Search

Metabolic-associated steatohepatitis liver disease (MASLD) currently impacts a quarter of the global population, and its incidence is expected to increase in the future. As a result, hepatocellular carcinoma associated with MASLD is also on the rise. Notably, this carcinoma does not always develop alongside liver cirrhosis, often leading to a more advanced stage at diagnosis. The challenge lies in accurately identifying patients who are at a higher risk to tailor screening processes effectively. Additionally, several therapeutic approaches are being explored to prevent hepatocellular carcinoma, although there are no universally accepted guidelines yet. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by the build-up of fat in the liver of individuals in the absence of alcohol consumption. This condition has become a burden in modern societies aggravated by the lack of appropriate predictive biomarkers (other than liver biopsy). To better understand this disease and to find appropriate biomarkers, a new technology has emerged in the last two decades with the ability to explore the unmapped role of lipids in this disease: lipidomics. This technology, based on the combination of chromatography and mass spectrometry, has been extensively used to explore the lipid metabolism of NAFLD. In this review, we aim to summarize the knowledge gained through lipidomics assays exploring tissues, plasma, and lipoproteins from individuals with NAFLD. Our goal is to identify common features and active pathways that could facilitate the finding of a reliable biomarker from this field. The most frequent observation was a variable decrease (1–9%) in polyunsaturated fatty acids in phospholipids and non-esterified fatty acids in NAFLD patients, both in plasma and liver. Additionally, a reduction in phosphatidylcholines is a common feature in the liver. Due to the scarcity of studies, further research is needed to properly detect lipoprotein, plasma, and tissue lipid signatures of NAFLD etiologies, and NAFLD subtypes, and to define the relevance of this technology in disease management strategies in the push toward personalized medicine. [ABSTRACT FROM AUTHOR]

Research on the microbiome has progressed from identifying specific microbial communities to exploring how these organisms produce and modify metabolites that impact a wide range of health conditions, including gastrointestinal, metabolic, autoimmune, and neurodegenerative diseases. This review provides an overview of the bacteria commonly found in the intestinal tract, focusing on their main functional outputs. We explore biomarkers that not only indicate a well-balanced microbiota but also potential dysbiosis, which could foreshadow susceptibility to future health conditions. Additionally, it discusses the establishment of the microbiota during the early years of life, examining factors such as gestational age at birth, type of delivery, antibiotic intake, and genetic and environmental influences. Through a comprehensive analysis of current research, this article aims to enhance our understanding of the microbiota's foundational development and its long-term implications for health and disease management. [ABSTRACT FROM AUTHOR]

The eradication of the hepatitis C virus (HCV) has revolutionized the hepatology paradigm, halting the progression of advanced liver disease in patients with chronic infection and reducing the risk of hepatocarcinoma. In addition, treatment with direct-acting antivirals can reverse the lipid and carbohydrate abnormalities described in HCV patients. Although HCV eradication may reduce the overall risk of vascular events, it is uncertain whether altered lipid profiles increase the risk of cerebrovascular disease in certain patients. We have conducted a review on HCV and lipid and carbohydrate metabolism, as well as new scientific advances, following the advent of direct-acting antivirals. [ABSTRACT FROM AUTHOR]

Adipose tissue (AT), once considered a mere fat storage organ, is now recognized as a dynamic and complex entity crucial for regulating human physiology, including metabolic processes, energy balance, and immune responses. It comprises mainly two types: white adipose tissue (WAT) for energy storage and brown adipose tissue (BAT) for thermogenesis, with beige adipocytes demonstrating the plasticity of these cells. WAT, beyond lipid storage, is involved in various metabolic activities, notably lipogenesis and lipolysis, critical for maintaining energy homeostasis. It also functions as an endocrine organ, secreting adipokines that influence metabolic, inflammatory, and immune processes. However, dysfunction in WAT, especially related to obesity, leads to metabolic disturbances, including the inability to properly store excess lipids, resulting in ectopic fat deposition in organs like the liver, contributing to non-alcoholic fatty liver disease (NAFLD). This narrative review delves into the multifaceted roles of WAT, its composition, metabolic functions, and the pathophysiology of WAT dysfunction. It also explores diagnostic approaches for adipose-related disorders, emphasizing the importance of accurately assessing AT distribution and understanding the complex relationships between fat compartments and metabolic health. Furthermore, it discusses various therapeutic strategies, including innovative therapeutics like adipose-derived mesenchymal stem cells (ADMSCs)-based treatments and gene therapy, highlighting the potential of precision medicine in targeting obesity and its associated complications. [ABSTRACT FROM AUTHOR]

