MicroRNA-155 Deficiency Attenuates Liver Steatosis and Fibrosis without Reducing Inflammation in a Mouse Model of Steatohepatitis

BACKGROUND & AIM: MicroRNAs (miRs) regulate hepatic steatosis, inflammation and fibrosis. Fibrosis is the consequence of chronic tissue damage and inflammation. We hypothesized that deficiency of miR-155, a master regulator of inflammation, attenuates steatohepatitis and fibrosis. METHODS: Wild type (WT) and miR-155-deficient (KO) mice were fed methionine-choline-deficient (MCD) or -supplemented (MCS) control diet for 5 weeks. Liver injury, inflammation, steatosis and fibrosis were assessed. RESULTS: MCD diet resulted in steatohepatitis and increased miR-155 expression in total liver, hepatocytes and Kupffer cells. Steatosis and expression of genes involved in fatty acid metabolism were attenuated in miR-155 KO mice after MCD feeding. In contrast, miR-155 deficiency failed to attenuate inflammatory cell infiltration, nuclear factor kappa beta (NF-kappaB) activation and enhanced the expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFalpha) and monocyte chemoattractant protein-1 (MCP1) in MCD diet-fed mice. We found a significant attenuation of apoptosis (cleaved caspase-3) and reduction in collagen and alpha smooth muscle actin (alphaSMA) levels in miR-155 KO mice compared to WTs on MCD diet. In addition, we found attenuation of platelet derived growth factor (PDGF), a pro-fibrotic cytokine; SMAD family member 3 (Smad3), a protein involved in transforming growth factor-beta (TGFbeta) signal transduction and vimentin, a mesenchymal marker and indirect indicator of epithelial-to-mesenchymal transition (EMT) in miR-155 KO mice. Nuclear binding of CCAAT enhancer binding protein beta (C/EBPbeta) a miR-155 target involved in EMT was significantly increased in miR-155 KO compared to WT mice. CONCLUSIONS: Our novel data demonstrate that miR-155 deficiency can reduce steatosis and fibrosis without decreasing inflammation in steatohepatitis

Socio-demographic and lifestyle factors associated with overweight in a representative sample of 11-15 year olds in France: Results from the WHO-Collaborative Health Behaviour in School-aged Children (HBSC) cross-sectional study

<p>Abstract</p> <p>Background</p> <p>The prevalence of overweight in children and adolescents is high and overweight is associated with poor health outcomes over short- and long-term. Lifestyle factors can interact to influence overweight. Comprehensive studies linking overweight concomitantly with several demographic and potentially-modifiable lifestyle factors and health-risk behaviours are limited in adolescents - an age-group characterized by changes in lifestyle behaviours and high prevalence of overweight. Thus, the objective of the current study was to examine the association of overweight with several socio-demographic and lifestyle variables simultaneously in a representative sample of adolescents.</p> <p>Methods</p> <p>A nationally representative sample of 11-15 year-olds (n = 7154) in France participated as part of the WHO-Collaborative Health Behaviour in School-aged Children (HBSC) study. Students reported data on their age, height, weight, socio-demographic variables, lifestyle factors including nutrition practices, physical activity at two levels of intensity (moderate and vigorous), sedentary behaviours, as well as smoking and alcohol consumption patterns using standardized HBSC protocols. Overweight (including obesity) was defined using the IOTF reference. The multivariate association of overweight with several socio-demographic and lifestyle factors was examined with logistic regression models.</p> <p>Results</p> <p>The adjusted odds ratios for the association with overweight were: 1.80 (95% CI: 1.37-2.36) for low family affluence; 0.73 (0.60-0.88) for eating breakfast daily; 0.69 (0.56-0.84) for moderate to vigorous physical activity (MVPA); and 0.71 (0.59-0.86) for vigorous physical activity (VPA). Significant interactions between age and gender as well as television (TV) viewing and gender were noted: for boys, overweight was not associated with age or TV viewing; in contrast, for girls overweight correlated negatively with age and positively with TV viewing. Fruit and vegetable intake, computer and video-games use, smoking and alcohol consumption were not associated with overweight.</p> <p>Conclusions</p> <p>In multivariate model, family affluence, breakfast consumption and moderate to vigorous as well as vigorous physical activity were negatively associated with overweight. These findings extend previous research to a setting where multiple risk and protective factors were simultaneously examined and highlight the importance of multi-faceted approaches promoting physical activity and healthy food choices such as breakfast consumption for overweight prevention in adolescents.</p

