Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism

Heather A. Ferris, Rachel J. Perry, Gabriela V. Moreira, Gerald I. Shulman, Jay D. Horton, C. Ronald Kahn

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Cholesterol is important for normal brain function. The brain synthesizes its own cholesterol, presumably in astrocytes. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in sterol regulatory elementbinding protein 2 (SREBP2)-regulated transcription. Here we show that coculture of control astrocytes with neurons enhances neurite outgrowth, and this is reduced with SREBP2 knockdown astrocytes. In vivo, mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor defects. These mice also have altered energy balance, altered body composition, and a shift in metabolism toward carbohydrate oxidation driven by increased glucose oxidation by the brain. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain and neuronal development and function, and altered brain cholesterol synthesis may contribute to the interaction between metabolic diseases, such as diabetes and altered brain function.

Original languageEnglish (US)
Pages (from-to)1189-1194
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number5
DOIs
StatePublished - Jan 31 2017

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Keywords

  • Brain cholesterol metabolism
  • Glial cells
  • Glucose oxidation
  • Metabolic regulation
  • SREBP2

ASJC Scopus subject areas

  • General

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