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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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    • "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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