Article

Local regulation of fat metabolism

Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California 92037, USA.
Genes & Development (Impact Factor: 10.8). 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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    • "normalized density of cleaved caspase - 3 ( A ) and cleaved caspase - 9 ( B ) is shown . Values are means ± SEM of six independent experiments . * p < 0 . 05 . development and the remyelination process after nerve injury have revealed that cholesterol / lipid metabolism in peripheral nerve myelination is also important ( Nagarajan et al . , 2002 ; Verheijen et al . , 2003 ) . Next , we examined the activation of Acly , which is a marker of lipid - synthesis enzymes . Together with the expression of MBP , MeCbl promoted the expression of Acly in SCs in the differentiation medium but not in the growth medium ( Figure 4D ) . In addition , to clarify the increasing expression of MBP by MeCbl , we applied the"
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    • "Loss of expression of all three Srebf isoforms specifically in Schwann cells results in hypomyelination and neuropathy, demonstrating the vital role of lipid synthesis in peripheral nerve structure and function (Verheijen et al., 2009). Interestingly, FAs required for myelin formation can be either synthesized endogenously or slowly taken up from the circulation or from other nerve compartments (Bourre et al., 1987; Verheijen et al., 2003, 2009; Yao et al., 1980). This latter observation raises the question of whether endogenous FA synthesis is necessary to sustain myelin formation, maintain nerve integrity, and thus protect against the development of peripheral neuropathy. "

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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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