The prevalence of obesity is increasing and with it the prevalence of associated metabolic complications. Precisely how obesity results in metabolic disturbances remains unclear. In the face of ...persistent positive caloric balance, it has been postulated that the capacity of adipose tissue to safely store fat may be vital. This paper explores some of the evidence suggesting that the risk of developing metabolic disturbances is not related to how much fat an individual has, but how well their fat can expand to accommodate the caloric excess. If this is true, the metabolic consequences of obesity may arise from the inability to become more obese.
Although many transcriptional pathways regulating BAT have been identified, the role of lipid biosynthetic enzymes in thermogenesis has been less investigated. Whereas cold exposure causes changes in ...the fatty acid composition of BAT, the functional consequences of this remains relatively unexplored. In this study, we demonstrate that the enzyme Elongation of Very Long Chain fatty acids 6 (Elovl6) is necessary for the thermogenic action of BAT. Elovl6 is responsible for converting C16 non-essential fatty acids into C18 species. Loss of Elovl6 does not modulate traditional BAT markers; instead, it causes reduced expression of mitochondrial electron transport chain components and lower BAT thermogenic capacity. The reduction in BAT activity appears to be counteracted by increased beiging of scWAT. When beige fat is disabled by thermoneutrality or aging, Elovl6 KO mice gain weight and have increased scWAT mass and impaired carbohydrate metabolism. Overall, our study suggests fatty acid chain length is important for BAT function.
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•The fatty acid elongase Elovl6 is a thermogenically regulated gene in BAT•Elovl6 is necessary for full thermogenic recruitment of brown adipose tissue•Elovl6 acts by regulating mitochondrial function in brown adipose tissue
Tan et al. find that the elongation of non-essential C16 fatty acids to C18 species regulates mitochondrial function and is necessary for full recruitment of heat-generating brown adipose tissue.
Mitochondria are involved in a variety of cellular functions, including ATP production, amino acid and lipid biogenesis and breakdown, signalling and apoptosis. Mitochondrial dysfunction has been ...linked to neurodegenerative diseases, cancer and ageing. Although transcriptional mechanisms that regulate mitochondrial abundance are known, comparatively little is known about how mitochondrial function is regulated. Here we identify the metabolite stearic acid (C18:0) and human transferrin receptor 1 (TFR1; also known as TFRC) as mitochondrial regulators. We elucidate a signalling pathway whereby C18:0 stearoylates TFR1, thereby inhibiting its activation of JNK signalling. This leads to reduced ubiquitination of mitofusin via HUWE1, thereby promoting mitochondrial fusion and function. We find that animal cells are poised to respond to both increases and decreases in C18:0 levels, with increased C18:0 dietary intake boosting mitochondrial fusion in vivo. Intriguingly, dietary C18:0 supplementation can counteract the mitochondrial dysfunction caused by genetic defects such as loss of the Parkinson's disease genes Pink or Parkin in Drosophila. This work identifies the metabolite C18:0 as a signalling molecule regulating mitochondrial function in response to diet.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Upper tract urothelial carcinoma (UTUC) is a relatively uncommon urologic malignancy for which there has not been significant improvement in survival over the past few decades, highlighting the need ...for optimal multi-modality management.
A non-systematic review of the latest literature was performed to include relevant articles up to June 2019. It summarizes the epidemiologic risk factors associated with UTUC, including smoking, carcinogenic aromatic amines, arsenic, aristolochic acid, and Lynch syndrome. Molecular pathways underlying UTUC and potential druggable targets are outlined.
Surgical management for UTUC includes kidney-sparing surgery (KSS) for low-risk disease and radical nephroureterectomy (RNU) for high-risk disease. Endoscopic management of UTUC may include ureteroscopic or percutaneous resection. Topical instillation therapy post-KSS aims to reduce recurrence, progression and to treat carcinoma-in-situ; this may be achieved retrogradely (via ureteric catheterization), antegradely (via percutaneous nephrostomy) or via reflux through double-J stent. RNU, which may be performed via open, laparoscopic or robot-assisted approaches, is the gold standard treatment for high-risk UTUC. The distal cuff may be dealt with extravesical, transvesical or endoscopic techniques. Peri-operative chemotherapy and immunotherapy are increasingly utilized; level 1 evidence exists for adjuvant chemotherapy, but neoadjuvant chemotherapy is favored as kidney function is better prior to RNU. Immunotherapy is primarily reserved for metastatic UTUC but is currently being investigated in the perioperative setting.
The optimal management of UTUC includes a firm understanding of the epidemiological factors and molecular pathways. Surgical management includes KSS for low-risk disease and RNU for high-risk disease. Peri-operative immunotherapy and chemotherapy may be considered as evidence mounts.
Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin ...pairs discordant for obesity but still metabolically compensated. In parallel we studied more evolved states of obesity by investigating a separated set of individuals considered to be morbidly obese. Despite lower dietary polyunsaturated fatty acid intake, the obese twin individuals had increased proportions of palmitoleic and arachidonic acids in their adipose tissue, including increased levels of ethanolamine plasmalogens containing arachidonic acid. Information gathered from these experimental groups was used for molecular dynamics simulations of lipid bilayers combined with dependency network analysis of combined clinical, lipidomics, and gene expression data. The simulations suggested that the observed lipid remodeling maintains the biophysical properties of lipid membranes, at the price, however, of increasing their vulnerability to inflammation. Conversely, in morbidly obese subjects, the proportion of plasmalogens containing arachidonic acid in the adipose tissue was markedly decreased. We also show by in vitro Elovl6 knockdown that the lipid network regulating the observed remodeling may be amenable to genetic modulation. Together, our novel approach suggests a physiological mechanism by which adaptation of adipocyte membranes to adipose tissue expansion associates with positive energy balance, potentially leading to higher vulnerability to inflammation in acquired obesity. Further studies will be needed to determine the cause of this effect.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we ...demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.
Whilst the potential of neural stem cell (NSC)-based treatment is recognized worldwide and seems to offer a promising therapeutic option for stroke treatments, there is currently no full ...understanding regarding the effects of hypoxic and baicalein-enriched fraction (BEF) preconditioning approaches on the therapeutic potential of these cells for stroke. The potential of preconditioned NSC can be determined based on the expression of several key neuroprotective genes using qRT-PCR technique. However, prior to that, it is imperative and extremely important to carefully select reference gene(s) for accurate qRT-PCR data normalization to avoid error in data interpretation. This study aimed to evaluate the stability of ten candidate reference genes via comprehensive analysis using three algorithms software: geNorm, NormFinder and BestKeeper. Our results revealed that HPRT1 and RPL13A were the most reliable reference genes for BEF-preconditioned NSCs, but ironically, HPRT1 was ranked as the least stable reference gene for hypoxic-preconditioned NSCs. On the other hand, RPLP1 and RPL13A were selected as the most stably expressed pair of reference genes for hypoxic-preconditioned NSCs. In conclusion, this study has pointed out the importance of identifying valid reference genes and has presented the first significant validation on best reference genes recommended for qRT-PCR study involves NSC preconditioned with hypoxia or with BEF extracted from Oroxylum indicum medicinal plant.
Peroxisome proliferator‐activated receptor gamma‐coactivator‐1 alpha (PGC1a) is involved in energy and lipid metabolism, and its loss leads to neurodegenerative changes in the striatum. Here we ...performed lipidomic analysis on brain extracts from PGC1a mutant and wild‐type mice. We found increased phosphatidylcholine and decreased ceramides in the brain of PGC1a‐deficient mice. An analysis of lipid raft fractions revealed increased ceramide, glucocylceramides and GM1 ganglioside in the PGC1a mutants. In the cerebellum, we observed a decrease in proteins associated with myelination, but were unable to detect any morphological abnormalities in compact myelin formation in PGC1a mutants compared with wild‐type mice. Although PGC1a is involved in lipid biosynthesis, we concluded that altered lipid composition in the PGC1a mutant did not directly affect central nervous system myelin morphology.
Peroxisome proliferator‐activated receptor gamma‐coactivator‐1 alpha (PGC1a) is involved in energy and lipid metabolism, and its loss leads to neurodegeneration. Ablation of PGC1a increased phosphatidylcholine and decreased ceramides in the brain. An analysis of lipid raft fractions revealed increased ceramide, glucocylceramides and GM1 ganglioside in the PGC1a mutants. We suggest that PGC1a coactivator coordinates brain age‐dependent sphingolipid metabolism and oligodendrocyte differentiation.
Objective
Emerging evidence suggest that antibiotic prophylaxis may be omitted in early cirrhosis patients with upper gastrointestinal bleeding (UGIB), which question the benefits of antibiotic ...prophylaxis on rebleeding, mortality related to ongoing bleeding, and the need for salvage therapy. As the management of UGIB has improved over time since the last review a decade ago, we performed an updated meta‐analysis to review the benefits of antibiotic prophylaxis in cirrhosis patients with UGIB.
Method
Six electronic databases including PubMed/MEDLINE, EMBASE, Scopus, Web of Science, Cochrane library, and ClinicalTrial.gov were systematically searched up to December 1, 2021. The primary outcome was 6 weeks mortality. Secondary outcomes include the risk of infection, rebleeding at 7 days and 6 weeks, mortality related to ongoing bleeding, need for salvage therapy, and infection‐related mortality.
Result
Eighteen studies (12 randomized controlled trials RCT, 6 non‐RCT) from 3180 subjects were identified among 2129 citations. Antibiotic prophylaxis reduces mortality at 6 weeks, risk of infection, and infection‐related mortality (pooled relative risk: 0.72, 0.39, and 0.41, respectively). Although antibiotics reduce the risk of rebleeding and the amount of blood transfusion, they did not reduce the risk of mortality from ongoing bleeding nor the need for salvage therapy. Antibiotic prophylaxis may shorten the length of stay in the intensive care unit.
Conclusion
Antibiotic prophylaxis reduces rebleeding, 6‐week mortality, and infection‐related mortality. Due to the low risk of infection and death, dedicated studies are warranted to evaluate the benefit of antibiotic prophylaxis in early cirrhosis with UGIB.
Highlights
Our updated meta‐analysis reaffirms the benefit of antibiotic prophylaxis in reducing the mortality at 6 weeks, risk of infection, and infection‐related mortality.
Although antibiotics reduce the risk of rebleeding and the amount of blood transfusion, they did not reduce the risk of mortality from ongoing bleeding nor the need for salvage therapy.
Antibiotic prophylaxis may reduce the length of stay in the intensive care unit.
Dedicated studies are required to study the benefit of prophylactic antibiotic among early cirrhosis patients with upper gastrointestinal bleeding.
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