From fat to FAT (CD36/SR-B2):Understanding the regulation of cellular fatty acid uptake

The molecular mechanisms underlying the cellular uptake of long-chain fatty acids and the regulation of this process have been elucidated in appreciable detail in the last decades. Two main players in this field, each discovered in the early 1990s, are (i) a membrane-associated protein first identified in adipose ('fat') tissue and referred to as putative fatty acid translocase (FAT)/CD36 (now officially designated as SR-B2) which facilitates the transport of fatty acids across the plasma membrane, and (ii) the family of transcription factors designated peroxisome proliferator-activated receptors (PPAR alpha, PPAR gamma, and PPAR(beta/delta) for which fatty acids and fatty acid metabolites are the preferred ligand. CD36/SR-B2 is the predominant membrane protein involved in fatty acid uptake into intestinal enterocytes, adipocytes and cardiac and skeletal myocytes. The rate of cellular fatty acid uptake is regulated by the subcellular vesicular recycling of CD36/SR-B2 from endosomes to the plasma membrane. Fatty acid-induced activation of PPARs results in the upregulation of the expression of genes encoding various proteins and enzymes involved in cellular fatty acid utilization. Both CD36/SR-B2 and the PPARs have been implicated in the derangements in fatty acid and lipid metabolism occurring with the development of pathophysiological conditions, such as high fat diet-induced insulin resistance and diabetic cardiomyopathy, and have been suggested as targets for metabolic intervention. In this brief review we discuss the discovery and current understanding of both CD36/SR-B2 and the PPARs in metabolic homeostasis. (C) 2016 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved

Thermoelectric performance of weakly coupled granular materials

We study thermoelectric properties of inhomogeneous nanogranular materials for weak tunneling conductance between the grains, g_t < 1. We calculate the thermopower and figure of merit taking into account the shift of the chemical potential and the asymmetry of the density of states in the vicinity of the Fermi surface. We show that the weak coupling between the grains leads to a high thermopower and low thermal conductivity resulting in relatively high values of the figure of merit on the order of one. We estimate the temperature at which the figure of merit has its maximum value for two- and three-dimensional samples. Our results are applicable for many emerging materials, including artificially self-assembled nanoparticle arrays.Comment: 4 pages, 3 figure

Risk Factors for Major Early Adverse Events Related to Cardiac Catheterization in Children and Young Adults With Pulmonary Hypertension: An Analysis of Data From the IMPACT (Improving Adult and Congenital Treatment) Registry.

BACKGROUND: Cardiac catheterization is the gold standard for assessment and follow-up of patients with pulmonary hypertension (PH). To date, there are limited data about the factors that influence the risk of catastrophic adverse events after catheterization in this population. METHODS AND RESULTS: A retrospective multicenter cohort study was performed to measure risk of catastrophic adverse outcomes after catheterization in children and young adults with PH and identify risk factors for these outcomes. All catheterizations in children and young adults, aged 0 to 21 years, with PH at hospitals submitting data to the IMPACT (Improving Adult and Congenital Treatment) registry between January 1, 2011, and December 31, 2015, were studied. Using mixed-effects multivariable regression, we assessed the association between prespecified subject-, procedure-, and center-level covariates and the risk of death, cardiac arrest, or mechanical circulatory support during or after cardiac catheterization. A total of 8111 procedures performed in 7729 subjects at 77 centers were studied. The observed risk of the composite outcome was 1.4%, and the risk of death before discharge was 5.2%. Catheterization in prematurely born neonates and nonpremature infants was associated with increased risk of catastrophic adverse event, as was precatheterization treatment with inotropes and lower systemic arterial saturation. Secondary analyses demonstrated the following: (1) increasing volumes of catheterization in patients with PH were associated with reduced risk of composite outcome (odds ratio, 0.8 per 10 procedures; CONCLUSIONS: Young patients with PH are a high-risk population for diagnostic and interventional cardiac catheterization. Hospital experience with PH is associated with reduced risk, independent of total catheterization case volume

Munc18c provides stimulus-selective regulation of GLUT4 but not fatty acid transporter trafficking in skeletal muscle

Insulin-, and contraction-induced GLUT4 and fatty acid (FA) transporter translocation may share common trafficking mechanisms. Our objective was to examine the effects of partial Munc18c ablation on muscle glucose and FA transport, FA oxidation, GLUT4 and FA transporter (FAT/CD36, FAB-Ppm, FATP1, FATP4) trafficking to the sarcolemma, and FAT/CD36 to mitochondria. In Munc18c(-/+) mice, insulin-stimulated glucose transport and GLUT4 sarcolemmal appearance were impaired, but were unaffected by contraction. Insulin- and contraction-stimulated FA transport, sarcolemmal FA transporter appearance, and contraction-mediated mitochondrial FAT/CD36 were increased normally in Munc18c(-/+) mice. Hence, Munc18c provides stimulus-specific regulation of GLUT4 trafficking, but not FA transporter trafficking

