Nitrogen is one of the most important nutrient sources for the growth of microalgae. We studied the effects of nitrogen starvation on the growth responses, biochemical composition, and fatty acid profile of Dunaliella tertiolecta, Phaeodactylum tricornutum, and Nannochloropsis oculata. The lack of nitrogen caused changes in carbohydrate, protein, lipid, and fatty acid composition in all examined microalgae. The carbohydrate content increased 59% in D. tertiolecta, while the lipid level increased 139% in P. tricornutum under nitrogen stress conditions compared to the control groups. Nitrogen starvation increased the oligosaccharide and polysaccharide contents of D. tertiolecta 4.1-fold and 3.6-fold, respectively. Furthermore, triacylglycerol (TAG) levels in N. oculata and P. tricornutum increased 2.3-fold and 7.4-fold, respectively. The dramatic increase in the amount of TAG is important for the use of these microalgae as raw materials in biodiesel. Nitrogen starvation increased the amounts of oligosaccharides and polysaccharides of D. tertiolecta, while increased eicosapentaenoic acid (EPA) in N. oculata and docosahexaenoic acid (DHA) content in P. tricornutum. The amount of polyunsaturated fatty acids (PUFAs), EPA, DHA, oligosaccharides, and polysaccharides in microalgal species can be increased without using the too costly nitrogen source in the culture conditions, which can reduce the most costly of living feeding.
OBJECTIVE: This study tested the hypothesis that limited subcutaneous adipose tissue (SAT) expansion represents a primary predisposition to the development of type 2 diabetes mellitus (T2DM), independent of obesity, and identified novel markers of SAT dysfunction in the inheritance of T2DM. METHODS: First-degree relatives (FDR) of T2DM patients (n = 19) and control individuals (n = 19) without obesity (fat mass < 25%) were cross-sectionally compared. Body composition (bioimpedance, computed tomography) and insulin sensitivity (IS; oral glucose tolerance test, clamp) were measured. SAT obtained by needle biopsy was used to analyze adipocyte size, lipidome, mRNA expression, and inflammatory markers. Primary cultures of adipose precursors were analyzed for adipogenic capacity and metabolism. RESULTS: Compared with control individuals, FDR individuals had lower IS and a higher amount of visceral fat. However, SAT-derived adipose precursors did not differ in their ability to proliferate and differentiate or in metabolic parameters (lipolysis, mitochondrial oxidation). In SAT of FDR individuals, lipidomic and mRNA expression analysis revealed accumulation of triglycerides containing polyunsaturated fatty acids and increased mRNA expression of lysyl oxidase (LOX). These parameters correlated with IS, visceral fat accumulation, and mRNA expression of inflammatory and cellular stress genes. CONCLUSIONS: The intrinsic adipogenic potential of SAT is not affected by a family history of T2DM. However, alterations in LOX mRNA and polyunsaturated fatty acids in triacylglycerols are likely related to the risk of developing T2DM independent of obesity.
- MeSH
- diabetes mellitus 2. typu * genetika metabolismus MeSH
- inzulinová rezistence * genetika MeSH
- lidé MeSH
- messenger RNA metabolismus MeSH
- nenasycené mastné kyseliny metabolismus MeSH
- nitrobřišní tuk metabolismus MeSH
- obezita genetika metabolismus MeSH
- podkožní tuk metabolismus MeSH
- průřezové studie MeSH
- triglyceridy metabolismus MeSH
- tuková tkáň metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
This study investigated the therapeutic potential of probiotic bifidobacteria, isolated from Iranian fermented dairy products, in a hyperlipidemic animal model. Bifidobacterium strains were extracted from traditional dairy samples and screened using physiological and phenotypic examinations, 16S rRNA analysis, and probiotic properties such as tolerance to gastrointestinal juice, antimicrobial activity, and antibiotic susceptibility. The ability of the screened bifidobacteria to reduce serum and liver lipids in vivo was tested using male Wistar rats. Six strains of bifidobacteria were isolated from traditional Iranian fermented dairy. These strains showed promising in vitro activity in lowering triglyceride and cholesterol, tolerance to simulated gastrointestinal juice, the ability to adhere to Caco-2 cells, acceptable antibiotic susceptibility, and a broad spectrum of antibacterial activity. The diet supplemented with isolated bifidobacteria significantly reduced serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), liver tissue lipid levels, and hepatic enzymes in animals when compared to a high-fat diet without strains (p < 0.01). Additionally, the potential probiotic-supplemented diet significantly increased bile acid excretion in the feces and upregulated hepatic CYP7A1 expression levels (p < 0.05), while NPC1L1, ACAT2, and MTP gene expressions in small intestinal cells were downregulated (p < 0.05). Bifidobacteria isolated from Iranian traditional dairy showed potential for use in the production of fermented foods that have hypolipemic activity in the host.
- MeSH
- antibakteriální látky farmakologie MeSH
- Bifidobacterium * genetika izolace a purifikace metabolismus MeSH
- Caco-2 buňky MeSH
- cholesterol-7-alfa-hydroxylasa genetika metabolismus MeSH
- cholesterol krev metabolismus MeSH
- feces mikrobiologie MeSH
- hyperlipidemie * MeSH
- játra metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- mléčné výrobky mikrobiologie MeSH
- modely nemocí na zvířatech MeSH
- potkani Wistar * MeSH
- probiotika * aplikace a dávkování farmakologie MeSH
- RNA ribozomální 16S genetika MeSH
- triglyceridy krev metabolismus MeSH
- žlučové kyseliny a soli metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Írán MeSH
The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is associated with abnormalities of liver lipid metabolism. On the contrary, a diet enriched with n-3 polyunsaturated fatty acids (n-3-PUFAs) has been reported to ameliorate the progression of NAFLD. The aim of our study was to investigate the impact of dietary n-3-PUFA enrichment on the development of NAFLD and liver lipidome. Mice were fed for 6 weeks either a high-fat methionine choline-deficient diet (MCD) or standard chow with or without n-3-PUFAs. Liver histology, serum biochemistry, detailed plasma and liver lipidomic analyses, and genome-wide transcriptome analysis were performed. Mice fed an MCD developed histopathological changes characteristic of NAFLD, and these changes were ameliorated with n-3-PUFAs. Simultaneously, n-3-PUFAs decreased serum triacylglycerol and cholesterol concentrations as well as ALT and AST activities. N-3-PUFAs decreased serum concentrations of saturated and monounsaturated free fatty acids (FAs), while increasing serum concentrations of long-chain PUFAs. Furthermore, in the liver, the MCD significantly increased the hepatic triacylglycerol content, while the administration of n-3-PUFAs eliminated this effect. Administration of n-3-PUFAs led to significant beneficial differences in gene expression within biosynthetic pathways of cholesterol, FAs, and pro-inflammatory cytokines (IL-1 and TNF-α). To conclude, n-3-PUFA supplementation appears to represent a promising nutraceutical approach for the restoration of abnormalities in liver lipid metabolism and the prevention and treatment of NAFLD.
- MeSH
- cholesterol metabolismus MeSH
- cholin metabolismus MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- játra metabolismus MeSH
- kyseliny mastné neesterifikované metabolismus MeSH
- kyseliny mastné omega-3 * farmakologie terapeutické užití metabolismus MeSH
- methionin metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nealkoholová steatóza jater * etiologie genetika MeSH
- nenasycené mastné kyseliny metabolismus MeSH
- Racemethionin metabolismus farmakologie MeSH
- triglyceridy metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- ateroskleróza * etiologie metabolismus patofyziologie MeSH
- hypertriglyceridemie etiologie farmakoterapie MeSH
- lidé MeSH
- lipoproteiny * klasifikace metabolismus škodlivé účinky MeSH
- rizikové faktory kardiovaskulárních chorob MeSH
- triglyceridy metabolismus škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- směrnice pro lékařskou praxi MeSH
Nonalcoholic steatohepatitis (NASH) is a severe liver disorder characterized by triglyceride accumulation, severe inflammation, and fibrosis. With the recent increase in prevalence, NASH is now the leading cause of liver transplant, with no approved therapeutics available. Although the exact molecular mechanism of NASH progression is not well understood, a widely held hypothesis is that fat accumulation is the primary driver of the disease. Therefore, diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in triglyceride synthesis, has been explored as a NASH target. RNAi-based therapeutics is revolutionizing the treatment of liver diseases, with recent chemical advances supporting long-term gene silencing with single subcutaneous administration. Here, we identified a hyper-functional, fully chemically stabilized GalNAc-conjugated small interfering RNA (siRNA) targeting DGAT2 (Dgat2-1473) that, upon injection, elicits up to 3 months of DGAT2 silencing (>80%-90%, p < 0.0001) in wild-type and NSG-PiZ "humanized" mice. Using an obesity-driven mouse model of NASH (ob/ob-GAN), Dgat2-1473 administration prevents and reverses triglyceride accumulation (>85%, p < 0.0001) without increased accumulation of diglycerides, resulting in significant improvement of the fatty liver phenotype. However, surprisingly, the reduction in liver fat did not translate into a similar impact on inflammation and fibrosis. Thus, while Dgat2-1473 is a practical, long-lasting silencing agent for potential therapeutic attenuation of liver steatosis, combinatorial targeting of a second pathway may be necessary for therapeutic efficacy against NASH.
- MeSH
- diacylglycerol-O-acyltransferasa genetika metabolismus MeSH
- fibróza MeSH
- játra metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši obézní MeSH
- myši MeSH
- nealkoholová steatóza jater * farmakoterapie terapie MeSH
- obezita genetika terapie MeSH
- terapie založená na RNAi MeSH
- triglyceridy metabolismus terapeutické užití MeSH
- zánět metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Zvýšené hladiny LDL-cholesterolu (LDL-C) a triglyceridů (TG) představují významné rizikové faktory aterosklerotických kardiovaskulárních onemocnění (ASKVO). Přes významné pokroky medicíny v oblasti hypolipidemik nedokážeme v současné době u řady pacientů dosáhnout cílů v léčbě dyslipidemií. Během posledních dvou dekád je intenzivně studována molekula ANGPTL3 (angiopoietin-like 3), jejíž inaktivace pomocí monoklonálních protilátek, antisense oligonukleotidů aj. představuje nový a slibný léčebný prostředek ke snížení plazmatické koncentrace LDL-C a TG. ANGPTL3 je faktor secernovaný játry, který inhibuje lipoproteinovou lipázu (LPL) a jiné lipázy cestou tvorby komplexu s příbuzným proteinem ANGPTL8. Rozsáhlé genetické studie u jedinců, kteří jsou nositelé genetických variant spojených se ztrátou funkce (LOF – loss-of-function) ANGPTL3, prokázaly vliv na snížení plazmatických koncentrací LDL-C a TG, ale i na snížení rizika ASKVO. Známy jsou již také výsledky klinických studií u pacientů s různými formami dyslipidemií, ve kterých inaktivace ANGPTL3 pomocí monoklonálních protilátek nebo antisense oligonukleotidů významně snižovala plazmatickou koncentraci LDL-C a TG. Z tohoto pohledu mají postupy využívající inhibici ANGPTL3 slibný terapeutický potenciál k redukci plazmatické koncentrace LDL-C a triglyceridů u vybraných skupin pacientů s dyslipidemií.
Elevated LDL-cholesterol (LDL-C) and triglyceride (TG) levels are significant risk factors for atherosclerotic cardiovascular diseases (ASCVD). Despite significant medical advances in the field of hypolipidemic drugs, we are currently unable to achieve our goals in treating dyslipidaemias in many patients. During the last two decades, the angiopoietin-like 3 (ANGPTL3) molecule has been intensively studied, and its inactivation by monoclonal antibodies, antisense oligonucleotides, etc. represents a new and promising therapeutic approach to reduce plasma LDL-C and TG concentrations. ANGPTL3 is a liver- secreted factor that inhibits lipoprotein lipase (LPL) and other lipases by forming a complex with the related protein ANGPTL8. Extensive genetic studies in individuals carrying ANGPTL3 loss-of-function variants have shown an effect on reducing plasma concentrations of LDL-C and TG, as well as the risk of ASCVD. Results from clinical trials in patients with various forms of dyslipidaemia, in which inactivation of ANGPTL3 with monoclonal antibodies or antisense oligonucleotides significantly reduced plasma LDL-C and TG concentrations, are also known. From this perspective, approaches using ANGPTL3 inhibition have promising therapeutic potential to reduce plasma LDL-C and triglyceride concentrations in selected groups of patients with dyslipidaemia.
- Klíčová slova
- endoteliální lipáza, evinakumab,
- MeSH
- angiopoetinu podobný protein 3 antagonisté a inhibitory fyziologie MeSH
- arteriální okluzní nemoci farmakoterapie MeSH
- dyslipidemie * farmakoterapie MeSH
- LDL-cholesterol analýza MeSH
- lidé MeSH
- lipoproteinlipasa fyziologie MeSH
- lipoproteiny metabolismus MeSH
- monoklonální protilátky farmakologie terapeutické užití MeSH
- regulace genové exprese účinky léků MeSH
- triglyceridy metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
OBJECTIVE: Classical ATP-independent non-shivering thermogenesis enabled by uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is activated, but not essential for survival, in the cold. It has long been suspected that futile ATP-consuming substrate cycles also contribute to thermogenesis and can partially compensate for the genetic ablation of UCP1 in mouse models. Futile ATP-dependent thermogenesis could thereby enable survival in the cold even when brown fat is less abundant or missing. METHODS: In this study, we explore different potential sources of UCP1-independent thermogenesis and identify a futile ATP-consuming triglyceride/fatty acid cycle as the main contributor to cellular heat production in brown adipocytes lacking UCP1. We uncover the mechanism on a molecular level and pinpoint the key enzymes involved using pharmacological and genetic interference. RESULTS: ATGL is the most important lipase in terms of releasing fatty acids from lipid droplets, while DGAT1 accounts for the majority of fatty acid re-esterification in UCP1-ablated brown adipocytes. Furthermore, we demonstrate that chronic cold exposure causes a pronounced remodeling of adipose tissues and leads to the recruitment of lipid cycling capacity specifically in BAT of UCP1-knockout mice, possibly fueled by fatty acids from white fat. Quantification of triglyceride/fatty acid cycling clearly shows that UCP1-ablated animals significantly increase turnover rates at room temperature and below. CONCLUSION: Our results suggest an important role for futile lipid cycling in adaptive thermogenesis and total energy expenditure.
- MeSH
- adenosintrifosfát metabolismus MeSH
- hnědá tuková tkáň * metabolismus MeSH
- mastné kyseliny metabolismus MeSH
- myši knockoutované MeSH
- myši MeSH
- termogeneze * MeSH
- triglyceridy metabolismus MeSH
- uncoupling protein 1 genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Breast milk is a complex mixture containing underexplored bioactive lipids. We performed an observational case-control study to compare the impact of delivery mode: caesarean section (CS) and vaginal birth (VB); and term (preterm and term delivery) on the levels of lipokines in human milk at different stages of lactation. Metabolomic analysis of the milk identified triacylglycerol estolides as a metabolic reservoir of the anti-inflammatory lipid mediator 5-palmitic acid ester of hydroxystearic acid (5-PAHSA). We found that triacylglycerol estolides were substrates of carboxyl ester lipase and 5-PAHSA-containing lipids were the least preferred substrates among tested triacylglycerol estolide isomers. This explained exceptionally high colostrum levels of 5-PAHSA in the VB group. CS and preterm birth negatively affected colostrum lipidome, including 5-PAHSA levels, but the lipidomic profiles normalized in mature milk. Mothers delivering term babies vaginally produce colostrum rich in 5-PAHSA, which could contribute to the prevention of intestinal inflammation in newborns.
- MeSH
- císařský řez MeSH
- estery metabolismus MeSH
- kojenec MeSH
- kolostrum metabolismus MeSH
- kyselina palmitová metabolismus MeSH
- laktace MeSH
- lidé MeSH
- lipasa metabolismus MeSH
- mateřské mléko * metabolismus MeSH
- novorozenec MeSH
- předčasný porod * metabolismus MeSH
- studie případů a kontrol MeSH
- těhotenství MeSH
- triglyceridy metabolismus MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- novorozenec MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND AND AIMS: We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. APPROACH AND RESULTS: We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL-apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL5,6 , and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A. CONCLUSIONS: Metabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratification.
- MeSH
- apolipoproteiny B MeSH
- fosfolipasy metabolismus MeSH
- játra patologie MeSH
- kardiovaskulární nemoci * epidemiologie etiologie MeSH
- lipoproteiny VLDL MeSH
- myši MeSH
- nealkoholová steatóza jater * patologie MeSH
- rizikové faktory kardiovaskulárních chorob MeSH
- rizikové faktory MeSH
- triglyceridy metabolismus MeSH
- VLDL-cholesterol metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
