properties that are formed in white adipose tissue (WAT) via de novo lipogenesis, but their biosynthetic enzymes are unknown. Using a combination of lipidomics in WAT, quantitative trait locus mapping, and correlation analyses in rat BXH/HXB recombinant inbred strains, as well as response to oxidative stress in murine models, we elucidated the potential pathway of biosynthesis of several FAHFAs. Comprehensive analysis of WAT samples identified ∼160 regioisomers, documenting the complexity of this lipid class. The linkage analysis highlighted several members of the nuclear factor, erythroid 2 like 2 (Nrf2)-mediated antioxidant defense system (Prdx6, Mgst1, Mgst3), lipid-handling proteins (Cd36, Scd6, Acnat1, Acnat2, Baat), and the family of flavin containing monooxygenases (Fmo) as the positional candidate genes. Transgenic expression of Nrf2 and deletion of Prdx6 genes resulted in reduction of palmitic acid ester of 9-hydroxystearic acid (9-PAHSA) and 11-PAHSA levels, while oxidative stress induced by an inhibitor of glutathione synthesis increased PAHSA levels nonspecifically. Our results indicate that the synthesis of FAHFAs via carbohydrate-responsive element-binding protein-driven de novo lipogenesis depends on the adaptive antioxidant system and suggest that FAHFAs may link activity of this system with insulin sensitivity in peripheral tissues.

• MeSH
• bílá tuková tkáň enzymologie   metabolismus   MeSH
• biologické markery metabolismus   MeSH
• estery chemie   metabolismus   MeSH
• faktor 2 související s NF-E2 genetika   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kyselina palmitová chemie   metabolismus   MeSH
• kyseliny stearové chemie   metabolismus   MeSH
• metabolomika metody   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• náhodné rozdělení MeSH
• oxidační stres * MeSH
• peroxiredoxin VI genetika   metabolismus   MeSH
• potkani inbrední BN MeSH
• potkani inbrední SHR MeSH
• potkani transgenní MeSH
• regulace genové exprese enzymů * MeSH
• stanovení celkové genové exprese MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 9-hydroxystearic acid MeSH Prohlížeč
• biologické markery MeSH
• estery MeSH
• faktor 2 související s NF-E2 MeSH
• kyselina palmitová MeSH
• kyseliny stearové MeSH
• Nfe2l2 protein, mouse MeSH Prohlížeč
• Nfe2l2 protein, rat MeSH Prohlížeč
• peroxiredoxin VI MeSH
• Prdx6 protein, mouse MeSH Prohlížeč