Obesity is a major risk factor for the development of nonalcoholic fatty liver disease (NAFLD), and the subcutaneous white adipose tissue (scWAT) is the primary lipid storage depot and regulates lipid fluxes to other organs. Our previous work identified genes upregulated in scWAT of patients with NAFLD: SOCS3, DUSP1, and SIK1. Herein, we knocked down (KD) their expression in human adipose-derived mesenchymal stem cells (hADMSCs) using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology and characterized their phenotype. We found that SOCS3, DUSP1, and SIK1 expression in hADMSC-derived adipocytes was not critical for adipogenesis. However, the metabolic characterization of the cells suggested that the genes played important roles in lipid metabolism. Reduction of SIK1 expression significantly increased both de novo lipogenesis (DNL) and palmitate-induced lipogenesis (PIL). Editing out SOCS3 reduced DNL while increasing isoproterenolinduced lipolysis and insulin-induced palmitate accumulation. Conversely, DUSP1 reduced PIL and DNL. Moreover, RNAsequencing analysis of edited cells showed that these genes not only altered lipid metabolism but also other biological pathways related to inflammatory processes, in the case of DUSP1, extracellular matrix remodeling for SOCS3, or cellular transport for SIK1. Finally, to evaluate a possible adipocyte-hepatocyte axis, human hepatoma HepG2 cells were cocultured with edited hADMSCs-derived adipocytes in the presence of [3H]-palmitate. All HepG2 cells cultured with DUSP1-, SIK1-, or SOCS3-KD adipocytes decreased [3H]-palmitate accumulation compared with control adipocytes. These results support our hypotheses that SOCS3, DUSP1, and SIK1 regulate multiple aspects of adipocyte function, which may play a role in the progression of obesityassociated comorbidities, such as NAFLD. [ABSTRACT FROM AUTHOR]

Background: Numerous scores are designed to predict outcomes of patients with liver cirrhosis. Our study aimed to evaluate the ability of the Liver Disease Undernutrition Screening Tool (LDUST) in predicting mortality and decompensation in outpatients with clinically significant portal hypertension (CSPH). We hypothesized that LDUST could help identify patients in need of nutritional supplementation and intervention. Methods: A prospective study of 57 CSPH patients (36.8% female, mean age: 63.5 ± 9.9 years) with a median follow-up of 41 months was conducted. Baseline liver function, nutrition, and sarcopenia were assessed, alongside LDUST. During follow-up, the occurrence of liver decompensation, hospital admission, need for emergency care, and mortality were evaluated. Results: A total of 56.1% of patients were Child A, and the most frequent etiology was alcohol (50.9%). Malnutrition risk according to LDUST raised mortality (HR: 25.96 (1.47–456.78)), decompensation (HR 9.78 (2.08–45.89)), and admission (HR 4.86 (1.09–21.61)) risks in multivariate Cox analysis. Combining LDUST with Child and MELD scores improved their decompensation prediction (0.936 vs. 0.811 and 0.866 vs. 0.700). Conclusions: The LDUST has a solid ability to predict complications in cirrhosis outpatients with CSPH, and its integration with Child and MELD models enhances their predictive power. LDUST implementation could identify individuals necessitating early nutritional support. [ABSTRACT FROM AUTHOR]

