Animal models of NASH: getting both pathology and metabolic context right

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of referral to liver clinics, and its progressive form, non-alcoholic steatohepatitis (NASH), can lead to cirrhosis and end-stage liver disease. The main risk factors for NAFLD/NASH are the metabolic abnormalities commonly observed in metabolic syndrome: insulin resistance, visceral obesity, dyslipidemia and altered adipokine profile. At present, the causes of progression from NAFLD to NASH remain poorly defined, and research in this area has been limited by the availability of suitable animal models of this disease. In the past, the main models used to investigate the pathogenesis of steatohepatitis have either failed to reproduce the full spectrum of liver pathology that characterizes human NASH, or the liver pathology has developed in a metabolic context that is not representative of the human condition. In the last few years, a number of models have been described in which the full spectrum of liver pathology develops in an appropriate metabolic context. In general, the underlying cause of metabolic defects in these models is chronic caloric overconsumption, also known as overnutrition. Overnutrition has been achieved in a number of different ways, including forced feeding, administration of high-fat diets, the use of genetically hyperphagic animals, or a combination of these approaches. The purpose of the present review is to critique the liver pathology and metabolic abnormalities present in currently available animal models of NASH, with particular focus on models described in approximately the last 5 years.This research was funded through a grant. - Research in the authors' laboratory is supported by program grant 358398 from the Australian National Health and Medical Research Council (NHMRC)

Growth in Skull Length and Width of the Arctic Wolf: Comparison of Models and Ontogeny of Sexual Size Dimorphism

We compared four classical nonlinear growth curves (Gompertz, Logistic, Richards, and von Bertalanffy) in modeling observed skull condylobasal length and zygomatic width as a function of age in wild arctic wolves (Canis lupus arctos). We analyzed gender-specific growth patterns and the ontogeny of sexual size dimorphism in this species as revealed by the best model from these alternatives. For both genders and skull size measurements, the size-at-age data provided the best support for the von Bertalanffy model because of higher fitting degrees, lower root mean squared standard deviation of data points about the fitted growth curve, Akaike weight of 37.4% or higher, and fewer parameters derived directly from metabolic laws. Male asymptotic condylobasal length was 3.2% longer, and zygomatic width 4.1% wider, than in females. Sexual size dimorphism in this species develops in part because males grow faster, which might benefit them in terms of reproductive success and the capture and killing of large ungulate prey.Nous avons comparé quatre courbes de croissance non linéaires classiques (Gompertz, logistique, Richards et von Bertalanffy) se rapportant à la modélisation de la longueur condylobasale de crânes observés et à leur largeur zygomatique en fonction de l’âge chez les loups arctiques sauvages (Canis lupus arctos). Ensuite, nous avons analysé les tendances de croissance en fonction de la sexospécificité et de l’ontogenèse de dimorphisme sexuel chez cette espèce, tel que révélé par le meilleur de ces modèles. Dans le cas des données relatives au sexe et aux mesures de tailles de crânes, les données propres aux tailles selon l’âge ont fourni le meilleur support pour le modèle de von Bertalanffy en raison de degrés de raccord plus élevés, d’un écart-type moyen inférieur des points de données sur la courbe de croissance ajustée, d’un poids Akaike de ≥ 37,4 % et de moins de paramètres directement dérivés des lois métaboliques. La longueur condylobasale asymptotique du mâle était de 3,2 % plus prononcée et sa largeur zygomatique était de 4,1 % plus grande que celles de la femelle. Chez cette espèce, le dimorphisme sexuel se développe en partie parce que les mâles grandissent plus vite, ce qui pourrait avantager les mâles en matière de réussite de reproduction, de même que les aider à capturer et à tuer les grosses proies ongulées

Mapping submarine glacial landforms using acoustic methods

The mapping of submarine glacial landforms is largely dependent on marine geophysical survey methods capable of imaging the seafloor and sub-bottom through the water column. Full global coverage of seafloor mapping, equivalent to that which exists for the Earth's land surface, has, to date, only been achieved by deriving bathymetry from radar altimeters on satellites such as GeoSat and ERS-1 (Smith & Sandwell 1997). The horizontal resolution is limited by the footprint of the satellite sensors and the need to average out local wave and wind effects, resulting in a cell size of about 15 km (Sandwell et al. 2001). A further problem in high latitudes is that the altimeter data are extensively contaminated by the presence of sea ice, which degrades the derived bathymetry (McAdoo & Laxon 1997). Consequently, the satellite altimeter method alone is not suitable for mapping submarine glacial landforms, given that their morphological characterization usually requires a much finer level of detail. Acoustic mapping methods based on marine echo-sounding principles are currently the most widely used techniques for mapping submarine glacial landforms because they are capable of mapping at a much higher resolution

A novel route for identifying starch diagenetic products in the archaeological record

