Lipids are basic organic components of living cells. These biomolecules do not show catalytic activities. Despite this fact, lipids participate in a several important cell functions. At the organism level, they serve as energy sources (neutral lipids, fatty acids) or as mediators of signalling molecules. At the cellular level, lipids (glycerophospholipids, sphingolipids and sterols) are structural components of membranes determining the establishment, maintenance and identity of intracellular compartments. In the membrane matrix, the composition of lipids determines physical and chemical properties of the membrane. In addition, lipids, due to their ability to form subdomains with membrane proteins, create appropriate conditions for optimal catalytic activity and/or stability of proteins and thereby influence several regulatory and signalling functions associated with these membranes.

• MeSH
• eukaryotické buňky * fyziologie   MeSH
• glycerofosfolipidy fyziologie   chemie   MeSH
• homeostáza * MeSH
• lidé MeSH
• mastné kyseliny fyziologie   chemie   MeSH
• metabolismus lipidů * MeSH
• neutrální glykosfingolipidy fyziologie   chemie   MeSH
• poruchy metabolismu lipidů MeSH
• sfingolipidy fyziologie   chemie   MeSH
• steroly chemie   MeSH
• Check Tag
• lidé MeSH

The mitochondrial inner membrane glycerophospholipid cardiolipin (CL) associates with mitochondrial proteins to regulate their activities and facilitate protein complex and supercomplex formation. Loss of CL leads to destabilized respiratory complexes and mitochondrial dysfunction. The role of CL in an organism lacking a conventional electron transport chain (ETC) has not been elucidated. Trypanosoma brucei bloodstream forms use an unconventional ETC composed of glycerol-3-phosphate dehydrogenase and alternative oxidase (AOX), while the mitochondrial membrane potential (ΔΨm) is generated by the hydrolytic action of the Fo F1 -ATP synthase (aka Fo F1 -ATPase). We now report that the inducible depletion of cardiolipin synthase (TbCls) is essential for survival of T brucei bloodstream forms. Loss of CL caused a rapid drop in ATP levels and a decline in the ΔΨm. Unbiased proteomic analyses revealed a reduction in the levels of many mitochondrial proteins, most notably of Fo F1 -ATPase subunits and AOX, resulting in a strong decline of glycerol-3-phosphate-stimulated oxygen consumption. The changes in cellular respiration preceded the observed decrease in Fo F1 -ATPase stability, suggesting that the AOX-mediated ETC is the first pathway responding to the decline in CL. Select proteins and pathways involved in glucose and amino acid metabolism were upregulated to counteract the CL depletion-induced drop in cellular ATP.

• MeSH
• adenosintrifosfát metabolismus   MeSH
• elektronový transportní řetězec metabolismus   MeSH
• energetický metabolismus genetika   MeSH
• geneticky modifikované organismy MeSH
• genový knockout * MeSH
• glycerolfosfátdehydrogenasa metabolismus   MeSH
• kardiolipiny genetika   metabolismus   MeSH
• membránové proteiny genetika   metabolismus   MeSH
• membránový potenciál mitochondrií genetika   MeSH
• mitochondriální membrány metabolismus   MeSH
• mitochondriální proteiny metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• oxidoreduktasy metabolismus   MeSH
• proteom MeSH
• proteomika MeSH
• protozoální proteiny genetika   metabolismus   MeSH
• rostlinné proteiny metabolismus   MeSH
• spotřeba kyslíku genetika   MeSH
• transferasy pro jiné substituované fosfátové skupiny genetika   metabolismus   MeSH
• Trypanosoma brucei brucei klasifikace   genetika   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cylindrospermopsin, a potent hepatotoxin produced by harmful cyanobacterial blooms, poses environmental and human health concerns. We used a 3D human liver in vitro model based on spheroids of HepG2 cells, in combination with molecular and biochemical assays, automated imaging, targeted LC-MS-based proteomics, and lipidomics, to explore cylindrospermopsin effects on lipid metabolism and the processes implicated in hepatic steatosis. Cylindrospermopsin (1 μM, 48 h) did not significantly affect cell viability but partially reduced albumin secretion. However, it increased neutral lipid accumulation in HepG2 spheroids while decreasing phospholipid levels. Simultaneously, cylindrospermopsin upregulated genes for lipogenesis regulation (SREBF1) and triacylglycerol synthesis (DGAT1/2) and downregulated genes for fatty acid synthesis (ACLY, ACCA, FASN, SCD1). Fatty acid uptake, oxidation, and lipid efflux genes were not significantly affected. Targeted proteomics revealed increased levels of perilipin 2 (adipophilin), a major hepatocyte lipid droplet-associated protein. Lipid profiling quantified 246 lipid species in the spheroids, with 28 significantly enriched and 15 downregulated by cylindrospermopsin. Upregulated species included neutral lipids, sphingolipids (e.g., ceramides and dihexosylceramides), and some glycerophospholipids (phosphatidylethanolamines, phosphatidylserines), while phosphatidylcholines and phosphatidylinositols were mostly reduced. It suggests that cylindrospermopsin exposures might contribute to developing and progressing towards hepatic steatosis or metabolic dysfunction-associated steatotic liver disease (MASLD).

