Cholesterol Synthesis Is Down‐Regulated During Regeneration of Peripheral Nerve

Abstract

The discovery of apolipoprotein E synthesis and secretion by injured peripheral nerve to the hypothesis that endoneurial apolipoprotein E serves to salvage degenerating myelin cholesterol. This salvaged cholesterol could then be reutilized by Schwann cells during remyelination via uptake through low-density lipoprotein receptors. As a test of this hypothesis, we measured the rate of cholesterol synthesis in rat sciatic nerve endoneurium during development and at various times following a crush injury at 50 days of age. In control nerves [14C]acetate incorporation into cholesterol and 3-hydroxy-3-methylglutaryl-CoA reductase activity were closely linked throughout development, indicating that reductase activity in nerve, as in other tissues, is a good indicator of cholesterol's synthetic rate. In the crushed nerves cholesterol synthesis fell to nearly zero during the first week after the crush. There was a partial recovery during the second to fourth weeks, but unlike that of other lipids, cholesterol synthesis remained well below control nerve values throughout most of the 15-week post-crush period examined. Thus, cholesterol synthesis is at very low levels during the myelination of regenerating axons. These results are consistent with a receptor-mediated down-regulation of cholesterol synthesis by lipoproteins, and would be expected if Schwann cells were utilizing an external source of cholesterol as postulated above.

Fate of myelin lipids during degeneration and regeneration of peripheral nerve: an autoradiographic study

“…Glycerol, which is used in the recycling of fatty acids as well as in de novo lipid synthesis, was especially effective in labeling the fibroblasts' lipid droplets. These results are consistent with previous biochemical studies demonstrating that an increase in the esterification reactions utilizing glycerol is a very early event in Wallerian degeneration (White et al, 1989;Goodrum, 1990). White et al (1989) postulated that the large pool of free fatty acids generated by the breakdown of myelin phospholipids promotes the increase in esterification reactions utilizing glycerol.…”

“…This observation is consistent with our previous report that cholesterol synthesis in regenerating nerve is depressed for up to 15 weeks (Goodrum, 1990). On the other hand, the levels of apolipoproteins in regenerating nerve are nearing control levels by 10 weeks (Boyles et al, 1990), making significant lipoprotein-mediated reutilization of cholesterol unlikely after 10 weeks.…”

“…Hematogenously derived macrophages, attracted to the nerve by the degenerating nerve fibers, are the source of the endoneurial apoE, and are postulated to be a storage depot for the salvaged cholesterol (see Mahley, 1988, for review). There is now considerable evidence supporting this hypothesis (Boyles et al, 1989(Boyles et al, , 1990Goodrum, 1990Goodrum, , 1991Gelman et al, 199 l), although we have recently shown that apoE is not necessary for fiber regeneration or the local reutilization of cholesterol (Popko et al, 1993). We have followed by electron microscopic (EM) autoradiography the distribution of prelabeled myelin lipids (predominantly cholesterol) from 1 d to 10 weeks following a nerve crush and the distribution of newly synthesized lipids at 2 d after nerve crush to test whether these proposed sequences of myelin metabolism during Wallerian degeneration are valid.…”

Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease

“…In response to nerve injury, cholesterol synthesis in neurons is inhibited (145) and there is increased neuronal expression of apoE (146). At the same time, glial cell apoE synthesis and lipid transport from glial cells to neurons are increased, so that cholesterol is available to repair the injured neurons (147). Steady-state intracellular levels of apoE reflect a balance between the synthesis and degradation of both newly synthesized and recycled apoE, whereas secreted apoE levels reflect a balance between apoE released from the glia and reuptake of apoE via apoE receptors that are expressed on the cell surface.…”

Lipoprotein lipase

“…The lipids released by myelin degradation, primarily cholesterol and FAs derived from phospholipids and glycolipids, are actively reutilized by the regenerating proximal end. HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis, is down-regulated as cholesterol released from the degrading myelin sheath is reutilized for new myelin synthesis (62). Axonal components also degenerate, leaving behind Schwann cells that proliferate in response to axonal and myelin debris.…”