This work introduces a novel analytical chemistry method potentially applicable to the study of archaeological starch residues. The investigation involved the laboratory synthesis of model Maillard reaction mixtures and their analysis through Fourier-Transform Ion Cyclotron Resonance Mass Spectrometry (FTICR-MS). Thus, starch from sixteen plant species were matured while reacting it with the amino acid glycine. The FTICR-MS analysis revealed > 5,300 molecular compounds, with numerous unique heteroatom rich compound classes, ranging from 20 (Zea mays) to 50 (Sorghum bicolor). These classes were investigated as repositories of chemical structure retaining source and process-specific character, linked back to botanical provenance. We discussed the Maillard reaction products thus generated, a possible pathway for the preservation of degraded starch, while also assessing diagenetic recalcitrance and adsorption potential to mineral surfaces. In some cases, hydrothermal experimentation on starches without glycine reveals that the chemical complexity of the starch itself is sufficient to produce some Maillard reaction products. The article concludes that FTICR-MS offers a new analytical window to characterize starchy residue and its diagenetic products, and is able to recognize taxonomic signals with the potential to persist in fossil contexts.Introduction Materials and methods - Sample preparation and characterization - FTICR-MS analysis Results - Characterization of Maillard reaction products based on atomic ratios (H/C, O/C, N/C, N/O) and compound class distribution - Variations in molecular distribution Discussion - The Maillard reaction products - Preservation pathway - Diagenetic recalcitrance of Maillard reaction products Conclusion

Serum Levels of the Adipokine FGF21 Depend on Renal Function

OBJECTIVE—To investigate renal elimination of the adipokine fibroblast growth factor 21 (FGF21) by determining circulating FGF21 levels in patients on chronic hemodialysis (CD) as compared with control subjects with a glomerular filtration rate (GFR) >50 ml/min

A Multi-Scale Test of the Forage Maturation Hypothesis in a Partially Migratory Ungulate Population

The forage maturation hypothesis (FMH) proposes that ungulate migration is driven by selection for high forage quality. Because quality declines with plant maturation, but intake declines at low biomass, ungulates are predicted to select for intermediate forage biomass to maximize energy intake by following phenological gradients during the growing season. We tested the FMH in the Canadian Rocky Mountains by comparing forage availability and selection by both migrant and nonmigratory resident elk (Cervus elaphus) during three growing seasons from 2002-2004. First, we confirmed that the expected trade-off between forage quality and quantity occurred across vegetation communities. Next, we modeled forage biomass and phenology during the growing season by combining ground and remote-sensing approaches. The growing season started 2.2 days earlier every 1 km east of the continental divide, was delayed by 50 days for every 1000-m increase in elevation, and occurred 8 days earlier on south aspects. Migrant and resident selection for forage biomass was then compared across three spatial scales (across the study area, within summer home ranges, and along movement paths) using VHF and GPS telemetry locations from 119 female elk. Migrant home ranges occurred closer to the continental divide in areas of higher topographical diversity, resulting in migrants consistently selecting for intermediate biomass at the two largest scales, but not at the. nest scale along movement paths. In contrast, residents selected maximum forage biomass across all spatial scales. To evaluate the consequences of selection, we compared exposure at telemetry locations of migrant and resident elk to expected forage biomass and digestibility. The expected digestibility for migrant elk in summer was 6.5% higher than for residents, which was corroborated with higher fecal nitrogen levels for migrants. The observed differences in digestibility should increase migrant elk body mass, pregnancy rates, and adult and calf survival rates. Whether bottom-up effects of improved forage quality are realized will ultimately depend on trade-offs between forage and predation. Nevertheless, this study provides comprehensive evidence that montane ungulate migration leads to greater access to higher-quality forage relative to nonmigratory congeners, as predicted by the forage maturation hypothesis, resulting primarily from large-scale selection patterns

Suboptimal maternal nutrition, during early fetal liver development, promotes lipid accumulation in the liver of obese offspring

Maternal nutrition during the period of early organ development can modulate the offspring's ability to metabolise excess fat as young adults when exposed to an obesogenic environment. This study examined the hypothesis that exposing offspring to nutrient restriction coincident with early hepatogenesis would result in endocrine and metabolic adaptations that subsequently lead to increased ectopic lipid accumulation within the liver. Pregnant sheep were fed either 50 or 100% of total metabolisable energy requirements from 30 to 80 days gestation and 100% thereafter. At weaning, offspring were made obese, and at ∼1 year of age livers were sampled. Lipid infiltration and molecular indices of gluconeogenesis, lipid metabolism and mitochondrial function were measured. Although hepatic triglyceride accumulation was not affected by obesity per se, it was nearly doubled in obese offspring born to nutrient-restricted mothers. This adaptation was accompanied by elevated gene expression for peroxisome proliferator-activated receptor γ (PPARG) and its co-activator PGC1α, which may be indicative of changes in the rate of hepatic fatty acid oxidation. In contrast, maternal diet had no influence on the stimulatory effect of obesity on gene expression for a range of proteins involved in glucose metabolism and energy balance including glucokinase, glucocorticoid receptors and uncoupling protein 2. Similarly, although gene expressions for the insulin and IGF1 receptors were suppressed by obesity they were not influenced by the prenatal nutritional environment. In conclusion, excess hepatic lipid accumulation with juvenile obesity is promoted by suboptimal nutrition coincident with early development of the fetal liver