Thermoelectric performance of granular semiconductors

We study thermoelectric properties of granular semiconductors with weak tunneling conductance between the grains, g_t < 1. We calculate the thermopower and figure of merit taking into account the shift of the chemical potential and the asymmetry of the density of states in the vicinity of the Fermi surface due to n- or p-type doping in the Efros-Shklovskii regime for temperatures less than the charging energy. We show that for weakly coupled semiconducting grains the figure of merit is optimized for grain sizes of order 5nm for typical materials and its values can be larger than one. We also study the case of compensated granular semiconductors and show that in this case the thermopower can be still finite, although two to three orders of magnitude smaller than in the uncompensated regime.Comment: 4 pages, 4 figure

One-dimensional Disordered Density Waves and Superfluids: The Role of Quantum Phase Slips and Thermal Fluctuations

The low temperature phase diagram of 1D disordered quantum systems like charge or spin density waves, superfluids and related systems is considered by a full finite T renormalization group approach, presented here for the first time. At zero temperature the consideration of quantum phase slips leads to a new scenario for the unpinning (delocalization) transition. At finite T a rich cross-over diagram is found which reflects the zero temperature quantum critical behavior.Comment: 4 pages, 2 figure

Caffeine-stimulated fatty acid oxidation is blunted in CD36 null mice

Aim: The increase in skeletal muscle fatty acid metabolism during exercise has been associated with the release of calcium. We examined whether this increase in fatty acid oxidation was attributable to a calcium-induced translocation of the fatty acid transporter CD36 to the sarcolemma, thereby providing an enhanced influx of fatty acids to increase their oxidation.Methods: Calcium release was triggered by caffeine (3 mM) to examine fatty acid oxidation in intact soleus muscles of WT and CD36-KO mice, while fatty acid transport and mitochondrial fatty acid oxidation were examined in giant vesicles and isolated mitochondria, respectively, from caffeine-perfused hindlimb muscles of WT and CD36-KO mice. Western blotting was used to examine calcium-induced signalling.Results: In WT, caffeine stimulated muscle palmitate oxidation (+136%), but this was blunted in CD36-KO mice (-70%). Dantrolene inhibited (WT) or abolished (CD36-KO) caffeine-induced palmitate oxidation. In muscle, caffeine-stimulated palmitate oxidation was not attributable to altered mitochondrial palmitate oxidation. Instead, in WT, caffeine increased palmitate transport (+55%) and the translocation of fatty acid transporters CD36, FABPpm, FATP1 and FATP4 (26-70%) to the sarcolemma. In CD36-KO mice, caffeine-stimulated FABPpm, and FATP1 and 4 translocations were normal, but palmitate transport was blunted (-70%), comparable to the reductions in muscle palmitate oxidation. Caffeine did not alter the calcium-/calmodulin-dependent protein kinase II phosphorylation but did increase the phosphorylation of AMPK and acetyl-CoA carboxylase comparably in WT and CD36-KO.Conclusion: These studies indicate that sarcolemmal CD36-mediated fatty acid transport is a primary mediator of the calcium-induced increase in muscle fatty acid oxidation

Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1 alpha) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats

Aims/hypothesis Reductions in peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1 alpha) levels have been associated with the skeletal muscle insulin resistance. However, in vivo, the therapeutic potential of PGC-1 alpha has met with failure, as supra-physiological overexpression of PGC-1 alpha induced insulin resistance, due to fatty acid translocase (FAT)-mediated lipid accumulation. Based on physiological and metabolic considerations, we hypothesised that a modest increase in PGC-1 alpha levels would limit FAT upregulation and improve lipid metabolism and insulin sensitivity, although these effects may differ in lean and insulin-resistant muscle. Methods Pgc-1 alpha was transfected into lean and obese Zucker rat muscles. Two weeks later we examined mitochondrial biogenesis, intramuscular lipids (triacylglycerol, diacylglycerol, ceramide), GLUT4 and FAT levels, insulin-stimulated glucose transport and signalling protein phosphorylation (thymoma viral proto-oncogene 2 [Akt2], Akt substrate of 160 kDa [AS160]), and fatty acid oxidation in subsarcolemmal and intermyofibrillar mitochondria. Results Electrotransfection yielded physiologically relevant increases in Pgc-1 alpha (also known as Ppargc1a) mRNA and protein (similar to 25%) in lean and obese muscle. This induced mitochondrial biogenesis, and increased FAT and GLUT4 levels, insulin-stimulated glucose transport, and Akt2 and AS160 phosphorylation in lean and obese animals, while bioactive intramuscular lipids were only reduced in obese muscle. Concurrently, PGC-1 alpha increased palmitate oxidation in subsarcolemmal, but not in intermyofibrillar mitochondria, in both groups. In obese compared with lean animals, the PGC-1 alpha-induced improvement in insulin-stimulated glucose transport was smaller, but intramuscular lipid reduction was greater. Conclusions/interpretations Increases in PGC-1 alpha levels, similar to those that can be induced by physiological stimuli, altered intramuscular lipids and improved fatty acid oxidation, insulin signalling and insulin-stimulated glucose transport, albeit to different extents in lean and insulin-resistant muscle. These positive effects are probably attributable to limiting the PGC-1 alpha-induced increase in FAT, thereby preventing bioactive lipid accumulation as has occurred in transgenic PGC-1 alpha animals