Obesity is a highly prevalent condition often associated with dysfunctional adipose tissue. Stem cell-based therapies have become a promising tool for therapeutic intervention in the context of regenerative medicine. Among all stem cells, adipose-derived mesenchymal stem cells (ADMSCs) are the most easily obtained, have immunomodulatory properties, show great ex vivo expansion capacity and differentiation to other cell types, and release a wide variety of angiogenic factors and bioactive molecules, such as growth factors and adipokines. However, despite the positive results obtained in some pre-clinical studies, the actual clinical efficacy of ADMSCs still remains controversial. Transplanted ADMSCs present a meager rate of survival and proliferation, possibly because of the damaged microenvironment of the affected tissues. Therefore, there is a need for novel approaches to generate more functional ADMSCs with enhanced therapeutic potential. In this context, genetic manipulation has emerged as a promising strategy. In the current review, we aim to summarize several adipose-focused treatments of obesity, including cell therapy and gene therapy. Particular emphasis will be given to the continuum from obesity to metabolic syndrome, diabetes, and underlying non-alcoholic fatty liver disease (NAFLD). Furthermore, we will provide insights into the potential shared adipocentric mechanisms involved in these pathophysiological processes and their remediation using ADMSCs. [ABSTRACT FROM AUTHOR]

Objective: Adipose tissue stores a substantial amount of body cholesterol in humans. Obesity is associated with decreased concentrations of serum cholesterol. During weight gain, adipose tissue dysfunction might be one of the causes of metabolic syndrome. The aim of this study is to evaluate cholesterol storage and oxidized metabolites in adipose tissue and their relationship with metabolic clinical characteristics. Methods: Concentrations of cholesterol and oxysterols (27-hydroxycholesterol and 24S-hydroxycholesterol) in subcutaneous and visceral adipose tissue were determined by high-performance liquid chromatography with tandem mass spectrometry in 19 adult women with body mass index between 23 and 40 kg/m2 from the FAT expandability (FATe) study. Tissue concentration values were correlated with biochemical and clinical characteristics using nonparametric statistics. Results: Insulin correlated directly with 24S-hydroxycholesterol in both adipose tissues and with 27-hydroxycholesterol in visceral tissue. Leptin correlated directly with 24S-hydroxycholesterol in subcutaneous adipose tissue. Tissue cholesterol correlated directly with 27-hydroxycholesterol in both adipose tissues and with 24S-hydroxycholesterol in visceral tissue, where cholesterol correlation with 24S-hydroxycholesterol was higher than with 27-hydroxycholesterol. In addition, some tendencies were observed: serum high-density lipoprotein cholesterol tended to be inversely correlated with visceral adipose tissue cholesterol; high-sensitivity C-reactive protein tended to be correlated directly with subcutaneous adipose 24S-hydroxycholesterol and inversely with visceral 27-hydroxycholesterol. Conclusions: Adipose tissue oxysterols are associated with blood insulin and insulin resistance. Tissue cholesterol correlated more with 27-hydroxycholesterol in subcutaneous adipose tissue and with 24S-hydroxycholesterol in visceral adipose tissue. Levels of adipose 24S-hydroxycholesterol seem to be correlated with some metabolic syndrome symptoms and inflammation while adipose 27-hydroxycholesterol could represent some protection against them. [ABSTRACT FROM AUTHOR]

Background: Hepatitis C virus (HCV) produces changes at multiple levels in host metabolism, especially in lipid profile and cardio-metabolic risk. It is unclear how HCV eradication by direct-acting antivirals (DAAs) modifies those changes. Objective: To evaluate the impact of DAA treatment on different risk factors associated with cardiovascular disease. Methods: Prospective study with two-year follow-up. All patients treated with DAAs in the Liver Clinic of a tertiary hospital were included. Patients co-infected with HBV or HIV, with other causes of liver disease, on lipid-lowering treatment, pregnant, or with previous HCV treatment were excluded. The results were analyzed using linear mixed models. Results: 167 patients (53% female, 9.6% cirrhosis) were included. Low plasma lipid levels were observed before initiating HCV eradication. During the first year after treatment with DAA, we observed a sustained increase in cholesterol, triglycerides, HDL cholesterol (only in men), and LDL-cholesterol levels. An ameliorated glycemic control was also observed with a decrease in fasting insulin and reduced HOMA. Iron metabolism and coagulation function also improved with lower levels of serum ferritin and prothrombin activity; these biochemical changes resulted in a new diagnosis of hypercholesterolaemia in 17.4% of patients, requiring initiation of statins in 15%. Two non-fatal cardiovascular events were observed during the first 2 years of follow-up. Conclusions: DAA treatments returned plasma lipids to the normal range without increasing either the occurrence of cardiovascular events or the consumption of lipid-lowering medication beyond what is normal in a sex- and age-matched population. [ABSTRACT FROM AUTHOR]