The quantitative significance of Syntrophaceae and syntrophic partnerships in methanogenic degradation of crude oil alkanes

Libraries of 16S rRNA genes cloned from methanogenic oil degrading microcosms amended with North Sea crude oil and inoculated with estuarine sediment indicated that bacteria from the genera Smithella (Deltaproteobacteria, Syntrophaceace) and Marinobacter sp. (Gammaproteobacteria) were enriched during degradation. Growth yields and doubling times (36 days for both Smithella and Marinobacter) were determined using qPCR and quantitative data on alkanes, which were the predominant hydrocarbons degraded. The growth yield of the Smithella sp. [0.020 g(cell-C)/g(alkane-C)], assuming it utilized all alkanes removed was consistent with yields of bacteria that degrade hydrocarbons and other organic compounds in methanogenic consortia. Over 450 days of incubation predominance and exponential growth of Smithella was coincident with alkane removal and exponential accumulation of methane. This growth is consistent with Smithella's occurrence in near surface anoxic hydrocarbon degrading systems and their complete oxidation of crude oil alkanes to acetate and/or hydrogen in syntrophic partnership with methanogens in such systems. The calculated growth yield of the Marinobacter sp., assuming it grew on alkanes, was [0.0005 g(cell-C)/g(alkane-C)] suggesting that it played a minor role in alkane degradation. The dominant methanogens were hydrogenotrophs (Methanocalculus spp. from the Methanomicrobiales). Enrichment of hydrogen-oxidizing methanogens relative to acetoclastic methanogens was consistent with syntrophic acetate oxidation measured in methanogenic crude oil degrading enrichment cultures. qPCR of the Methanomicrobiales indicated growth characteristics consistent with measured rates of methane production and growth in partnership with Smithella

Middle Miocene to Pliocene History of Antarctica and the Southern Ocean

This chapter explores the Middle Miocene to Pliocene terrestrial and marine records of Antarctica and the Southern Ocean. The structure of the chapter makes a clear distinction between terrestrial and marine records as well as proximal (on or around Antarctica) and more distal records (Southern Ocean). Particular geographical regions are identified that reflect the areas for which the majority of palaeoenvironmental and palaeoclimatic information exist. Specifically, the chapter addresses the terrestrial sedimentary and fjordal environments of the Transantarctic Mountains and Lambert Glacier region, the terrestrial fossil record of Antarctic climate, terrestrial environments of West Antarctica, and the marine records of the East Antarctic Ice Sheet (EAIS), the West Antarctic Ice Sheet (WAIS) and the Antarctic Peninsula Ice Sheet (APIS), as well as the marine record of the Southern Ocean. Previous and current studies focusing on modelling Middle Miocene to Pliocene climate, environments and ice sheets are discussed.Published401-4631.8. Osservazioni di geofisica ambientale3.8. Geofisica per l'ambientereserve

Anaerobic microbial communities and their potential for bioenergy production in heavily biodegraded petroleum reservoirs

Most of the oil in low temperature, non‐uplifted reservoirs is biodegraded due to millions of years of microbial activity, including via methanogenesis from crude oil. To evaluate stimulating additional methanogenesis in already heavily biodegraded oil reservoirs, oil sands samples were amended with nutrients and electron acceptors, but oil sands bitumen was the only organic substrate. Methane production was monitored for over 3000 days. Methanogenesis was observed in duplicate microcosms that were unamended, amended with sulfate or that were initially oxic, however methanogenesis was not observed in nitrate‐amended controls. The highest rate of methane production was 0.15 μmol CH4 g−1 oil d−1, orders of magnitude lower than other reports of methanogenesis from lighter crude oils. Methanogenic Archaea and several potential syntrophic bacterial partners were detected following the incubations. GC–MS and FTICR–MS revealed no significant bitumen alteration for any specific compound or compound class, suggesting that the very slow methanogenesis observed was coupled to bitumen biodegradation in an unspecific manner. After 3000 days, methanogenic communities were amended with benzoate resulting in methanogenesis rates that were 110‐fold greater. This suggests that oil‐to‐methane conversion is limited by the recalcitrant nature of oil sands bitumen, not the microbial communities resident in heavy oil reservoirs