Long chain omega-3 fatty acids (FAs) are effective for reducing plasma triglyceride (TG) levels. At the pharmaceutical dose, 3.4g/day, they reduce plasma TG by about 25–50% after one month of ...treatment, resulting primarily from the decline in hepatic very low density lipoprotein (VLDL-TG) production, and secondarily from the increase in VLDL clearance. Numerous mechanisms have been shown to contribute to the TG overproduction, but a key component is an increase in the availability of FAs in the liver. The liver derives FAs from three sources: diet (delivered via chylomicron remnants), de novo lipogenesis, and circulating non-esterified FAs (NEFAs). Of these, NEFAs contribute the largest fraction to VLDL-TG production in both normotriglyceridemic subjects and hypertriglyceridemic, insulin resistant patients. Thus reducing NEFA delivery to the liver would be a likely locus of action for fish oils (FO). The key regulator of plasma NEFA is intracellular adipocyte lipolysis via hormone sensitive lipase (HSL), which increases as insulin sensitivity worsens. FO counteracts intracellular lipolysis in adipocytes by suppressing adipose tissue inflammation. In addition, FO increases extracellular lipolysis by lipoprotein lipase (LpL) in adipose, heart and skeletal muscle and enhances hepatic and skeletal muscle β-oxidation which contributes to reduced FA delivery to the liver. FO could activate transcription factors which control metabolic pathways in a tissue specific manner regulating nutrient traffic and reducing plasma TG. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.
► Pharmaceutical long chain omega-3 fatty acids effectively reduce plasma triglyceride levels. ► Fish oil reduces the rate of VLDL synthesis in the liver. ► Reduced NEFA delivery to the liver is a likely locus of action for fish oils. ► Fish oil counteracts the lipolytic release of NEFA from adipose tissue by suppressing inflammation. ► Fish oil increases FA uptake and β-oxidation in adipose, heart and skeletal muscle.
Local translation regulates the axonal proteome, playing an important role in neuronal wiring and axon maintenance. How axonal mRNAs are localized to specific subcellular sites for translation, ...however, is not understood. Here we report that RNA granules associate with endosomes along the axons of retinal ganglion cells. RNA-bearing Rab7a late endosomes also associate with ribosomes, and real-time translation imaging reveals that they are sites of local protein synthesis. We show that RNA-bearing late endosomes often pause on mitochondria and that mRNAs encoding proteins for mitochondrial function are translated on Rab7a endosomes. Disruption of Rab7a function with Rab7a mutants, including those associated with Charcot-Marie-Tooth type 2B neuropathy, markedly decreases axonal protein synthesis, impairs mitochondrial function, and compromises axonal viability. Our findings thus reveal that late endosomes interact with RNA granules, translation machinery, and mitochondria and suggest that they serve as sites for regulating the supply of nascent pro-survival proteins in axons.
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•Ribonucleoprotein particles are associated with endosomes in axons•Rab7a endosomes provide sites for axonal local translation•Rab7a endosomes support axonal synthesis of survival factors•CMT2B-Rab7a mutations affect axonal translation and mitochondrial integrity
Late endosomes are sites of local translation of mRNAs important for mitochondrial maintenance, and perturbing this process can contribute to neuropathology, as seen in Charcot Marie-Tooth disease.
Using a mouse model of human MLL-AF9 leukemia, we identified the lysine-specific demethylase KDM1A (LSD1 or AOF2) as an essential regulator of leukemia stem cell (LSC) potential. KDM1A acts at ...genomic loci bound by MLL-AF9 to sustain expression of the associated oncogenic program, thus preventing differentiation and apoptosis. In vitro and in vivo pharmacologic targeting of KDM1A using tranylcypromine analogs active in the nanomolar range phenocopied Kdm1a knockdown in both murine and primary human AML cells exhibiting MLL translocations. By contrast, the clonogenic and repopulating potential of normal hematopoietic stem and progenitor cells was spared. Our data establish KDM1A as a key effector of the differentiation block in MLL leukemia, which may be selectively targeted to therapeutic effect.
► KDM1A is a key effector of the differentiation block in MLL leukemia ► KDM1A sustains expression of the MLL-AF9 oncogenic program ► Nanomolar KDM1A inhibitor concentrations induce differentiation of human AML cells ► KDM1A inhibition in vivo targets MLL-AF9 cells but spares normal repopulating cells
Circulating levels of n-3 polyunsaturated fatty acids (PUFAs) have been associated with frailty among Koreans (a population with a high intake of fish), but whether this association exists in Western ...populations with low fish intake is unknown. The present study examined the hypothesis that the prevalence of frailty was inversely associated with plasma levels of n-3 PUFAs, with the intake of oily fish, and with fish oil supplementation in older adults in the United Kingdom.
UK Biobank including 79 330 adults aged ≥65 years with dietary data, and 18 802 participants with plasma fatty acid data were used. Frailty was defined using the Cardiovascular Health Study index, plasma levels of n-3 PUFAs were measured by nuclear magnetic resonance, and intake of oily fish and/or fish oil supplements was collected via food frequency questionnaire.
Frailty prevalence was inversely associated with n-3 PUFA levels odds ratios (OR) per SD: 0.86, 95% confidence interval (CI) 0.79-0.94; p < .001, with oily fish intake (never vs ≥2 servings per week; OR 0.59, 95% CI 0.52-0.68, p < .001), and with the use of fish oil supplements (OR 0.72; 95% CI 0.66-0.78; p < .001) after adjusting for confounding factors. All 3 exposures were also associated with each frailty criterion, particularly low physical activity and walking pace.