β-Hydroxy-β-methylbutyrate (HMB) supplementation increases muscle and strength mass in some muscle-wasting disorders. Malnutrition and sarcopenia are often present in liver cirrhosis. We aimed to investigate the effects of oral HMB supplementation on changes in body composition and liver status in patients with cirrhosis and malnutrition. In a randomized, controlled, double-blind trial, 43 individuals were randomized to receive twice a day and for 12 weeks an oral nutritional supplement (ONS) enriched with 1.5 g of calcium HMB per bottle or another supplement with similar composition devoid of HMB. Inclusion criteria were liver cirrhosis with at least one previous decompensation and clinical malnutrition. Liver function, plasma biochemistry analyses, and physical condition assessment were carried out at baseline, then after six and 12 weeks of supplementation. A total of 34 patients completed the clinical trial. An improvement in liver function and an increase in fat mass index were observed in both groups. None of the two ONS changed the fat-free mass. However, we observed an upward trend in handgrip strength and a downward trend in minimal hepatic encephalopathy in the HMB group. At the end of the trial and regardless of the supplement administered, fat mass content increased with no change in fat-free mass, while liver function scores and nutritional analytic markers also improved. [ABSTRACT FROM AUTHOR]

Trans-10, cis-12-conjugated linoleic acid (CLA)-enriched diets promote atherosclerosis in mice despite increasing blood concentrations of HDL cholesterol. This suggests that under these conditions, the HDL apolipoproteins (apo) produced are abnormal. To test this hypothesis, apoE-deficient mice were fed a Western-type diet enriched with linoleic acid (control), cis-9, trans-11-CLA or trans-10, cis-12-CLA (1.0% wt/wt) for 12 wk, and the effects on HDL metabolism and apoC-III levels recorded. Compared with the control and cis-9, trans-11-CLA mice, those fed the trans-10, cis-12-CLA diet had significantly higher HDL cholesterol concentrations, and had a higher incidence of hypertriglyceridemia and hepatic steatosis. Plasma apoA-I and paraoxonase concentrations were significantly lower in the trans-10, cis-12-CLA group than in the cis-9, trans-11-CLA group. These reductions were associated with decreased hepatic expression of these proteins and a shift toward lipid-poor apolipoprotein particles. The plasma apoA-II concentration increased with its corresponding mRNA concentration in the liver, and was preferentially bound to HDL in the trans-10, cis-12-CLA mice, thus explaining the increased HDL cholesterol concentrations in this group. Significant, positive associations were found between apoA-II and C-III (r = 0.883, P < 0.001) and between apoA-II and atherosclerosis (r = 0.68, P < 0.001). These results indicate that trans-10, cis-12-CLA intake modifies HDL to form a proatherogenic apoA-II containing particle and promotes phenotypic changes compatible with metabolic syndrome. Cis-9, trans-11-CLA does not promote this detrimental effect. KEY WORDS: * conjugated linoleic acid * apolipoprotein * high density lipoproteins * atherosclerosis * paraoxonase

Background: Risk for severe COVID-19 increases with age. Different vaccination strategies are currently being considered, including those aimed at slowing down transmission and those aimed at providing direct protection to those most at risk. Methods: The objectives of the current study were i) to assess age-related incidence and survival between PCR-diagnosed COVID-19 cases (n = 61,993) in the Autonomous Community of Aragon from March to November 2020, and ii) to characterize age differences regarding the course of the disease in hospitalized patients in a tertiary university hospital. Results: We found a similar incidence of COVID-19 in individuals between 10 and 79 years. Incidence increased in those over 80 years possibly because of the elevated transmission within the nursing homes. We observed a profound disparity among age groups; case fatality rates (CFRs) were near 0 in cases younger than 39 years throughout different waves. In contrast, there was an age-dependent and progressive increase in the CFRs, especially during the first pandemic wave. SARS-CoV-2 infection caused a more severe and rapid progression in older patients. The elderly required faster hospitalization, presented more serious symptoms on admission, and had a worse clinical course. Hospitalized older individuals, even without comorbidities, had an increased mortality risk directly associated with their age. Lastly, the existence of comorbidities dramatically increased the CFRs in the elderly, especially in males. Conclusion: The elevated incidence of COVID-19 and the vulnerability of the elderly call for their prioritization in vaccination and targeted prevention measures specifically focused on this aged population. [ABSTRACT FROM AUTHOR]

