Lack of Sterol Regulatory Element Binding Factor-1c Imposes Glial Fatty Acid Utilization Leading to Peripheral Neuropathy

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.

Neuronal LXR Regulates Neuregulin-1 Expression and Sciatic Nerve-Associated Cell signaling

“…Many of the genes dysregulated were consistent with previous studies in others models of diabetic neuropathy (e.g. Abca1, Abcg1, Wnt, Srebpf1) 35-38 . In addition, we observed enrichment of gene involved in “PNS function” “cell survival”, “migration”, “axon guidance”, and “receptor interaction and signal transduction-related” pathways (ErbB2 and 3, Slit2, Sox10, Sirt2, Fgfr, Piezo 2) (Figure1F).…”

A Systems Biology Approach to Investigating Sex Differences in Cardiac Hypertrophy

“…In some studies, GW6471, a potent inhibitor of PPARα, was also given at 4 mg/kg per day. GW6471 has an IC 50 of 240 nmol/L and has been shown to function as an antagonist in mice within the range of 2 to 10 mg/kg per day . Following treatment, echocardiography was performed on the mice.…”

“…GW6471 has an IC 50 of 240 nmol/L and has been shown to function as an antagonist in mice within the range of 2 to 10 mg/kg per day. 21,22 Following treatment, echocardiography was performed on the mice. Mice were then anesthetized and euthanized.…”

Myelin Fat Facts: An Overview of Lipids and Fatty Acid Metabolism

“…reported that mice lacking SREBF1 exhibit a decrease in fatty acid synthesis and an increase in fatty oxidation. In spite of this, myelin defects in these animals are limited to an increase in myelin thickness and Remak bundles alterations [112].…”

“…SREBP1, like other SREBPs, is activated by a reduction of intracellular cholesterol, indicating a homeostatic link between fatty acid synthesis and cholesterol synthesis [108,109]. De novo fatty acid synthesis is critical for the correct formation and growth of myelin both in the PNS and in the CNS [33,48,[110][111][112]. Animals ablated for fatty acid synthase (encode by Fasn) in either Schwann cells or oligodendrocytes present a partial block in the onset and efficiency of myelination.…”