Jb Moore

Non-alcoholic fatty liver disease: the hepatic consequence of obesity and the metabolic syndrome.

Non-alcoholic fatty liver disease (NAFLD) is now the most common liver disease in both adults and children worldwide. As a disease spectrum, NAFLD may progress from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. An estimated 20-35% of the general population has steatosis, 10% of whom will develop the more progressive non-alcoholic steatohepatitis associated with markedly increased risk of cardiovascular- and liver-related mortality. Development of NAFLD is strongly linked to components of the metabolic syndrome including obesity, insulin resistance, dyslipidaemia and type 2 diabetes. The recognition that NAFLD is an independent risk factor for CVD is a major public health concern. There is a great need for a sensitive non-invasive test for the early detection and assessment of the stage of NAFLD that could also be used to monitor response to treatment. The cellular and molecular aetiology of NAFLD is multi-factorial; genetic polymorphisms influencing NAFLD have been identified and nutrition is a modifiable environmental factor influencing NAFLD progression. Weight loss through diet and exercise is the primary recommendation in the clinical management of NAFLD. The application of systems biology to the identification of NAFLD biomarkers and factors involved in NAFLD progression is an area of promising research.

Modulation of intestinal gene expression by dietary zinc status: Effectiveness of cDNA arrays for expression profiling of a single nutrient deficiency

Mammalian nutritional status affects the homeostatic balance of multiple physiological processes and their associated gene expression. Although DNA array analysis can monitor large numbers of genes, there are no reports of expression profiling of a micronutrient deficiency in an intact animal system. In this report, we have tested the feasibility of using cDNA arrays to compare the global changes in expression of genes of known function that occur in the early stages of rodent zinc deficiency. The gene-modulating effects of this deficiency were demonstrated by real-time quantitative PCR measurements of altered mRNA levels for metallothionein 1, zinc transporter 2, and uroguanylin, all of which have been previously documented as zinc-regulated genes. As a result of the low level of inherent noise within this model system and application of a recently reported statistical tool for statistical analysis of microarrays [Tusher, V.G., Tibshirani, R. & Chu, G. (2001) Proc. Natl. Acad. Sci. USA 98, 5116–5121], we demonstrate the ability to reproducibly identify the modest changes in mRNA abundance produced by this single micronutrient deficiency. Among the genes identified by this array profile are intestinal genes that influence signaling pathways, growth, transcription, redox, and energy utilization. Additionally, the influence of dietary zinc supply on the expression of some of these genes was confirmed by real-time quantitative PCR. Overall, these data support the effectiveness of cDNA array expression profiling to investigate the pleiotropic effects of specific nutrients and may provide an approach to establishing markers for assessment of nutritional status.

The Role of Dietary Sugars and De novo Lipogenesis in Non-Alcoholic Fatty Liver Disease

Dietary sugar consumption, in particular sugar-sweetened beverages and the monosaccharide fructose, has been linked to the incidence and severity of non-alcoholic fatty liver disease (NAFLD). Intervention studies in both animals and humans have shown large doses of fructose to be particularly lipogenic. While fructose does stimulate de novo lipogenesis (DNL), stable isotope tracer studies in humans demonstrate quantitatively that the lipogenic effect of fructose is not mediated exclusively by its provision of excess substrates for DNL. The deleterious metabolic effects of high fructose loads appear to be a consequence of altered transcriptional regulatory networks impacting intracellular macronutrient metabolism and altering signaling and inflammatory processes. Uric acid generated by fructose metabolism may also contribute to or exacerbate these effects. Here we review data from human and animal intervention and stable isotope tracer studies relevant to the role of dietary sugars on NAFLD development and progression, in the context of typical sugar consumption patterns and dietary recommendations worldwide. We conclude that the use of hypercaloric, supra-physiological doses in intervention trials has been a major confounding factor and whether or not dietary sugars, including fructose, at typically consumed population levels, effect hepatic lipogenesis and NAFLD pathogenesis in humans independently of excess energy remains unresolved.

