LRP1 regulates peroxisome biogenesis and cholesterol homeostasis in oligodendrocytes and is required for proper CNS myelin development and repair

Elife. 2017 Dec 18;6:e30498. doi: 10.7554/eLife.30498.

Abstract

Low-density lipoprotein receptor-related protein-1 (LRP1) is a large endocytic and signaling molecule broadly expressed by neurons and glia. In adult mice, global inducible (Lrp1flox/flox;CAG-CreER) or oligodendrocyte (OL)-lineage specific ablation (Lrp1flox/flox;Pdgfra-CreER) of Lrp1 attenuates repair of damaged white matter. In oligodendrocyte progenitor cells (OPCs), Lrp1 is required for cholesterol homeostasis and differentiation into mature OLs. Lrp1-deficient OPC/OLs show a strong increase in the sterol-regulatory element-binding protein-2 yet are unable to maintain normal cholesterol levels, suggesting more global metabolic deficits. Mechanistic studies revealed a decrease in peroxisomal biogenesis factor-2 and fewer peroxisomes in OL processes. Treatment of Lrp1-/- OPCs with cholesterol or activation of peroxisome proliferator-activated receptor-γ with pioglitazone alone is not sufficient to promote differentiation; however, when combined, cholesterol and pioglitazone enhance OPC differentiation into mature OLs. Collectively, our studies reveal a novel role for Lrp1 in peroxisome biogenesis, lipid homeostasis, and OPC differentiation during white matter development and repair.

Keywords: CNS Myelin Repair; Cholesterol Homeostasis; LRP1; Oligodendrocyte differentiation; Peroxisome Biogenesis; mouse; neuroscience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Cholesterol / metabolism*
  • Homeostasis*
  • Mice
  • Myelin Sheath / metabolism*
  • Oligodendrocyte Precursor Cells / physiology*
  • Organelle Biogenesis*
  • Peroxisomes / metabolism*
  • Receptors, LDL / metabolism*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Lrp1 protein, mouse
  • Receptors, LDL
  • Tumor Suppressor Proteins
  • Cholesterol