56 research outputs found
The endocannabinoid system:Overview of an emerging multi-faceted therapeutic target
The endocannabinoids anandamide (AEA) and 2-arachidonoylglyerol (2-AG) are endogenous lipid mediators that exert protective roles in pathophysiological conditions, including cardiovascular diseases. In this brief review, we provide a conceptual framework linking endocannabinoid signaling to the control of the cellular and molecular hallmarks, and categorize the key components of endocannabinoid signaling that may serve as targets for novel therapeutics. The emerging picture not only reinforces endocannabinoids as potent regulators of cellular metabolism but also reveals that endocannabinoid signaling is mechanistically more complex and diverse than originally thought
Editorial: The role of oxidative stress and systemic inflammation in diabetes and chronic kidney disease
The interaction between AMPK beta 2 and the PP1-targeting subunit R6 is dynamically regulated by intracellular glycogen content
11 páginas, 7 figuras.AMP-activated protein kinase (AMPK) is a metabolic stress-sensing kinase. We previously showed that glucose deprivation induces autophosphorylation of AMPKβ at threonine-148 (Thr-148), which prevents the binding of AMPK to glycogen. Furthermore, in MIN6 cells, AMPKβ1 binds to R6 (PPP1R3D), a glycogen-targeting subunit of protein phosphatase 1 (PP1), thereby regulating the glucose-induced inactivation of AMPK. Here, we further investigated the interaction of R6 with AMPKβ and the possible dependency on Thr-148 phosphorylation status. Yeast two-hybrid analyses and co-immunoprecipitation of the overexpressed proteins in HEK293T cells revealed that both AMPKβ1 and β2 wild-type (WT) isoforms bind to R6. The AMPKβ/R6 interaction was stronger with the muscle-specific β2-WT and required association with the substrate-binding motif of R6. When HEK293T cells or C2C12 myotubes were cultured in high-glucose medium, AMPKβ2-WT and R6 weakly interacted. In contrast, glycogen depletion significantly enhanced this protein interaction. Mutation of AMPKβ2 Thr-148 prevented the interaction with R6 irrespective of the intracellular glycogen content. Treatment with the AMPK activator oligomycin enhanced AMPKβ2/R6 interaction in conjunction with increased Thr-148 phosphorylation in cells grown in low glucose medium. These data are in accordance with R6 binding directly to AMPKβ2 when both proteins detach from the diminishing glycogen particle, which is simultaneous to increased AMPKβ2 Thr-148 autophosphorylation. Such model points to a possible control of AMPK by PP1-R6 upon glycogen depletion in muscle.DN is recipient of a VIDI-Innovational Research Grant from the Netherlands Organization of Scientific Research (NWO-ALW Grant no. 864.10.007). This work has further been supported by grants from the Spanish Ministry of Education and Science SAF2014-54604-C3-1-R and a grant from Generalitat Valenciana (PrometeoII/2014/029) to PS.Peer reviewe
Palmitate-Induced Vacuolar-Type H(+)-ATPase Inhibition Feeds Forward Into Insulin Resistance and Contractile Dysfunction
Dietary fat overconsumption leads to myocardial lipid accumulation through mechanisms that are incompletely resolved. Previously, we identified increased translocation of the fatty acid transporter CD36 from its endosomal storage compartment to the sarcolemma as the primary mechanism of excessive myocellular lipid import. Here, we show that increased CD36 translocation is caused by alkalinization of endosomes resulting from inhibition of proton pumping activity of vacuolar-type H+-ATPase (v-ATPase). Endosomal alkalinization was observed in hearts from rats fed a lard-based high-fat diet and in rodent and human cardiomyocytes upon palmitate overexposure, and appeared as an early lipid-induced event preceding the onset of insulin resistance. Either genetic or pharmacological inhibition of v-ATPase in cardiomyocytes exposed to low palmitate concentrations reduced insulin sensitivity and cardiomyocyte contractility, which was rescued by CD36 silencing. The mechanism of palmitate-induced v-ATPase inhibition involved its dissociation into two parts: the cytosolic V-1 and the integral membrane V-0 subcomplex. Interestingly, oleate also inhibits v-ATPase function, yielding triacylglycerol accumulation but not insulin resistance. In conclusion, lipid oversupply increases CD36-mediated lipid uptake that directly impairs v-ATPase function. This feeds forward to enhanced CD36 translocation and further increased lipid uptake. In the case of palmitate, its accelerated uptake ultimately precipitates into cardiac insulin resistance and contractile dysfunction
Science with the Daksha High Energy Transients Mission
We present the science case for the proposed Daksha high energy transients
mission. Daksha will comprise of two satellites covering the entire sky from
1~keV to ~MeV. The primary objectives of the mission are to discover and
characterize electromagnetic counterparts to gravitational wave source; and to
study Gamma Ray Bursts (GRBs). Daksha is a versatile all-sky monitor that can
address a wide variety of science cases. With its broadband spectral response,
high sensitivity, and continuous all-sky coverage, it will discover fainter and
rarer sources than any other existing or proposed mission. Daksha can make key
strides in GRB research with polarization studies, prompt soft spectroscopy,
and fine time-resolved spectral studies. Daksha will provide continuous
monitoring of X-ray pulsars. It will detect magnetar outbursts and high energy
counterparts to Fast Radio Bursts. Using Earth occultation to measure source
fluxes, the two satellites together will obtain daily flux measurements of
bright hard X-ray sources including active galactic nuclei, X-ray binaries, and
slow transients like Novae. Correlation studies between the two satellites can
be used to probe primordial black holes through lensing. Daksha will have a set
of detectors continuously pointing towards the Sun, providing excellent hard
X-ray monitoring data. Closer to home, the high sensitivity and time resolution
of Daksha can be leveraged for the characterization of Terrestrial Gamma-ray
Flashes.Comment: 19 pages, 7 figures. Submitted to ApJ. More details about the mission
at https://www.dakshasat.in
Molecular Basis of Endocrine Regulation by Orphan Nuclear Receptor Small Heterodimer Partner
D.C Performance Analysis of Sub-Threshold Source-Coupled Logic Circuit Using Double Gate Junction-Less Metal Oxide Semiconductor Field Effect Transistor for Low-Power Application
Post-translational modifications of CD36 (SR-B2): Implications for regulation of myocellular fatty acid uptake
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