Biomarkers and subtypes of deranged lipid metabolism in non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy. NAFLD covers a spectrum that ranges from simple steatosis, nonalcoholic steatohepatitis (NASH) with varying degrees of fibrosis, to cirrhosis, which is a major risk factor for hepatocellular carcinoma. Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity, type 2 diabetes mellitus and dyslipidemia, with a global prevalence of 25%. NAFLD arises when the uptake of fatty acids (FA) and triglycerides (TG) from circulation and de novo lipogenesis saturate the rate of FA β-oxidation and very-low density lipoprotein (VLDL)-TG export. Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH, and therefore, alterations in liver and serum lipidomic signatures are good indicators of the disease's development and progression. This review focuses on the importance of the classification of NAFLD patients into different subtypes, corresponding to the main alteration(s) in the major pathways that regulate FA homeostasis leading, in each case, to the initiation and progression of NASH. This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments

Methionine adenosyltransferases in liver cancer.

Methionine adenosyltransferases (MATs) are essential enzymes for life as they produce S-adenosylmethionine (SAMe), the biological methyl donor required for a plethora of reactions within the cell. Mammalian systems express two genes, MAT1A and MAT2A, which encode for MATα1 and MATα2, the catalytic subunits of the MAT isoenzymes, respectively. A third gene MAT2B, encodes a regulatory subunit known as MATβ which controls the activity of MATα2. MAT1A, which is mainly expressed in hepatocytes, maintains the differentiated state of these cells, whilst MAT2A and MAT2B are expressed in extrahepatic tissues as well as non-parenchymal cells of the liver (e.g., hepatic stellate and Kupffer cells). The biosynthesis of SAMe is impaired in patients with chronic liver disease and liver cancer due to decreased expression and inactivation of MATα1. A switch from MAT1A to MAT2A/MAT2B occurs in multiple liver diseases and during liver growth and dedifferentiation, but this change in the expression pattern of MATs results in reduced hepatic SAMe level. Decades of study have utilized the Mat1a-knockout (KO) mouse that spontaneously develops non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) to elucidate a variety of mechanisms by which MAT proteins dysregulation contributes to liver carcinogenesis. An increasing volume of work indicates that MATs have SAMe-independent functions, distinct interactomes and multiple subcellular localizations. Here we aim to provide an overview of MAT biology including genes, isoenzymes and their regulation to provide the context for understanding consequences of their dysregulation. We will highlight recent breakthroughs in the field and underscore the importance of MAT's in liver tumorigenesis as well as their potential as targets for cancer therapy

Compositional uniformity, domain patterning and the mechanism underlying nano-chessboard arrays

We propose that systems exhibiting compositional patterning at the nanoscale, so far assumed to be due to some kind of ordered phase segregation, can be understood instead in terms of coherent, single phase ordering of minority motifs, caused by some constrained drive for uniformity. The essential features of this type of arrangements can be reproduced using a superspace construction typical of uniformity-driven orderings, which only requires the knowledge of the modulation vectors observed in the diffraction patterns. The idea is discussed in terms of a simple two dimensional lattice-gas model that simulates a binary system in which the dilution of the minority component is favored. This simple model already exhibits a hierarchy of arrangements similar to the experimentally observed nano-chessboard and nano-diamond patterns, which are described as occupational modulated structures with two independent modulation wave vectors and simple step-like occupation modulation functions.Comment: Preprint. 11 pages, 11 figure

Langevin dynamics with a tilted periodic potential

We study a Langevin equation for a particle moving in a periodic potential in the presence of viscosity $\gamma$ and subject to a further external field $\alpha$. For a suitable choice of the parameters $\alpha$ and $\gamma$ the related deterministic dynamics yields heteroclinic orbits. In such a regime, in absence of stochastic noise both confined and unbounded orbits coexist. We prove that, with the inclusion of an arbitrarly small noise only the confined orbits survive in a sub-exponential time scale.Comment: 38 pages, 6 figure

Spiral ground state against ferroelectricity in the frustrated magnet BiMnFe2O6

The spiral magnetic structure and underlying spin lattice of BiMnFe2O6 are investigated by low-temperature neutron powder diffraction and density functional theory band structure calculations. In spite of the random distribution of the Mn3+ and Fe3+ cations, this compound undergoes a transition into an incommensurate antiferromagnetically ordered state below TN ~ 220 K. The magnetic structure is characterized by the propagation vector k=[0,beta,0] with beta ~ 0.14 and the P22_12_11'(0 \beta 0)0s0s magnetic superspace symmetry. It comprises antiferromagnetic helixes propagating along the b-axis. The magnetic moments lie in the ac plane and rotate about pi*(1+beta) ~ 204.8 deg angle between the adjacent magnetic atoms along b. The spiral magnetic structure arises from the peculiar frustrated arrangement of exchange couplings in the ab plane. The antiferromagnetic coupling along the c-axis leads to the cancellation of electric polarization, and results in the lack of ferroelectricity in BiMnFe2O6.Comment: 11 pages, 8 figures, 8 table

The 2006 Human Liver Proteome Project (HLPP) Workshops

In 2006, scientists participating to the Human Liver Proteome Project (HLPP) launched by the Human Proteome Organisation (HUPO) convened on two occasions to present and discuss their progress. A workshop was held over two days in May in Bilbao, Spain, and a brief 3-hour meeting was held in October in conjunction with the 5th HUPO World Congress in Long Beach, California. Highlights included progress on the construction of the human normal liver proteome expression profile and of subcellular proteomes, establishment of a liver ORFeome bank and of a liver antibody bank, identifications of protein-protein interaction maps in the liver, application of a robust strategy for quantitative proteomics and the characterization of fatty liver diseases using mouse models

Modifications of Gait as Predictors of Natural Osteoarthritis Progression in STR/Ort Mice

OBJECTIVE: Osteoarthritis (OA) is a common chronic disease for which disease-modifying therapies are not currently available. Studies to seek new targets for slowing the progress of OA rely on mouse models, but these do not allow for longitudinal monitoring of disease development. This study was undertaken to determine whether gait can be used to measure disease severity in the STR/Ort mouse model of spontaneous OA and whether gait changes are related to OA joint pain. METHODS: Gait was monitored using a treadmill-based video system. Correlations between OA severity and gait at 3 treadmill speeds were assessed in STR/Ort mice. Gait and pain behaviors of STR/Ort mice and control CBA mice were analyzed longitudinally, with monthly assessments. RESULTS: The best speed to identify paw area changes associated with OA severity in STR/Ort mice was found to be 17 cm · seconds(−1). Paw area was modified with age in CBA and STR/Ort mice, but this began earlier in STR/Ort mice and correlated with the onset of OA at 20 weeks of age. In addition, task noncompliance appeared at 20 weeks. Surprisingly, STR/Ort mice did not show any signs of pain with OA development, even when treated with the opioid antagonist naloxone, but did exhibit normal pain behaviors in response to complete Freund's adjuvant–induced arthritis. CONCLUSION: The present results identify an animal model in which OA severity and OA pain can be studied in isolation from one another. The findings suggest that paw area and treadmill noncompliance may be useful tools to longitudinally monitor nonpainful OA development in STR/Ort mice. This will help in providing a noninvasive means of assessing new therapies to slow the progression of OA