Fatty acid binding proteins: tissue-specific functions in health and disease

Purpose of reviewThe purpose of this study is to review recent evidence for the role of the cytosolic fatty acid binding proteins (FABPs) as central regulators of whole-body metabolic control. Recent findingsDysregulated FABPs have been associated with a number of diseases, including obesity and nonalcoholic fatty liver disease (FABP1, FABP2, FABP4), cardiovascular risk (FABP3) and cancer (FABP5, FABP7). As underlying mechanisms become better understood, FABPs may represent novel biomarkers for therapeutic targets. In addition, the role of FABPs as important signalling molecules has also been highlighted in recent years; for example, FABP3 may act as a myokine, matching whole-body metabolism to muscular energy demands and FABP4 functions as an adipokine in regulating macrophage and adipocyte interactions during inflammation. SummaryIn addition to their traditional role as fatty acid trafficking proteins, increasing evidence supports the role of FABPs as important controllers of global metabolism, with their dysregulation being linked to a host of metabolic diseases.

Response of rat adrenal neuropeptide Y and tyrosine hydroxylase mRNA to acute stress is enhanced by long-term voluntary exercise

Neuropeptide Y (NPY) and catecholamines are synthesized in response to stress. Adrenal NPY mRNA and tyrosine hydroxylase (TH) mRNA were measured by Northern analysis 2 h after a single 20 min bout of shaker stress in exercised and sedentary male Sprague-Dawley rats. Long-term exercise (18 weeks of voluntary wheel running) alone did not significantly alter adrenal NPY mRNA or TH mRNA levels. However, increases in stress-induced NPY and TH mRNA abundances were significantly enhanced by long-term exercise (P < 0.01). These results suggest that long-term physical activity may enhance the ability to synthesize NPY and catecholamines under conditions of stress.

Dietary zinc modulates gene expression in murine thymus: Results from a comprehensive differential display screening

Differential mRNA display was used to comprehensively screen the murine thymic transcriptome for genes modulated in vivo by dietary zinc. A moderate feeding protocol rendered young adult, outbred mice zinc-deficient and zinc-supplemented without alterations in feeding behavior or growth. However, these levels of deficiency and supplementation altered specific mRNA abundances in a manner detectable by differential display. In total, 240 primer-pair combinations were used to generate >48,000 interpretable cDNA bands derived from thymic total RNA, of which only 265 or 0.55% were identified as zinc-modulated under these moderate dietary conditions. The most strongly zinc-modulated cDNAs identified by display were reamplified and sequenced. No cDNAs encoding zinc-metalloenzymes or zinc-finger transcription factors were identified as zinc-modulated in this global screening. Those zinc-regulated genes independently confirmed by quantitative PCR included: heat shock proteins 40 and 60; heat shock cognate 70; histocompatibility 2, class II antigen A, α; and the T cell cytokine receptor. In addition, a variety of transcription- and translation-related factors (such as ribosomal proteins L3, L5, and L28; nuclear matrix protein 84; matrin cyclophilin; the H3 histone family 3A protein; β2 microglobulin; and a cleavage and polyadenylation factor) were identified as zinc-modulated. These profiling data show that differential expression of genes in the thymus in response to the dietary zinc supply precedes many of the phenotypic effects on thymic function associated with severe zinc restriction or supplementation. Several genes involved in T cell development were identified as regulated by zinc and will be targets to evaluate the effects of zinc on immune function.

Proteomics and Systems Biology: Current and Future Applications in the Nutritional Sciences

In the last decade, advances in genomics, proteomics, and metabolomics have yielded large-scale datasets that have driven an interest in global analyses, with the objective of understanding biological systems as a whole. Systems biology integrates computational modeling and experimental biology to predict and characterize the dynamic properties of biological systems, which are viewed as complex signaling networks. Whereas the systems analysis of disease-perturbed networks holds promise for identification of drug targets for therapy, equally the identified critical network nodes may be targeted through nutritional intervention in either a preventative or therapeutic fashion. As such, in the context of the nutritional sciences, it is envisioned that systems analysis of normal and nutrient-perturbed signaling networks in combination with knowledge of underlying genetic polymorphisms will lead to a future in which the health of individuals will be improved through predictive and preventative nutrition. Although high-throughput transcriptomic microarray data were initially most readily available and amenable to systems analysis, recent technological and methodological advances in MS have contributed to a linear increase in proteomic investigations. It is now commonplace for combined proteomic technologies to generate complex, multi-faceted datasets, and these will be the keystone of future systems biology research. This review will define systems biology, outline current proteomic methodologies, highlight successful applications of proteomics in nutrition research, and discuss the challenges for future applications of systems biology approaches in the nutritional sciences.

The effect of supplementation with alkaline potassium salts on bone metabolism: a meta-analysis.

