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


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-? 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.

SUBMITTER: Lin JP 

PROVIDER: S-EPMC5752207 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Lin Jing-Ping JP   Mironova Yevgeniya A YA   Shrager Peter P   Giger Roman J RJ  

eLife 20171218


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 (<i>Lrp1<sup>flox/flox</sup>;CAG-CreER</i>) or oligodendrocyte (OL)-lineage specific ablation (<i>Lrp1<sup>flox/flox</sup>;Pdgfra-CreER</i>) of <i>Lrp1</i> attenuates repair of damaged white matter. In oligodendrocyte progenitor cells (OPCs), <i>Lrp1</i> is required for cholesterol homeostasis and differentiation into mature  ...[more]

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