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)

Controls on variations in sedimentary deposits produced by a retreating ice stream grounding line

The majority of glaciers draining the Antarctic Peninsula Ice Sheet are thinning and retreating rapidly1. It is widely understood that these changes are driven by both a warming ocean and atmosphere. However, there are other mechanisms, including pinning points created by bathymetric highs and a reverse bed gradient, that are thought to have an important control on ice stream behaviour (Weertman, 1974; Jamieson et al., 2012). Our understanding of the interplay between these mechanisms and time-scales over which they are important is currently limited in time to the advent of satellite monitoring. By reconstructing the cause and style of ice stream retreat following the Last Glacial Maximum (LGM; 25-19 ka BP), it is possible to gain a greater insight into the mechanisms which drive glacier retreat (Ó Cofaigh et al., 2014). Sedimentary sequences deposited during the LGM and the subsequent deglaciation on polar continental shelves, provide an important archive of past changes (Ó Cofaigh et al., 2014). Previous studies have typically identified three sediment facies assemblages; sub-glacial, transitional and open marine (Ó Cofaigh et al., 2014; Domack et al., 1988; Smith et al., 2011). Transitional sediment facies are deposited at the grounding line and are often targeted for radiocarbon dating, as they represent the onset of glaciomarine sedimentation following the retreat of grounded ice (Domack et al., 1988; Smith et al., 2014; Heroy et al., 1996). Despite the development of depositional models to help explain the processes occurring at grounding lines (Powell et al., 1995 and 1996), there is still significant uncertainty about the temporal and spatial variations in grounding line sedimentation along and across a palaeo-ice stream trough. Here we use a multi-proxy approach (water content, shear strength, magnetic susceptibility, density, contents of biogenic opal, Total Organic Carbon and CaCO3, grain size distribution and X-radiographs) on marine sediment cores recovered from the Anvers-Hugo Palaeo-Ice Stream Trough (AHT), western Antarctic Peninsula shelf, to identify variability in transitional sediment facies deposited along and across the trough. We discuss possible controls on the variability in transitional sediment facies and how this is related to the rate and style of ice stream retreat. Our data reveal systematic variability in the types and volume of transitional sediments deposited during the last deglaciation of AHT. A detailed analysis of the transitional sediment facies shows that this variability reflects different phases of ice stream behaviour. Large volumes of ice proximal sediment facies recovered seawards of grounding zone wedges are indicative of episodes of grounding line still-stands. Re-advances of the grounding line, concurrent with a shallowing of the reverse bed gradient and a narrowing of the trough, appear to have occurred during the final stages of deglaciation. This is indicated by interlaminated ice-proximal and ice-distal sediment facies within inner shelf cores. Transitional sediment variability additionally captures the evolution of the ice stream during deglaciation, including the formation of a small ice shelf on the inner shelf. Keywords: Antarctic Peninsula, Last Glacial Maximum, ice stream, sediment cores References Cook, A. J., Holland, P. R., Meredith, M. P., Murray, T., Luckman, A. & Vaughan, D. G, 2016. Ocean forcing of glacier retreat in the western Antarctic Peninsula. Science, 353, 283-286. Weertman, J, 1974. Stability of the Junction of an Ice Sheet and an Ice Shelf. Journal of Glaciology, 13, 3-11. Jamieson, S. S. R., Vieli, A., Livingstone, S. J., Cofaigh, C. O., Stokes, C., Hillenbrand, C.-D. & Dowdeswell, J. A, 2012. Ice-stream stability on a reverse bed slope. Nature Geoscience, 5, 799-802. Ó Cofaigh, C., Davies, B. J., Livingstone, S. J., Smith, J. A., Johnson, J. S., Hocking, E. P., Hodgson, D. A., Anderson, J. B., Bentley, M. J., Canals, M., Domack, E., Dowdeswell, J. A., Evans, J., Glasser, N. F., Hillenbrand, C.-D., Larter, R. D., Roberts, S. J. & Simms, A. R, 2014. Reconstruction of ice-sheet changes in the Antarctic Peninsula since the Last Glacial Maximum. Quaternary Science Reviews, 100, 87-110. Domack, E. W. & Harris, P. T, 1998. A new depositional model for ice shelves, based upon sediment cores from the Ross Sea and the Mac. Robertson shelf, Antarctica. Annals of Glaciology, 27, 281-284. Smith, J. A., Hillenbrand, C.-D., Kuhn, G., Larter, R. D., Graham, A. G. C., Ehrmann, W., Moreton, S. G. & Forwick, M, 2011. Deglacial history of the West Antarctic Ice Sheet in the western Amundsen Sea Embayment. Quaternary Science Reviews, 30, 488-505. Smith, J. A., Hillenbrand, C.-D., Kuhn, G., Klages, J. P., Graham, A. G. C., Larter, R. D., Ehrmann, W., Moreton, S. G., Wiers, S. & Frederichs, T, 2014. New constraints on the timing of West Antarctic Ice Sheet retreat in the eastern Amundsen Sea since the Last Glacial Maximum. Global and Planetary Change, 122, 224-237. Heroy, D. C. & Anderson, J. B, 1996. Radiocarbon constraints on Antarctic Peninsula Ice Sheet retreat following the Last Glacial Maximum (LGM). Quaternary Science Reviews, 26, 3286-3297. Powell, R. D., Dawber, M., McInnes, J. N. & Pyne, A. R, 1996. Observations of the Grounding-line Area at a Floating Glacier Terminus. Annals of Glaciology, 22, 217-223. 1Powell, R. D. & Domack, E, 1995. Modern Glacimarine Environments. In: Glacial Environments, Volume 1 (ed. J Menzies). Butterworth-Heinemann, 445-486