Background: The Global Leadership Initiative on Malnutrition (GLIM) provided a new approach for the diagnosis of malnutrition based on a number of phenotypic and etiologic criteria. However, different diagnostic criteria could potentially lead to heterogeneity in the diagnosis. We identified different subsets of criteria to define malnutrition in a cohort of elder nursing‐home residents and investigated their clinical utility in terms of 1‐year survival. Methods: Our study included all residents (n = 485) from 3 nursing homes. We proposed 12 GLIM models based on different phenotypic and etiologic criteria. The main outcome was 1‐year all‐cause mortality. We also assessed the sensitivity and specificity for different phenotypic criteria using time‐dependent receiver operating characteristic curves, and cutoff values were calculated. Results: During 1 year of follow‐ups, 94 deaths occurred. The prevalence of malnutrition was 13.5% for models based on reduced food intake (RFI) and 10.45% for models based on inflammation associated with acute disease (IAD). Unadjusted Cox regression analyses showed that malnutrition was associated with a 2.31‐ to 4.64‐fold increase in mortality when diagnosed using IAD‐dependent models or with a 1.37‐ to 1.78‐fold increase in mortality using RFI‐dependent models. Cutoffs associated with mortality for the phenotypic criteria were lower than those recommended in the GLIM criteria. Conclusion: This study describes the association of several variations of the GLIM model with 1‐year mortality in nursing‐home residents. However, our data suggest a high heterogeneity to fulfill the GLIM criteria and the necessity of finding specific, tailored cutoff points for the studied populations. [ABSTRACT FROM AUTHOR]

Background: Diabetes and older age are associated with an increased risk of malnutrition and mortality. Recently, the Global Leadership Initiative on Malnutrition (GLIM) provided a 2‐step approach for the malnutrition diagnosis. In this study, we aimed to determine whether GLIM nutrition status at admission was associated with long‐term survival in elderly patients with type 2 diabetes mellitus (T2DM). Additionally, we aimed to identify which GLIM criteria were more able to become prognostic indicators of early or late death. Methods: Our study included a convenience sample of 159 patients with T2DM older than 65 years and admitted to the internal medicine wards of different Spanish hospitals: the VIDA‐survival cohort. Nutrition status was retrospectively assessed with the new GLIM criteria. The main outcome was long‐term mortality in the cohort during an 8‐year follow‐up. Bivariate tables summarized the variables of interest. Kaplan‐Meier survival curves and adjusted Cox regressions were also performed. Results: According to the GLIM criteria, we observed that the 35.8% and 16.3% of the VIDA‐survival cohort were categorized as having moderate and severe malnutrition, respectively. Severe malnutrition was associated with increased mortality (hazard ratio [HR] = 2.09; 95% CI, 1.29–3.38), compared with nonmalnourished participants. Moderate malnutrition had a neutral effect on all‐cause mortality (HR = 1.30; 95% CI, 0.88–1.92). Low plasma albumin levels, a surrogate marker of inflammation, were strongly associated with early mortality. Conclusion: Our study provides evidence that severe malnutrition according to GLIM criteria is associated with increased long‐term all‐cause mortality among elderly individuals with T2DM. [ABSTRACT FROM AUTHOR]

Purpose: Oral squamous cell carcinoma (OSCC) is a highly prevalent type of immunogenic cancer with a low survival rate in patients with comorbidities owing to toxic habits.Materials and Methods: A retrospective cohort study was conducted of patients with resectable OSCC at a tertiary Spanish hospital from 2011 to 2014. The primary predictor variables were comorbidity and immune biomarkers. Comorbidity was assessed using the Adult Comorbidity Evaluation-27 (ACE-27) and scored from 1 to 3 (mild to severe decompensation, respectively). The immune biomarkers were neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR). The primary outcome variable was 5-year overall survival (OS). Other study variables were stage, margin, and neck management. Receiver operating characteristic curves were built for each ratio. For the survey of immune biomarkers, area under the curve was computed to determine cutoff points and investigate their association with OS. Kaplan-Meier estimates of survival and Cox proportional hazards models were used for longitudinal analysis.Results: Overall 215 patients were identified (median age, 67 yr; range, 32 to 96 yr; median follow-up, 31 months; range, 7 to 78 months); 159 patients had at least 1 comorbid condition. Results showed that a severe comorbidity (according to the ACE-27) increased the risk of death by 4 times in patients with OSCC regardless of stage. NLR, dNLR, LMR, and PLR were associated with OS in the univariate study. Cutoff points to predict increased mortality were 3, 1.9, 2.6, and 66 for NLR, dNLR, LMR, and PLR, respectively. Age, comorbidity, stage, margins, and management of the neck were important independent predictors of decreased OS in OSCC. PLR was marginally associated with OS in the multivariate model.Conclusion: These results suggest that comorbidity and NLR, dNLR, LMR, and PLR are associated with 5-year OS in patients with resectable OSCC. [ABSTRACT FROM AUTHOR]

Healthy expansion of human adipose tissue requires mesenchymal stem cells (hMSC) able to proliferate and differentiate into mature adipocytes. Hence, characterization of those factors that coordinate hMSC-to-adipocyte transition is of paramount importance to modulate the adipose tissue expansion. It has been previously reported that the adipogenic program of hMSC can be disrupted by upregulating caveolar proteins, and polymerase I and transcript release factor (PTRF) is an integral component of caveolae, highly expressed in adipose tissue. Here, we hypothesized that the role of PTRF in adipocyte functionality might stem from an effect on hMSC. To test this hypothesis, we isolated hMSC from the subcutaneous fat depot. We found an upregulated expression of the PTRF associated with decreased adipogenic potential of hMSC, likely due to the existence of senescent adipocyte precursors. Employing short hairpin RNA-based constructs to stably reduce PTRF, we were able to restore insulin sensitivity and reduced basal lipolysis and leptin levels in human adipocytes with high levels of PTRF. Additionally, we pinpointed the detrimental effect caused by PTRF on the adipose tissue to the existence of senescent adipocyte precursors unable to proliferate and differentiate into adipocytes. This study provides evidence that impaired adipocyte functionality can be corrected, at least partially, by PTRF downregulation and warrants further in vivo research in patients with dysfunctional adipose tissue to prevent metabolic complications. [ABSTRACT FROM AUTHOR]

Background: Obesity is an excessive accumulation of fat frequently, but not always, associated with health problems, mainly type 2 diabetes and cardiovascular disease. During a positive energy balance, as caused by excessive intake or sedentary lifestyle, subcutaneous adipose tissue expands and accumulates lipids as triglycerides. However, the amount of adipose tissue per se is unlikely to be the factor linking obesity and metabolic complications. The expandability hypothesis states that, if this positive energy balance is prolonged, a point is eventually reached where subcutaneous adipose tissue can not further expand and energy surplus no longer can be safely stored. Once the limit on storage capacity has been exceeded, the dietary lipids start spilling and accumulate ectopically in other organs (omentum, liver, muscle, pancreas) forming lipid byproducts toxic to cells. Methods/Design: FATe is a multidisciplinary clinical project aimed to fill gaps that still exist in the expandability hypothesis. Imaging techniques (CT-scan), metabolomics, and transcriptomics will be used to identify the factors that set the limit expansion of subcutaneous adipose tissue in a cohort of caucasian individuals with varying degrees of adiposity. Subsequently, a set of biomarkers that inform the individual limits of expandability will be developed using computational and mathematical modeling. A different validation cohort will be used to minimize the risk of false positive rates and increase biomarkers' predictive performance. Discussion: The work proposed here will render a clinically useful screening method to predict which obese individuals will develop metabolic derangements, specially diabetes and cardiovascular disease. This study will also provide mechanistic evidence that promoting subcutaneous fat expansion might be a suitable therapy to reduce metabolic complications associated with positive energy balance characteristic of Westernized societies. [ABSTRACT FROM AUTHOR]

Background: The apolipoprotein E (APOE) gene is polymorphic, encoding one of 3 common alleles (ε2, ε3, ε4) produced from combinations of 2 non-synonymous SNPs (rs429358 and rs7412). APOE plays an important role controlling plasma lipids but its association with adipocyte functionality and body fatness remains to be determined. Methods: We analyzed fasting plasma lipids and genotyped the two main APOE-SNPs (rs429358 and rs7412), both located in the fourth exon of the APOE, in 4660 Caucasian middle-aged men free of cardiovascular disease. Results: The rs7412 SNP, which determines the APOE2 isoform, was significantly associated with Body Mass Index (BMI) and Waist Girth (WG) in a multivariate model accounting for age, smoking status and plasma lipids. BMI and WG were highest in TT homozygotes and lowest in CC homozygotes. This effect was independent of the rs429358 SNP, which failed to show any association with the BMI and WG variables. The odds ratio of being obese (BMI>30) for individuals carrying the APOε2 allele, present in 14% of the cohort and defined by the rs7412 SNP, was also significant in this multivariate model, with an OR of 1.27 (95% CI: 1.01–1.59). Conclusions: This study provides an evidence of a lipid-independent association between the APOE SNP rs7412 and body fatness surrogates, BMI and WG, in a large cohort of middle-aged males. [ABSTRACT FROM AUTHOR]

Impaired adipogenesis renders an adipose tissue unable to expand, leading to lipotoxicity and conditions such as diabetes and cardiovascular disease. While factors important for adipogenesis have been studied extensively, those that set the limits of adipose tissue expansion remain undetermined. Feeding a Western-type diet to apolipoprotein E2 knock-in mice, a model of metabolic syndrome, produced 3 groups of equally obese mice: mice with normal glucose tolerance, hyperinsulinemic yet glucose-tolerant mice, and prediabetic mice with impaired glucose tolerance and reduced circulating insulin. Using proteomics, we compared subcutaneous adipose tissues from mice in these groups and found that the expression of PTRF (polymerase I and transcript release factor) associated selectively with their glucose tolerance status. Lentiviral and pharmacologically overexpressed PTRF, whose function is critical for caveola formation, compromised adipocyte differentiation of cultured 3T3-L1 cells. In human adipose tissue, PTRF mRNA levels positively correlated with markers of lipolysis and cellular senescence. Furthermore, a negative relationship between telomere length and PTRF mRNA levels was observed in human subcutaneous fat. PTRF is associated with limited adipose tissue expansion underpinning the key role of caveolae in adipocyte regulation. Furthermore, PTRF may be a suitable adipocyte marker for predicting pathological obesity and inform clinical management. [ABSTRACT FROM AUTHOR]

Thiazolidinediones (TZDs) are insulin sensitizers used to treat patients with insulin resistance. To assess potential gene-drug interactions, mice expressing human apolipoprotein E3 or E4 (APOE3 or APOE4) were fed a Western-type high-fat diet for 12 wk, at which time they developed similarly impaired glucose tolerance. Supplementing the diet with rosiglitazone (1.5 mg/g body weight) for an additional 4 wk improved plasma lipid profiles in both APOE3 and APOE4 mice. However, glucose tolerance improved only in APOE3 mice. Induction of adipogenesis and lipogenesis was severely blunted in adipose tissues, but not in the livers, of APOE4 mice. Consequently, lipids were channeled to the liver, causing marked steatosis in these mice. Impaired glucose tolerance was not a prerequisite for this adverse effect, and long-term treatment with rosiglitazone altered liver enzymes and caused hepatic fibrosis in APOE4 mice. Finally, TZDs failed to stimulate PPARγ activation and adipocyte differentiation in preadipocytes and embryonic fibroblasts isolated from APOE4 mice compared to those from APOE3 mice. We conclude that the effects of TZDs are APOE isoform dependent, and that the metabolic damage observed in APOE4 mice is rooted in an impaired activation of the adipogenic program in the adipose tissues expressing APOE4. [ABSTRACT FROM AUTHOR]