• MeSH
• alkaloidy * farmakologie   MeSH
• bakteriální toxiny * metabolismus   MeSH
• buněčné sféroidy účinky léků   metabolismus   MeSH
• buňky Hep G2 MeSH
• homeostáza účinky léků   MeSH
• játra * metabolismus   účinky léků   MeSH
• lidé MeSH
• lipidomika MeSH
• lipogeneze účinky léků   MeSH
• metabolismus lipidů * účinky léků   MeSH
• proteomika MeSH
• toxiny kmene Cyanobacteria * MeSH
• uracil * analogy a deriváty   metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The composition of polyunsaturated fatty acids (PUFAs) in cell membranes and body tissues is altered in metabolic syndrome (MetS) and depressive disorder (DD). Within the cell, fatty acid coenzyme A (CoA) ligases (FACLs) activate PUFAs by esterifying with CoA. The FACL4 isoform prefers PUFAs (arachidonic and eicosapentaenoic acid) as substrates, and the FACL4 gene is mapped to Xq23. We have analyzed the association between the common single nucleotide polymorphism (SNP) (rs1324805, C to T substitution) in the first intron of the FACL4 gene and MetS or DD. The study included 113 healthy subjects (54 Males/59 Females), 56 MetS patients (34M/22F) and 41 DD patients (7M/34F). In MetS group, T-carriers and patients with CC or C0 (CC/C0) genotype did not differ in the values of metabolic indices of MetS and M/F ratio. Nevertheless, in comparison with CC/C0, the T-allele carriers were characterized by enhanced unfavorable changes in fatty acid metabolism typical for MetS: higher content of dihomogammalinolenic acid (P < 0.05) and lower content of arachidonic acid in plasma phosphatidylcholine (PC) (P = 0.052), lower index of Delta5 desaturation (P < 0.01) and unsaturation index (UI) (P < 0.001). In contrast, DD patients had higher concentrations of plasma glucose, insulin, conjugated dienes and index of insulin resistance, but showed no significant association with the studied SNP. The present study shows that the common SNP (C to T substitution) in the first intron of the FACL4 gene is associated with altered FA composition of plasma phosphatidylcholines in patients with MetS.

• MeSH
• chromatografie plynová MeSH
• deprese metabolismus   MeSH
• financování organizované MeSH
• fosfatidylcholiny krev   MeSH
• inzulin krev   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• koenzym A-ligasy genetika   MeSH
• krevní glukóza MeSH
• kyselina 8,11,14-eikosatrienová krev   MeSH
• kyselina arachidonová krev   MeSH
• lidé MeSH
• mastné kyseliny metabolismus   MeSH
• metabolický syndrom metabolismus   MeSH
• polymerázová řetězová reakce MeSH
• polymorfismus délky restrikčních fragmentů MeSH
• radioimunoanalýza MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH

T-2 toxin is a worldwide problem for feed and food safety, leading to livestock and human health risks. The objective of this study was to explore the mechanism of T-2 toxin-induced small intestine injury in broilers by integrating the advanced microbiomic, metabolomic and transcriptomic technologies. Four groups of 1-day-old male broilers (n = 4 cages/group, 6 birds/cage) were fed a control diet and control diet supplemented with T-2 toxin at 1.0, 3.0, and 6.0 mg/kg, respectively, for 2 weeks. Compared with the control, dietary T-2 toxin reduced feed intake, body weight gain, feed conversion ratio, and the apparent metabolic rates and induced histopathological lesions in the small intestine to varying degrees by different doses. Furthermore, the T-2 toxin decreased the activities of glutathione peroxidase, thioredoxin reductase and total antioxidant capacity but increased the concentrations of protein carbonyl and malondialdehyde in the duodenum in a dose-dependent manner. Moreover, the integrated microbiomic, metabolomic and transcriptomic analysis results revealed that the microbes, metabolites, and transcripts were primarily involved in the regulation of nucleotide and glycerophospholipid metabolism, redox homeostasis, inflammation, and apoptosis were related to the T-2 toxin-induced intestinal damage. In summary, the present study systematically elucidated the intestinal toxic mechanisms of T-2 toxin, which provides novel ideas to develop a detoxification strategy for T-2 toxin in animals.

• MeSH
• antioxidancia metabolismus   MeSH
• apoptóza MeSH
• dieta MeSH
• homeostáza MeSH
• krmivo pro zvířata analýza   MeSH
• kur domácí * metabolismus   MeSH
• lidé MeSH
• oxidace-redukce MeSH
• potravní doplňky MeSH
• T-2 toxin * toxicita   MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Non-alcoholic fatty liver disease (NAFLD), encompassing fatty liver and its progression into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), is one of the rapidly rising health concerns worldwide. SIRT6 is an essential nuclear sirtuin that regulates numerous pathological processes including insulin resistance and inflammation, and recently it has been implicated in the amelioration of NAFLD progression. SIRT6 overexpression protects from formation of fibrotic lesions. However, the underlying molecular mechanisms are not fully delineated. Moreover, new allelic variants of SIRT6 (N308K/A313S) were recently associated with the longevity in Ashkenazi Jews by improving genome maintenance and DNA repair, suppressing transposons and killing cancer cells. Whether these new SIRT6 variants play different or enhanced roles in liver diseases is currently unknown. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect liver metabolism and associated diseases. We present evidence that overexpression of centenarian-associated SIRT6 variants dramatically altered the metabolomic and secretomic profiles of unchallenged immortalized human hepatocytes (IHH). Most amino acids were increased in the SIRT6 N308K/A313S overexpressing IHH when compared to IHH transfected with the SIRT6 wild-type sequence. Several unsaturated fatty acids and glycerophospholipids were increased, and ceramide tended to be decreased upon SIRT6 N308K/A313S overexpression. Furthermore, we found that overexpression of SIRT6 N308K/A313S in a 3D hepatic spheroid model formed by the co-culture of human immortalized hepatocytes (IHH) and hepatic stellate cells (LX2) inhibited collagen deposition and fibrotic gene expression in absence of metabolic or dietary challenges. Hence, our findings suggest that novel longevity associated SIRT6 N308K/A313S variants could favor the prevention of NASH by altering hepatocyte proteome and lipidome.

• MeSH
• hepatocelulární karcinom * metabolismus   patologie   MeSH
• hepatocyty metabolismus   patologie   MeSH
• kolagen metabolismus   MeSH
• lidé MeSH
• nádory jater * metabolismus   patologie   MeSH
• nealkoholová steatóza jater * genetika   metabolismus   patologie   MeSH
• senioři nad 80 let MeSH
• sirtuiny * genetika   metabolismus   MeSH
• století lidé MeSH
• Check Tag
• lidé MeSH
• senioři nad 80 let MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• fosfatidylcholiny metabolismus   MeSH
• fosfolipidy metabolismus   MeSH
• kardiolipiny metabolismus   MeSH
• mozek metabolismus   MeSH
• psi MeSH
• sfingomyeliny metabolismus   MeSH
• tranzitorní ischemická ataka metabolismus   MeSH
• zvířata MeSH
• Check Tag
• psi MeSH
• zvířata MeSH

