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

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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 ( Lrp1 ^flox/flox;CAG-CreER ) or oligodendrocyte (OL)-lineage specific ablation ( Lrp1 ^flox/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.

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The mechanisms of action of PPARs.

Joel Berger, David E. Moller (2002)

The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPAR gamma, PPAR alpha, and PPAR delta, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.

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High cholesterol level is essential for myelin membrane growth.

Britta Brügger, Corinna Lappe-Siefke, Gesine Saher … (2005)

Cholesterol in the mammalian brain is a risk factor for certain neurodegenerative diseases, raising the question of its normal function. In the mature brain, the highest cholesterol content is found in myelin. We therefore created mice that lack the ability to synthesize cholesterol in myelin-forming oligodendrocytes. Mutant oligodendrocytes survived, but CNS myelination was severely perturbed, and mutant mice showed ataxia and tremor. CNS myelination continued at a reduced rate for many months, and during this period, the cholesterol-deficient oligodendrocytes actively enriched cholesterol and assembled myelin with >70% of the cholesterol content of wild-type myelin. This shows that cholesterol is an indispensable component of myelin membranes and that cholesterol availability in oligodendrocytes is a rate-limiting factor for brain maturation.

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The Peroxisome-Mitochondria Connection: How and Why?

Marc Fransen, Celien Lismont, Paul Walton (2017)

Over the past decades, peroxisomes have emerged as key regulators in overall cellular lipid and reactive oxygen species metabolism. In mammals, these organelles have also been recognized as important hubs in redox-, lipid-, inflammatory-, and innate immune-signaling networks. To exert these activities, peroxisomes must interact both functionally and physically with other cell organelles. This review provides a comprehensive look of what is currently known about the interconnectivity between peroxisomes and mitochondria within mammalian cells. We first outline how peroxisomal and mitochondrial abundance are controlled by common sets of cis- and trans-acting factors. Next, we discuss how peroxisomes and mitochondria may communicate with each other at the molecular level. In addition, we reflect on how these organelles cooperate in various metabolic and signaling pathways. Finally, we address why peroxisomes and mitochondria have to maintain a healthy relationship and why defects in one organelle may cause dysfunction in the other. Gaining a better insight into these issues is pivotal to understanding how these organelles function in their environment, both in health and disease.

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Author and article information

Contributors

Jing-Ping Lin:

ORCID: http://orcid.org/0000-0003-0686-0215

Yevgeniya A Mironova

Peter Shrager

Roman J Giger:

ORCID: http://orcid.org/0000-0002-2926-3336

Klaus-Armin Nave: Role: Reviewing Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 18 December 2017

Publication date Collection: 2017

Volume: 6

Electronic Location Identifier: e30498

Affiliations

[1 ]deptDepartment of Cell and Developmental Biology University of Michigan School of Medicine Ann Arbor, MIUnited States

[2 ]deptCellular and Molecular Biology Graduate Program University of Michigan Medical School Ann Arbor, MIUnited States

[3 ]deptDepartment of Neuroscience University of Rochester Medical Center Rochester, NYUnited States

[4 ]deptDepartment of Neurology University of Michigan Medical School Ann Arbor, MIUnited States

[5 ]deptInterdepartmental Neuroscience Graduate Program University of Michigan Medical School Ann Arbor, MIUnited States

Max-Planck-Institute for Experimental Medicine Germany

Author information

Jing-Ping Lin http://orcid.org/0000-0003-0686-0215

Roman J Giger http://orcid.org/0000-0002-2926-3336

Article

Publisher ID: 30498

DOI: 10.7554/eLife.30498

PMC ID: 5752207

PubMed ID: 29251594

SO-VID: f7236ee6-db09-4d08-82f7-1959a767e98f

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This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 17 July 2017

Date accepted : 15 December 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100009633, Eunice Kennedy Shriver National Institute of Child Health and Human Development;

Award ID: T32HD007505

Award Recipient : Yevgeniya A Mironova

Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;

Award ID: T32GM007315

Award Recipient : Yevgeniya A Mironova

Funded by: FundRef http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;

Award ID: R01NS081281

Award Recipient : Peter Shrager Roman J Giger

Funded by: Schmitt Program on Integrative Brain Research;

Award Recipient : Peter Shrager

Funded by: FundRef http://dx.doi.org/10.13039/100005984, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation;

Award ID: APNRR

Award Recipient : Roman J Giger

Funded by: Bradley Merrill Patten Fellowship;

Award Recipient : Jing-Ping Lin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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Author impact statement In oligodendrocyte progenitor cells, lipid metabolism and peroxisome biogenesis are regulated by the low-density lipoprotein related-receptor-1, and if disrupted, impair proper white matter development and adult repair.

ScienceOpen disciplines: Life sciences

Keywords: cns myelin repair,oligodendrocyte differentiation,peroxisome biogenesis,cholesterol homeostasis,lrp1,mouse

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: cns myelin repair, oligodendrocyte differentiation, peroxisome biogenesis, cholesterol homeostasis, lrp1, mouse

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

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Most cited references 71

The mechanisms of action of PPARs.

High cholesterol level is essential for myelin membrane growth.

The Peroxisome-Mitochondria Connection: How and Why?

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