Low plasma levels of branched chain amino acids (BCAA) in liver cirrhosis are associated with hepatic encephalopathy (HE). We aimed to identify a metabolic signature of minimal hepatic encephalopathy (MHE) in malnourished cirrhotic patients and evaluate its modification with oral nutritional supplements (ONS) enriched with ß-Hydroxy-ß-methylbutyrate (HMB), a derivative of the BCAA leucine. Post hoc analysis was conducted on a double-blind placebo-controlled trial of 43 individuals with cirrhosis and malnutrition, who were randomized to receive, for 12 weeks, oral supplementation twice a day with either 220 mL of Ensure® Plus Advance (HMB group, n = 22) or with 220 mL of Ensure® Plus High Protein (HP group, n = 21). MHE evaluation was by psychometric hepatic encephalopathy score (PHES). Compared to the HP group, an HMB-specific treatment effect led to a larger increase in Val, Leu, Phe, Trp and BCAA fasting plasma levels. Both treatments increased Fischer's ratio and urea without an increase in Gln or ammonia fasting plasma levels. MHE was associated with a reduced total plasma amino acid concentration, a reduced BCAA and Fischer´s ratio, and an increased Gln/Glu ratio. HMB-enriched ONS increased Fischer´s ratio without varying Gln or ammonia plasma levels in liver cirrhosis and malnutrition, a protective amino acid profile that can help prevent MHE. [ABSTRACT FROM AUTHOR]

Sarcopenia is a progressive and generalized loss of skeletal muscle mass and strength. It is frequently associated with malnutrition and dependence in nursing homes. Masticatory muscle strength could be the link between sarcopenia, malnutrition and dependence. We aimed to study the relation between sarcopenia, malnutrition and dependence with masseter muscle thickness measured by ultrasound. A cross-sectional study was realized, with 464 patients from 3 public nursing homes in Zaragoza (Spain). The diagnosis of sarcopenia was assessed according to the European Working Group on Sarcopenia in Older People 2 criteria, malnutrition by the Mini Nutritional Assessment (MNA) and the Global Leadership Initiative on Malnutrition (GLIM) criteria and functional capacity by the Barhel Index and the texture diet. Masseter muscle thickness (MMT) was measured by ultrasound. The median age was 84.7 years, and 70% of the participants were women. Sarcopenia was confirmed in 39.2% of patients, malnutrition in 26.5% (risk 47.8%), total dependence in 37.9% and diet texture was modified in 44.6%. By logistic regression, once the model was adjusted for age, sex, Barthel index and texture diet, our analyses indicated that each 1 mm decrease in MMT increased the risk of sarcopenia by ~57% (OR: 0.43), the risk of malnutrition by MNA by ~63% (OR: 0.37) and the risk of malnutrition by GLIM by ~34% (OR: 0.66). We found that MMT was reduced in sarcopenic, malnourished and dependent patients, and it could be the common point of a vicious cycle between sarcopenia and malnutrition. Further studies are needed to establish causality. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (APOE) is a multifunctional protein synthesized and secreted by multiple mammalian tissues. Although hepatocytes contribute about 75% of the peripheral pool, APOE can also be expressed in adipose tissue, the kidney, and the adrenal glands, among other tissues. High levels of APOE production also occur in the brain, where it is primarily synthesized by glia, and peripheral and brain APOE pools are thought to be distinct. In humans, APOE is polymorphic, with three major alleles (ε2 , ε3 , and ε4). These allelic forms dramatically alter APOE structure and function. Historically, the vast majority of research on APOE has centered on the important role it plays in modulating risk for cardiovascular disease and Alzheimer's disease. However, the established effects of this pleiotropic protein extend well beyond these two critical health challenges, with demonstrated roles across a wide spectrum of biological conditions, including adipose tissue function and obesity, metabolic syndrome and diabetes, fertility and longevity, and immune function. While the spectrum of biological systems in which APOE plays a role seems implausibly wide at first glance, there are some potential unifying mechanisms that could tie these seemingly disparate disorders together. In the current review, we aim to concisely summarize a wide breadth of APOE-associated pathologies and to analyze the influence of APOE in the development of several distinct disorders in order to provide insight into potential shared mechanisms implied in these various pathophysiological processes. [ABSTRACT FROM AUTHOR]