Local regulation of fat metabolism in peripheral nerves

Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California 92037, USA.
Genes & Development (Impact Factor: 12.64). 11/2003; 17(19):2450-64. DOI: 10.1101/gad.1116203
Source: PubMed

ABSTRACT We comprehensively analyzed gene expression during peripheral nerve development by performing microarray analyses of premyelinating, myelinating, and postmyelinating mouse sciatic nerves, and we generated a database of candidate genes to be tested in mapped peripheral neuropathies. Unexpectedly, we identified a large cluster of genes that are (1) maximally expressed only in the mature nerve, after myelination is complete, and (2) tied to the metabolism of storage (energy) lipids. Many of these late-onset genes are expressed by adipocytes, which we find constitute the bulk of the epineurial compartment of the adult nerve. However, several such genes, including SREBP-1, SREBP-2, and Lpin1, are also expressed in the endoneurium. We find that Lpin1 null mutations lead to lipoatrophy of the epineurium, and to the dysregulation of a battery of genes required for the regulation of storage lipid metabolism in both the endoneurium and peri/epineurium. Together with the observation that these mutations also result in peripheral neuropathy, our findings demonstrate a crucial role for local storage lipid metabolism in mature peripheral nerve function, and have important implications for the understanding and treatment of peripheral neuropathies that are commonly associated with metabolic diseases such as lipodystrophy and diabetes.

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Available from: Roman Chrast, Mar 18, 2015
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    • "The glial component of the peripheral nervous system requires massive amounts of FAs to properly myelinate peripheral nerves (Garbay et al., 2000). Schwann cells fulfill this requirement by synthesizing FAs and by taking up FAs from the bloodstream and from other nerve structures (Bourre et al., 1987; Verheijen et al., 2003, 2009; Yao et al., 1980). To directly evaluate the relevance of endogenous FA synthesis on peripheral nerve structure and function, here we studied a mouse model of blunted FA synthesis (Liang et al., 2002), the Srebf1c KO. "
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    ABSTRACT: Myelin is a membrane characterized by high lipid content to facilitate impulse propagation. Changes in myelin fatty acid (FA) composition have been associated with peripheral neuropathy, but the specific role of peripheral nerve FA synthesis in myelin formation and function is poorly understood. We have found that mice lacking sterol regulatory element-binding factor-1c (Srebf1c) have blunted peripheral nerve FA synthesis that results in development of peripheral neuropathy. Srebf1c-null mice develop Remak bundle alterations and hypermyelination of small-caliber fibers that impair nerve function. Peripheral nerves lacking Srebf1c show decreased FA synthesis and glycolytic flux, but increased FA catabolism and mitochondrial function. These metabolic alterations are the result of local accumulation of two endogenous peroxisome proliferator-activated receptor-α (Pparα) ligands, 1-palmitoyl-2-oleyl-sn-glycerol-3-phosphatidylcholine and 1-stearoyl-2-oleyl-sn-glycerol-3-phosphatidylcholine. Treatment with a Pparα antagonist rescues the neuropathy of Srebf1c-null mice. These findings reveal the importance of peripheral nerve FA synthesis to sustain myelin structure and function. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 03/2015; 21(4). DOI:10.1016/j.cmet.2015.02.016 · 16.75 Impact Factor
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    • "An aspect that still needs to be fully clarified is how and to which extent fatty acids reach the nervous system. While exchange of lipids, including fatty acids, between plasma and/or other nerve compartments of PNS is possible [32] [33], the transfer of circulating fatty acids across the blood brain barrier at different ages is still debated. Experimental evidences indicate that non-esterified fatty acids complexed with albumin can cross the blood brain barrier by passive diffusion [34]. "
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    ABSTRACT: Lipids in the nervous system accomplish a great number of key functions, from synaptogenesis to impulse conduction, and more. Most of the lipids of the nervous system are localized in myelin sheaths. It has long been known that myelin structure and brain homeostasis rely on specific lipid-protein interactions and on specific cell-to-cell signaling. In more recent years, the growing advances in large-scale technologies and genetically modified animal models have provided valuable insights into the role of lipids in the nervous system. Key findings recently emerged in these areas are here summarized. In addition, we briefly discuss how this new knowledge can open novel approaches for the treatment of diseases associated to alteration of lipid metabolism/homeostasis in the nervous system. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. Guest Editors: Antonio Moschetta and Maurizio Crestani.
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 08/2014; 1851(1). DOI:10.1016/j.bbalip.2014.08.011 · 4.50 Impact Factor
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    • "This supports the view that RBPs such as HuR perform their overall biological functions by coordinately regulating expression of multiple functionally related mRNAs, known as " RNA operons " (Keene, 2007). This association of HuR with mRNAs is dynamic, with a significant decrease in the population of target mRNAs in P5 nerves compared with NB nerves, coinciding with a general decrease in mRNA expression of some of them (Verheijen et al., 2003). This is in line with other studies, which show dynamic changes in the association of HuR with target mRNAs (Mazan-Mamczarz et al., 2008; Mukherjee et al., 2009), and supports the view that RNA accessibility partially determines the formation of RBP–mRNA complexes (Kazan et al., 2010). "
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    ABSTRACT: An important prerequisite to myelination in peripheral nerves is the establishment of one-to-one relationships between axons and Schwann cells. This patterning event depends on immature Schwann cell proliferation, apoptosis, and morphogenesis, which are governed by coordinated changes in gene expression. Here, we found that the RNA-binding protein human antigen R (HuR) was highly expressed in immature Schwann cells, where genome-wide identification of its target mRNAs in vivo in mouse sciatic nerves using ribonomics showed an enrichment of functionally related genes regulating these processes. HuR coordinately regulated expression of several genes to promote proliferation, apoptosis, and morphogenesis in rat Schwann cells, in response to NRG1, TGFβ, and laminins, three major signals implicated in this patterning event. Strikingly, HuR also binds to several mRNAs encoding myelination-related proteins but, contrary to its typical function, negatively regulated their expression, likely to prevent ectopic myelination during development. These functions of HuR correlated with its abundance and subcellular localization, which were regulated by different signals in Schwann cells.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2012; 32(14):4944-58. DOI:10.1523/JNEUROSCI.5868-11.2012 · 6.75 Impact Factor
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