Dietary composition and metabolism of fatty acids (FA) influence insulin resistance, atherogenic dyslipidemia and other components of the metabolic syndrome (MS). It is known that patients with MS exhibit a heterogeneous phenotype; however, the relationships of individual FA to MS components have not yet been consistently studied. We examined the plasma phosphatidylcholine FA composition of 166 individuals (68F/98M) with MS and of 188 (87F/101M) controls. Cluster analysis of FA divided the groups into two clusters. In cluster 1, there were 65.7 % of MS patients and 37.8 % of controls, cluster 2 contained 34.3 % of patients and 62.2 % of controls (P<0.001). Those with MS within cluster 1 (MS1) differed from individuals with MS in cluster 2 (MS2) by concentrations of glucose (P<0.05), NEFA (P<0.001), HOMA-IR (P<0.05), and levels of conjugated dienes in LDL (P<0.05). The FA composition in MS1 group differed from MS2 by higher contents of palmitoleic (+30 %), gamma-linolenic (+22 %), dihomo-gamma-linolenic (+9 %) acids and by a lower content of linoleic acid (-25 %) (all P<0.01). These FA patterns are supposed to be connected with the progression and/or impaired biochemical measures of MS (lipolysis, oxidative stress, dysglycidemia, and insulin resistance).

• MeSH
• fosfatidylcholiny krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mastné kyseliny krev   MeSH
• metabolický syndrom krev   klasifikace   diagnóza   MeSH
• senioři MeSH
• shluková analýza MeSH
• stravovací zvyklosti fyziologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Drosophila melanogaster is a chill-susceptible insect. Previous studies on this fly focused on acute direct chilling injury during cold shock and showed that lower lethal temperature (LLT, approximately -5°C) exhibits relatively low plasticity and that acclimations, both rapid cold hardening (RCH) and long-term cold acclimation, shift the LLT by only a few degrees at the maximum. PRINCIPAL FINDINGS: We found that long-term cold acclimation considerably improved cold tolerance in fully grown third-instar larvae of D. melanogaster. A comparison of the larvae acclimated at constant 25°C with those acclimated at constant 15°C followed by constant 6°C for 2 d (15°C→6°C) showed that long-term cold acclimation extended the lethal time for 50% of the population (Lt(50)) during exposure to constant 0°C as much as 630-fold (from 0.137 h to 86.658 h). Such marked physiological plasticity in Lt(50) (in contrast to LLT) suggested that chronic indirect chilling injury at 0°C differs from that caused by cold shock. Long-term cold acclimation modified the metabolomic profiles of the larvae. Accumulations of proline (up to 17.7 mM) and trehalose (up to 36.5 mM) were the two most prominent responses. In addition, restructuring of the glycerophospholipid composition of biological membranes was observed. The relative proportion of glycerophosphoethanolamines (especially those with linoleic acid at the sn-2 position) increased at the expense of glycerophosphocholines. CONCLUSION: Third-instar larvae of D. melanogaster improved their cold tolerance in response to long-term cold acclimation and showed metabolic potential for the accumulation of proline and trehalose and for membrane restructuring.

• MeSH
• aklimatizace MeSH
• aminokyseliny metabolismus   MeSH
• analýza přežití MeSH
• časové faktory MeSH
• Drosophila melanogaster metabolismus   fyziologie   MeSH
• larva metabolismus   fyziologie   MeSH
• mastné kyseliny metabolismus   MeSH
• metabolismus sacharidů MeSH
• metabolom MeSH
• nízká teplota škodlivé účinky   MeSH
• polymery metabolismus   MeSH
• zmrazování škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• Alzheimerova nemoc etiologie   metabolismus   patofyziologie   MeSH
• ceramidy krev   metabolismus   škodlivé účinky   MeSH
• cholesterol krev   metabolismus   škodlivé účinky   MeSH
• deprese etiologie   metabolismus   patofyziologie   MeSH
• fosfolipidy metabolismus   nedostatek   MeSH
• glycerofosfolipidy metabolismus   nedostatek   MeSH
• kanabinoidy metabolismus   škodlivé účinky   MeSH
• kyseliny mastné omega-3 metabolismus   MeSH
• lidé MeSH
• mastné kyseliny metabolismus   MeSH
• metabolismus lipidů * MeSH
• mozek enzymologie   metabolismus   patofyziologie   MeSH
• poruchy metabolismu lipidů * komplikace   MeSH
• schizofrenie etiologie   metabolismus   MeSH
• sebevražda MeSH
• statiny škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH