Hepatic microRNA Expression by PGC-1α and PGC-1β in the Mouse.

The fine-tuning of liver metabolism is essential to maintain the whole-body homeostasis and to prevent the onset of diseases. The peroxisome proliferator-activated receptor-γ coactivators (PGC-1s) are transcriptional key players of liver metabolism, able to regulate mitochondrial function, gluconeogenesis and lipid metabolism. Their activity is accurately modulated by post-translational modifications. Here, we showed that specific PGC-1s expression can lead to the upregulation of different microRNAs widely implicated in liver physiology and diseases development and progression, thus offering a new layer of complexity in the control of hepatic metabolism

Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis (i.e., nonalcoholic fatty liver [NAFL]) to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Currently, the driver for this progression is not fully understood; in particular, it is not known how NAFLD and its early progression affects the distribution of lipids in the liver, producing lipotoxicity and inflammation. In this study, we used dietary and genetic mouse models of NAFL and NASH and translated the results to humans by correlating the spatial distribution of lipids in liver tissue with disease progression using advanced mass spectrometry imaging technology. We identified several lipids with distinct zonal distributions in control and NAFL samples and observed partial to complete loss of lipid zonation in NASH. In addition, we found increased hepatic expression of genes associated with remodeling the phospholipid membrane, release of arachidonic acid (AA) from the membrane, and production of eicosanoid species that promote inflammation and cell injury. The results of our immunohistochemistry analyses suggest that the zonal location of remodeling enzyme LPCAT2 plays a role in the change in spatial distribution for AA-containing lipids. This results in a cycle of AA-enrichment in pericentral hepatocytes, membrane release of AA, and generation of proinflammatory eicosanoids and may account for increased oxidative damage in pericentral regions in NASH. Conclusion: NAFLD is associated not only with lipid enrichment, but also with zonal changes of specific lipids and their associated metabolic pathways. This may play a role in the heterogeneous development of NAFLD. (Hepatology 2017;65:1165-1180)

Episodic overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt does not increase mortality in patients with cirrhosis

Background & Aims: Overt hepatic encephalopathy (OHE) is a major complication of transjugular intrahepatic portosystemic shunt (TIPS) placement, given its high incidence and possibility of refractoriness to medical treatment. Nevertheless, the impact of post-TIPS OHE on mortality has not been investigated in a large population. Methods: We designed a multicenter, non-inferiority, observational study to evaluate the mortality rate at 30 months in patients with and without OHE after TIPS. We analyzed a database of 614 patients who underwent TIPS in three Italian centers and estimated the cumulative incidence of OHE and mortality with competitive risk analyses, setting the non-inferiority limit at 0.12. Results: During a median follow-up of 30 months (IQR 12-30), 293 patients developed at least one episode of OHE. Twenty-seven (9.2%) of them experienced recurrent/persistent OHE. Patients with OHE were older (64 [57-71] vs. 59 [50-67] years, p <0.001), had lower albumin (3.1 [2.8-3.5] vs. 3.25 [2.9-3.6] g/dl, p = 0.023), and had a higher prevalence of pre-TIPS OHE (15.4% vs. 9.0%, p = 0.023). Child-Pugh and MELD scores were similar. The 30-month difference in mortality between patients with and without post-TIPS OHE was 0.03 (95% CI -0.042 to 0.102). Multivariable analysis showed that age (subdistribution hazard ratio 1.04, 95% CI 1.02–1.05, p <0.001) and MELD score (subdistribution hazard ratio 1.09, 95% CI 1.05–1.13, p <0.001), but not post-TIPS OHE, were associated with a higher mortality rate. Similar results were obtained when patients undergoing TIPS for variceal re-bleeding prophylaxis (n = 356) or refractory ascites (n = 258) were analyzed separately. The proportion of patients with persistent OHE after TIPS was significantly higher in the group of patients who died. The robustness of these results was increased following propensity score matching. Conclusion: Episodic OHE after TIPS is not associated with mortality in patients undergoing TIPS, regardless of the indication. Impact and implications: Overt hepatic encephalopathy (OHE) is a common complication in patients with advanced liver disease and it is particularly frequent following transjugular intrahepatic portosystemic shunt (TIPS) placement. In patients with cirrhosis outside the setting of TIPS, the development of OHE negatively impacts survival, regardless of the severity of cirrhosis or the presence of acute-on-chronic liver failure. In this multicenter, non-inferiority, observational study we demonstrated that post-TIPS OHE does not increase the risk of mortality in patients undergoing TIPS, irrespective of the indication. This finding alleviates concerns regarding the weight of this complication after TIPS. Intensive research to improve patient selection and risk stratification remains crucial to enhance the quality of life of patients and caregivers and to avoid undermining the positive effects of TIPS on survival

Changes in LXR signaling influence early-pregnancy lipogenesis and protect against dysregulated fetoplacental lipid homeostasis

Human pregnancy is associated with enhanced de novo lipogenesis in the early stages followed by hyperlipidemia during advanced gestation. Liver X receptors (LXRs) are oxysterol-activated nuclear receptors that stimulate de novo lipogenesis and also promote the efflux of cholesterol from extrahepatic tissues followed by its transport back to the liver for biliary excretion. Although LXR is recognized as a master regulator of triglyceride and cholesterol homeostasis, it is unknown whether it facilitates the gestational adaptations in lipid metabolism. To address this question, biochemical profiling, protein quantification, and gene expression studies were used, and gestational metabolic changes in T0901317-treated wild-type mice and Lxrab-/- mutants were investigated. Here, we show that altered LXR signaling contributes to the enhanced lipogenesis in early pregnancy by increasing the expression of hepatic Fas and stearoyl-CoA desaturase 1 (Scd1). Both the pharmacological activation of LXR with T0901317 and the genetic ablation of its two isoforms disrupted the increase in hepatic fatty acid biosynthesis and the development of hypertriglyceridemia during early gestation. We also demonstrate that absence of LXR enhances maternal white adipose tissue lipolysis, causing abnormal accumulation of triglycerides, cholesterol, and free fatty acids in the fetal liver. Together, these data identify LXR as an important factor in early-pregnancy lipogenesis that is also necessary to protect against abnormalities in fetoplacental lipid homeostasis

Tau protein modulates an epigenetic mechanism of cellular senescence in human SH-SY5Y neuroblastoma cells

Introduction: Progressive Tau deposition in neurofibrillary tangles and neuropil threads is the hallmark of tauopathies, a disorder group that includes Alzheimer’s disease. Since Tau is a microtubule-associated protein, a prevalent concept to explain the pathogenesis of tauopathies is that abnormal Tau modification contributes to dissociation from microtubules, assembly into multimeric β-sheets, proteotoxicity, neuronal dysfunction and cell loss. Tau also localizes in the cell nucleus and evidence supports an emerging function of Tau in DNA stability and epigenetic modulation.Methods: To better characterize the possible role of Tau in regulation of chromatin compaction and subsequent gene expression, we performed a bioinformatics analysis of transcriptome data obtained from Tau-depleted human neuroblastoma cells.Results: Among the transcripts deregulated in a Tau-dependent manner, we found an enrichment of target genes for the polycomb repressive complex 2. We further describe decreased cellular amounts of the core components of the polycomb repressive complex 2 and lower histone 3 trimethylation in Tau deficient cells. Among the de-repressed polycomb repressive complex 2 target gene products, IGFBP3 protein was found to be linked to increased senescence induction in Tau-deficient cells.Discussion: Our findings propose a mechanism for Tau-dependent epigenetic modulation of cell senescence, a key event in pathologic aging

Alterations in PGC1[alfa] expression levels are involved in colorectal cancer risk: a qualitative systematic review

Background: Colorectal cancer (CRC) is a major global public health problem and the second leading cause of cancer-related death. Mitochondrial dysfunction has long been suspected to be involved in this type of tumorigenesis, as supported by an accumulating body of research evidence. However, little is known about how mitochondrial alterations contribute to tumorigenesis. Mitochondrial biogenesis is a fundamental cellular process required to maintain functional mitochondria and as an adaptive mechanism in response to changing energy requirements. Mitochondrial biogenesis is regulated by peroxisome proliferator-activated receptor gamma coactivator 1-? (PPARGC1A or PGC1?). In this paper, we report a systematic review to summarize current evidence on the role of PGC1? in the initiation and progression of CRC. The aim is to provide a basis for more comprehensive research. Methods: The literature search, data extraction and quality assessment were performed according to the document Guidance on the Conduct of Narrative Synthesis in Systematic Reviews and the PRISMA declaration. Results: The studies included in this review aimed to evaluate whether increased or decreased PGC1? expression affects the development of CRC. Each article proposes a possible molecular mechanism of action and we create two concept maps. Conclusion: Our systematic review indicates that altered expression of PGC1? modifies CRC risk. Most studies showed that overexpression of this gene increases CRC risk, while some studies indicated that lower than normal expression levels could increase CRC risk. Thus, various authors propose PGC1? as a good candidate molecular target for cancer therapy. Reducing expression of this gene could help to reduce risk or progression of CRC

Do we need rules for 'what's mine is yours'? Governance in collaborative consumption communities

AbstractWith collaborative consumption, people are provided with access to a good rather than owning it. The current study addresses the problem of regulation in collaborative consumption communities, investigating whether governance increases cooperation, if and why consumers support a governance system and whether supporters and non-supporters differ in their distrust in others. To address these questions, an experiment (within-subject design) was conducted. After reading vignettes, participants indicated how likely they would cooperate and whether they support governance or not—giving reasons for their evaluation. The majority of participants support governance and governance increases cooperation. Supporters argue that humans are egoistic, whereas non-supporters are concerned about negative consequences, asking for alternative incentives. Supporters of governance also differ from non-supporters according to their trust in others. The current study allows valuable recommendation, as more and more sharing networks are created, facing the problem of whether to regulate access or not

Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease.

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis (i.e., nonalcoholic fatty liver [NAFL]) to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Currently, the driver for this progression is not fully understood; in particular, it is not known how NAFLD and its early progression affects the distribution of lipids in the liver, producing lipotoxicity and inflammation. In this study, we used dietary and genetic mouse models of NAFL and NASH and translated the results to humans by correlating the spatial distribution of lipids in liver tissue with disease progression using advanced mass spectrometry imaging technology. We identified several lipids with distinct zonal distributions in control and NAFL samples and observed partial to complete loss of lipid zonation in NASH. In addition, we found increased hepatic expression of genes associated with remodeling the phospholipid membrane, release of arachidonic acid (AA) from the membrane, and production of eicosanoid species that promote inflammation and cell injury. The results of our immunohistochemistry analyses suggest that the zonal location of remodeling enzyme LPCAT2 plays a role in the change in spatial distribution for AA-containing lipids. This results in a cycle of AA-enrichment in pericentral hepatocytes, membrane release of AA, and generation of proinflammatory eicosanoids and may account for increased oxidative damage in pericentral regions in NASH. CONCLUSION: NAFLD is associated not only with lipid enrichment, but also with zonal changes of specific lipids and their associated metabolic pathways. This may play a role in the heterogeneous development of NAFLD. (Hepatology 2017;65:1165-1180).Medical Research Council (MRC). Horizon 2020 Framework Program of the European Union

A beer a minute in Texas football: Heavy drinking and the heroizing of the antihero in Friday Night Lights

This article applies a qualitative framing analysis to the first three seasons of the television series Friday Night Lights, focusing particularly on its incorporation of heavy drinking into narrative representations of the player whose character is most consistently central to the game of football as fictionally mediated in small-town Texas over the course of those three seasons. The analysis suggests that over the course of that period Friday Night Lights embeds nuanced social meanings in its framing of alcohol use by that player and other characters so as to associate it with multiple potential outcomes. Yet among those outcomes, the most dominant framing works to, in effect, reverse a progression through which media representations historically evolved from a heroic model toward an antihero model, with heavy drinking central to that narrative process of meaning-making in such messages.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

PGC-1β regulates mitochondrial metabolic pathways in the gut-liver axis

ROS production is proportional to the increase in mitochondrial respiration and electron chain activity. Numerous factors (including radiations, oxygen shortage, carcinogens and inflammation) can give rise to ROS, ultimately leading to ROS- mediated genomic instability and cancer. Under normal conditions, the balance between ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressor, including enzymes such as superoxide dismutase, catalase, and those involved in glutathione metabolism. Some components of the ROS scavenging pathway are linked to mitochondrial oxidative metabolism by the PGC-l coactivators that enable cells to maintain normal redox status in response to changing oxidative capacity. The increase in mitochondrial number stimulated by these proteins could cause an increase in the production of ROS. Therefore, if ROS production were proportional to the increase of electron transport activity stimulated by the PGC-l proteins, these molecules would ultimately drive ROS levels higher. However, PGC-la is able to upgrade aerobic energy metabolism in tissues with high aerobic demand promoting ROS formation on one hand and ROS scavenging .systems on the other. Since the role of PGC-l ß in this process is completely unknown and ROS production is .commonly linked to mitochondrial dysfunctions that, in turn, are linked with several diseases, such as intestinal cancer and several metabolic diseases including steatohepatitis, we decided to investigate whether PGC-l ß could be involved in the mitochondrial homeostasis and ROS generation in two different organs, the intestine and the liver.EThOS - Electronic Theses Online ServiceGBUnited Kingdo