SummaryThe role of acid–base metabolism in bone health is controversial. In this meta-analysis, potassium bicarbonate and potassium citrate lowered urinary calcium and acid excretion and reduced the excretion of the bone resorption marker NTX. These salts may thus be beneficial to bone health by conserving bone mineral.IntroductionThe role of acid–base homeostasis as a determinant of bone health and the contribution of supplemental alkali in promoting skeletal integrity remain a subject of debate. The objective of this study was, therefore, to conduct a meta-analysis to assess the effects of supplemental potassium bicarbonate (KHCO3) and potassium citrate (KCitr) on urinary calcium and acid excretion, markers of bone turnover and bone mineral density (BMD) and to compare their effects with that of potassium chloride (KCl).MethodsA total of 14 studies of the effect of alkaline potassium salts on calcium metabolism and bone health, identified by a systematic literature search, were analysed with Review Manager (Version 5; The Cochrane Collaboration) using a random-effects model. Authors were contacted to provide missing data as required. Results are presented as the standardised (SMD) or unstandardized mean difference (MD) (95xa0% confidence intervals).ResultsUrinary calcium excretion was lowered by intervention with both KHCO3 (Pu2009=u20090.04) and KCitr (Pu2009=u20090.01), as was net acid excretion (NAE) (Pu2009=u20090.002 for KHCO3 and Pu2009=u20090.0008 for KCitr). Both salts significantly lowered the bone resorption marker NTX (Pu2009<u20090.00001). There was no effect on bone formation markers or BMD. KHCO3 and KCitr lowered calcium excretion to a greater extent than did KCl.ConclusionsThis meta-analysis confirms that supplementation with alkaline potassium salts leads to significant reduction in renal calcium excretion and acid excretion, compatible with the concept of increased buffering of hydrogen ions by raised circulating bicarbonate. The observed reduction in bone resorption indicates a potential benefit to bone health

Systems biology approaches for studying the pathogenesis of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a progressive disease of increasing public health concern. In western populations the disease has an estimated prevalence of 20%-40%, rising to 70%-90% in obese and type II diabetic individuals. Simplistically, NAFLD is the macroscopic accumulation of lipid in the liver, and is viewed as the hepatic manifestation of the metabolic syndrome. However, the molecular mechanisms mediating both the initial development of steatosis and its progression through non-alcoholic steatohepatitis to debilitating and potentially fatal fibrosis and cirrhosis are only partially understood. Despite increased research in this field, the development of non-invasive clinical diagnostic tools and the discovery of novel therapeutic targets has been frustratingly slow. We note that, to date, NAFLD research has been dominated by in vivo experiments in animal models and human clinical studies. Systems biology tools and novel computational simulation techniques allow the study of large-scale metabolic networks and the impact of their dysregulation on health. Here we review current systems biology tools and discuss the benefits to their application to the study of NAFLD. We propose that a systems approach utilising novel in silico modelling and simulation techniques is key to a more comprehensive, better targeted NAFLD research strategy. Such an approach will accelerate the progress of research and vital translation into clinic.

Assessment of Diet and Physical Activity in Paediatric Non-Alcoholic Fatty Liver Disease Patients: A United Kingdom Case Control Study

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children, with prevalence rising alongside childhood obesity rates. This study aimed to characterise the habitual diet and activity behaviours of children with NAFLD compared to obese children without liver disease in the United Kingdom (UK). Twenty-four biopsy-proven paediatric NAFLD cases and eight obese controls without biochemical or radiological evidence of NAFLD completed a 24-h dietary recall, a Physical Activity Questionnaire (PAQ), a Dutch Eating Behavior Questionnaire (DEBQ) and a 7-day food and activity diary (FAD), in conjunction with wearing a pedometer. Groups were well matched for age and gender. Obese children had higher BMI z-scores (p = 0.006) and BMI centiles (p = 0.002) than participants with NAFLD. After adjusting for multiple hypotheses testing and controlling for differences in BMI, no differences in macro- or micronutrient intake were observed as assessed using either 24-h recall or 7-day FAD (p > 0.001). Under-reporting was prevalent (NAFLD 75%, Obese Control 87%: p = 0.15). Restrained eating behaviours were significantly higher in the NAFLD group (p = 0.005), who also recorded more steps per day than the obese controls (p = 0.01). In conclusion, this is the first study to assess dietary and activity patterns in a UK paediatric NAFLD population. Only a minority of cases and controls were meeting current dietary and physical activity recommendations. Our findings do not support development of specific dietary/ physical activity guidelines for children with NAFLD; promoting adherence with current general paediatric recommendations for health should remain the focus of clinical management.