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Cell Metab. 2017 Nov 7;26(5):719-737.e6. doi: 10.1016/j.cmet.2017.08.024. Epub 2017 Sep 28.

The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D.

Author information

1
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
2
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA; Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA.
3
Department of Molecular and Cellular Biology and Advanced Technology Cor, Baylor College of Medicine, Houston, TX 77030, USA.
4
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
5
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hbellen@bcm.edu.

Abstract

Elevated reactive oxygen species (ROS) induce the formation of lipids in neurons that are transferred to glia, where they form lipid droplets (LDs). We show that glial and neuronal monocarboxylate transporters (MCTs), fatty acid transport proteins (FATPs), and apolipoproteins are critical for glial LD formation. MCTs enable glia to secrete and neurons to absorb lactate, which is converted to pyruvate and acetyl-CoA in neurons. Lactate metabolites provide a substrate for synthesis of fatty acids, which are processed and transferred to glia by FATP and apolipoproteins. In the presence of high ROS, inhibiting lactate transfer or lowering FATP or apolipoprotein levels decreases glial LD accumulation in flies and in primary mouse glial-neuronal cultures. We show that human APOE can substitute for a fly glial apolipoprotein and that APOE4, an Alzheimer's disease susceptibility allele, is impaired in lipid transport and promotes neurodegeneration, providing insights into disease mechanisms.

KEYWORDS:

APOE2; APOE3; APOE4; ARSAL; Aats-met; Alzheimer’s disease; CMT2A; Drosophila melanogaster; Leigh syndrome; MARS2; Marf; Mitofusin; Mus musculus; NDUFAF6; astrocytes; reactive oxygen species; sicily

PMID:
28965825
PMCID:
PMC5677551
DOI:
10.1016/j.cmet.2017.08.024
[Indexed for MEDLINE]
Free PMC Article

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