History of Anvers-Hugo Trough, western Antarctic Peninsula shelf, since the Last Glacial Maximum. Part I: Deglacial history based on new sedimentological and chronological data

Reconstructing the advance and retreat of past ice sheets provides important long-term context for recent change(s) and enables us to better understand ice sheet responses to forcing mechanisms and external boundary conditions that regulate grounding line retreat. This study applies various radiocarbon dating techniques, guided by a detailed sedimentological analyses, to reconstruct the glacial history of Anvers-Hugo Trough (AHT), one of the largest bathymetric troughs on the western Antarctic Peninsula (WAP) shelf. Existing records from AHT indicate that the expanded Antarctic Peninsula Ice Sheet (APIS) advanced to, or close to, the continental shelf edge during the Last Glacial Maximum (LGM; 23-19 cal kyr BP [ = calibrated kiloyears before present]), with deglaciation of the outer shelf after ∼16.3 cal kyr BP. Our new chronological data show that the APIS had retreated to the middle shelf by ∼15.7 cal kyr BP. Over this 600-year interval, two large grounding-zone wedges (GZW) were deposited across the middle (GZW2) and inner shelf (GZW3), suggesting that their formation occurred on centennial rather than millennial timescales. Expanded sequences of sub-ice shelf sediments occur seaward of the inner GZW3, which suggests that the grounding line remained stationary for a prolonged period over the middle shelf. Grounding-line retreat rates indicate faster retreat across the outer to middle shelf compared to retreat across the middle to inner shelf. We suggest that variable retreat rates relate to the broad-scale morphology of the trough, which is characterised by a relatively smooth, retrograde seabed on the outer to middle shelf and rugged morphology with a locally landward shallowing bed and deep basin on the inner shelf. A slowdown in retreat rate could also have been promoted by convergent ice flow over the inner shelf and the availability of pinning points associated with bathymetric highs around Anvers Island and Hugo Island

Non-alcoholic Fatty Liver Disease: From Steatosis to Cirrhosis

Nonalcoholic steatohepatitis (NASH), the lynchpin between steatosis and cirrhosis in the spectrum of nonalcoholic fatty liver disorders (NAFLD), was barely recognized in 1981. NAFLD is now present in 17% to 33% of Americans, has a worldwide distribution

A fresh look at NASH pathogenesis. Part 1: The metabolic movers

The strong relationship between over-nutrition, central obesity, insulin resistance/metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) suggest pathogenic interactions, but key questions remain. NAFLD starts with over-nutrition, imbalance between energy input and output for which the roles of genetic predisposition and environmental factors (diet, physical activity) are being redefined. Regulation of energy balance operates at both central nervous system and peripheral sites, including adipose and liver. For example, the endocannabinoid system could potentially be modulated to provide effective pharmacotherapy of NAFLD. The more profound the metabolic abnormalities complicating over-nutrition (glucose intolerance, hypoadiponectinemia, metabolic syndrome), the more likely is NAFLD to take on its progressive guise of non-alcoholic steatohepatitis (NASH). Interactions between steatosis and insulin resistance, visceral adipose expansion and subcutaneous adipose failure (with insulin resistance, inflammation and hypoadiponectinemia) trigger amplifying mechanisms for liver disease. Thus, transition from simple steatosis to NASH could be explained by unmitigated hepatic lipid partitioning with failure of local adaptive mechanisms leading to lipotoxicity. In part one of this review, we discuss newer concepts of appetite and metabolic regulation, bodily lipid distribution, hepatic lipid turnover, insulin resistance and adipose failure affecting adiponectin secretion. We review evidence that NASH only occurs when over-nutrition is complicated by insulin resistance and a highly disordered metabolic milieu, the same 'metabolic movers' that promote type 2 diabetes and atheromatous cardiovascular disease. The net effect is accumulation of lipid molecules in the liver. Which lipids and how they cause injury, inflammation and fibrosis will be discussed in part two

MCD-induced steatohepatitis is associated with hepatic adiponectin resistance and adipogenic transformation of hepatocytes

Background/Aims: In these studies, we tested the hypothesis that increased lipid intake would exacerbate the severity of nutritional steatohepatitis. Methods: C57Bl/6J mice were fed methionine-and-choline deficient (MCD) diets containing 20% (high) or 5

Peroxisome proliferator-activated receptor-α agonist, Wy 14,643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis

Background and Aims: Lipid accumulation precedes hepatocellular injury and liver inflammation in non-alcoholic steatohepatitis (NASH). The peroxisome proliferator-activated receptor (PPAR)α regulates hepatic lipid disposal. We studied whether pharmacolo