Deletion of angiotensin II type I receptor reduces hepatic steatosis

Background/Aims: A distinct subgroup of angiotensin II type I receptor (AT1R) blockers (ARBs) have been reported to suppress the development of hepatic steatosis. These effects were generally explained by selective peroxisome proliferator-activated receptor (PPAR) gamma modulating properties of ARBs, independent of their AT1R blocking actions. Here, we provide genetic evidence of the direct role for AT1R in hepatic steatosis. Methods: The effect of AT1R deletion on steatohepatitis was investigated in AT1a(-/-) mice. Furthermore, the influence of AT1R inhibition by telmisartan as well as gene silencing of AT1R by siRNA was assessed in an in vitro experiment using HepG2 cells. Results: Compared to wild-type (WT), A T1a(-/-) mice fed methionine-choline deficient (MCD) diet resulted in negligible lipid accumulation in the liver with marked induction of PPAR alpha mRNA. In vitro experiments also demonstrated reduced cellular lipid accumulation by telmisartan and AT1R knockdown following exposure of long chain fatty acids. This is pre-sumably explained by the observation that the expression of PPAR alpha and its target genes were significantly up-regulated in specific siRNA treated HepG2 cells. Conclusions: Our data indicate, in addition to pharmacological effect of ARBs on PPAR gamma activation, a key biological role for AT1R in the regulation of hepatic lipid metabolism

Completing signaling networks by abductive reasoning with perturbation experiments

International audienceWe propose in this paper an abductive method that allows, given a biological network, to check whether some experimental observations can be causally explained by the network and to use the unexplained observations to complete the network. We then apply the method on the FSHR-induced signaling network

Kinetic Models and Qualitative Abstraction for Relational Learning in Systems Biology

Best student paper award http://www.bioinformatics.biostec.org/previous_awards.aspThis paper presents a method for enabling the relational learning or inductive logic programming (ILP) frame- work to deal with quantitative information from experimental data in systems biology. The study of systems biology through ILP aims at improving the understanding of the physiological state of the cell and the interpre- tation of the interactions between metabolites and signaling networks. A logical model of the glycolysis and pentose phosphate pathways of E. Coli is proposed to support our method description. We explain our original approach to building a symbolic model applied to kinetics based on Michaelis-Menten equation, starting with the discretization of the changes in concentration of some of the metabolites over time into relevant levels. We can then use them in our ILP-based model. Logical formulae on concentrations of some metabolites, which could not be measured during the dynamic state, are produced through logical abduction. Finally, as this re- sults in a large number of hypotheses, they are ranked with an expectation maximization algorithm working on binary decision diagrams

Structural Insight into an Alzheimer’s Brain-Derived Spherical Assembly of Amyloid β by Solid-State NMR

Accumulating evidence suggests that various neuro­degenerative diseases, including Alzheimer’s disease (AD), are linked to cytotoxic diffusible aggregates of amyloid proteins, which are metastable intermediate species in protein misfolding. This study presents the first site-specific structural study on an intermediate called amylo­spheroid (ASPD), an AD-derived neurotoxin composed of oligomeric amyloid-β (Aβ). Electron microscopy and immunological analyses using ASPD-specific “conformational” antibodies established synthetic ASPD for the 42-residue Aβ(1–42) as an excellent structural/morphological analogue of native ASPD extracted from AD patients, the level of which correlates with the severity of AD. ¹³C solid-state NMR analyses of approximately 20 residues and interstrand distances demonstrated that the synthetic ASPD is made of a homogeneous single conformer containing parallel β-sheets. These results provide profound insight into the native ASPD, indicating that Aβ is likely to self-assemble into the toxic intermediate with β-sheet structures in AD brains. This approach can be applied to various intermediates relevant to amyloid diseases