Fear of falling in obese women under 50 years of age: a cross-sectional study with exploration of the relationship with physical activity

An understanding of capacity for physical activity in obese populations should help guide interventions to promote physical activity. Fear of falling is a phenomenon reported in the elderly, which is associated with reduced mobility and lower physical activity levels. However, although falls are reportedly common in obese adults, fear of falling and its relationship with activity has not been investigated in younger obese populations. In a cross-sectional study, fear of falling was measured in 63 women aged 18 to 49 years, with mean BMI 42.1 kg/m (SD 10.3) using the Modified Falls Efficacy (MFES), the Consequences of Falling (COF) and the Modified Survey of Activities and Fear of Falling in the Elderly (MSAFFE) scales. The choice of scales was informed by prior qualitative interviews with obese younger women. Physical activity levels were measured at the same time using the International Physical Activity Questionnaire. The mean score for fear of falling scales, with 95% confidence intervals, were estimated. Chi-square tests and t-tests were used to explore differences in age, body mass index and fear of falling scores between fallers and non-fallers. For each fear of falling scale, binomial logistic regression was used to explore its relationship with physical activity. Mean scores suggested high levels of fear of falling: MFES [mean 7.7 (SD 2.7); median 8.5]; COF [mean 31.3 (SD 9.4)]; MSAFFE [mean 25.9 (SD 8.7); median 23]. Scores were significantly worse in fallers (  = 42) compared to non-fallers (  = 21). MFES and MSAFFE were independently associated with lower levels of physical activity [odds ratio = 0.65, 95% Cl 0.44 to 0.96 and odds ratio = 1.14, 95% CI 1.01 to 1.28 respectively], when adjusted for age, BMI and depression. This study confirms that fear of falling is present in obese women under 50 years of age. It suggests that it is associated with low levels of physical activity. These novel findings warrant further research to understand capacity for physical and incidental activity in obese adults in both genders and suggest innovative interventions to promote lifestyle changes and/or consideration of falls prevention in this population

HMGA1 Reprograms Somatic Cells into Pluripotent Stem Cells by Inducing Stem Cell Transcriptional Networks

PMC3499526BACKGROUND: Although recent studies have identified genes expressed in human embryonic stem cells (hESCs) that induce pluripotency, the molecular underpinnings of normal stem cell function remain poorly understood. The high mobility group A1 (HMGA1) gene is highly expressed in hESCs and poorly differentiated, stem-like cancers; however, its role in these settings has been unclear. METHODS/PRINCIPAL FINDINGS: We show that HMGA1 is highly expressed in fully reprogrammed iPSCs and hESCs, with intermediate levels in ECCs and low levels in fibroblasts. When hESCs are induced to differentiate, HMGA1 decreases and parallels that of other pluripotency factors. Conversely, forced expression of HMGA1 blocks differentiation of hESCs. We also discovered that HMGA1 enhances cellular reprogramming of somatic cells to iPSCs together with the Yamanaka factors (OCT4, SOX2, KLF4, cMYC - OSKM). HMGA1 increases the number and size of iPSC colonies compared to OSKM controls. Surprisingly, there was normal differentiation in vitro and benign teratoma formation in vivo of the HMGA1-derived iPSCs. During the reprogramming process, HMGA1 induces the expression of pluripotency genes, including SOX2, LIN28, and cMYC, while knockdown of HMGA1 in hESCs results in the repression of these genes. Chromatin immunoprecipitation shows that HMGA1 binds to the promoters of these pluripotency genes in vivo. In addition, interfering with HMGA1 function using a short hairpin RNA or a dominant-negative construct blocks cellular reprogramming to a pluripotent state. CONCLUSIONS: Our findings demonstrate for the first time that HMGA1 enhances cellular reprogramming from a somatic cell to a fully pluripotent stem cell. These findings identify a novel role for HMGA1 as a key regulator of the stem cell state by inducing transcriptional networks that drive pluripotency. Although further studies are needed, these HMGA1 pathways could be exploited in regenerative medicine or as novel therapeutic targets for poorly differentiated, stem-like cancers.JH Libraries Open Access Fun