Inverse associations between plasma n-3 PUFA levels and measures of frailty suggest that higher intakes of oily fish or the use of fish oil supplements may help prevent frailty in older adults in the United Kingdom.
We present a hierarchical Bayesian method for estimating the total mass and mass profile of the Milky Way Galaxy. The new hierarchical Bayesian approach further improves the framework presented by ...Eadie et al. and Eadie and Harris and builds upon the preliminary reports by Eadie et al. The method uses a distribution function to model the Galaxy and kinematic data from satellite objects, such as globular clusters (GCs), to trace the Galaxy's gravitational potential. A major advantage of the method is that it not only includes complete and incomplete data simultaneously in the analysis, but also incorporates measurement uncertainties in a coherent and meaningful way. We first test the hierarchical Bayesian framework, which includes measurement uncertainties, using the same data and power-law model assumed in Eadie and Harris and find the results are similar but more strongly constrained. Next, we take advantage of the new statistical framework and incorporate all possible GC data, finding a cumulative mass profile with Bayesian credible regions. This profile implies a mass within 125 kpc of with a 95% Bayesian credible region of . Our results also provide estimates of the true specific energies of all the GCs. By comparing these estimated energies to the measured energies of GCs with complete velocity measurements, we observe that (the few) remote tracers with complete measurements may play a large role in determining a total mass estimate of the Galaxy. Thus, our study stresses the need for more remote tracers with complete velocity measurements.
Several recent randomized trials and subsequent meta-analyses have questioned the value of n-3 fatty acid supplementation in cardiovascular disease risk reduction.
This report focuses on four ...clinical trials published between 2010 and 2012 that have failed to show benefits of n-3 fatty acids, and on one meta-analysis from 2012 that used a controversial statistical approach in reaching a conclusion of no effect.
The question of the extent to which n-3 fatty acid supplementation reduces risk for cardiovascular disease remains open. Future studies must be properly powered, use doses of n-3 fatty acids significantly higher than those provided in background diets, focus on patient populations with low n-3 fatty acid tissue levels, treat for longer periods of time, and consider the effects of these agents in the great majority of patients who are not on guideline-directed therapeutic regimens. The strong evidence-base from prospective cohort studies and the ever-deepening understanding of the cellular effects of long-chain n-3 fatty acids together support the need for these nutrients in reducing cardiovascular risk. Short-term findings from randomized controlled trials need to be interpreted in the light of all the evidence.
Human acyl protein thioesterases (APTs) catalyze the depalmitoylation of S‐acylated proteins attached to the plasma membrane, facilitating reversible cycles of membrane anchoring and detachment. We ...previously showed that a bacterial APT homologue, FTT258 from the gram‐negative pathogen Francisella tularensis, exists in equilibrium between a closed and open state based on the structural dynamics of a flexible loop overlapping its active site. Although the structural dynamics of this loop are not conserved in human APTs, the amino acid sequence of this loop is highly conserved, indicating essential but divergent functions for this loop in human APTs. Herein, we investigated the role of this loop in regulating the catalytic activity, ligand binding, and protein folding of human APT1, a depalmitoylase connected with cancer, immune, and neurological signaling. Using a combination of substitutional analysis with kinetic, structural, and biophysical characterization, we show that even in its divergent structural location in human APT1 that this loop still regulates the catalytic activity of APT1 through contributions to ligand binding and substrate positioning. We confirmed previously known roles for multiple residues (Phe72 and Ile74) in substrate binding and catalysis while adding new roles in substrate selectivity (Pro69), in catalytic stabilization (Asp73 and Ile75), and in transitioning between the membrane binding β‐tongue and substrate‐binding loops (Trp71). Even conservative substitution of this tryptophan (Trp71) fulcrum led to complete loss of catalytic activity, a 13°C decrease in total protein stability, and drastic drops in ligand affinity, indicating that the combination of the size, shape, and aromaticity of Trp71 are essential to the proper structure of APT1. Mixing buried hydrophobic surface area with contributions to an exposed secondary surface pocket, Trp71 represents a previously unidentified class of essential tryptophans within α/β hydrolase structure and a potential allosteric binding site within human APTs.
Background
Edge wear is an adverse factor that can negatively impact certain THAs. In some metal-on-metal THAs, it can lead to adverse tissue reactions including aseptic lymphocytic ...vasculitis-associated lesions and even to pseudotumor formation. In some ceramic-on-ceramic THAs, it can lead to squeaking and/or stripe wear. Edge wear in metal-on-metal and ceramic-on-ceramic THAs can also be associated with accelerated wear across the articulation of these joints.
Questions/purposes
I asked: Does edge wear occur in metal-on-polyethylene (MOP) articulations? And if so, does it increase joint wear?
Methods
I examined the evidence in the literature for edge wear occurring in MOP THA and then assessed the evidence in the literature for data supporting the concept that edge wear in MOP hips could accelerate wear across the articulation over time.
Results
Extensive data in the literature confirm edge wear is common in MOP THA. Surprisingly, the evidence does not support that it accelerates wear across the articulation. In fact, substantial data support the concept that it does not.
Conclusions
These observations suggest, in terms of edge wear accelerating overall wear, MOP articulation may have a privileged position compared to hard-on-hard THA articulations.
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