Oxysterol-binding protein ORP6 regulates lipid metabolism and brain Aβ production

Arlette A Kasongo; Viyashini Vijithakumar; Khaled S Abd-Elrahman; Radhika Prabhune; Lara Gharibeh; Rachel Nadeau; Isabelle Robillard; Shoshana Spring; Sabrina Robichaud; Shaza Asif; Derrick Gibbings; Kathryn J Moore; John G Sled; Matthieu Ruiz; Mathieu Lavallée-Adam; Stephen S G Ferguson; Baptiste Lacoste; Diane C Lagace; Mireille Ouimet

doi:10.1016/j.jlr.2025.100868

Oxysterol-binding protein ORP6 regulates lipid metabolism and brain Aβ production

J Lipid Res. 2025 Sep;66(9):100868. doi: 10.1016/j.jlr.2025.100868. Epub 2025 Jul 25.

Authors

Arlette A Kasongo¹, Viyashini Vijithakumar¹, Khaled S Abd-Elrahman², Radhika Prabhune¹, Lara Gharibeh¹, Rachel Nadeau³, Isabelle Robillard⁴, Shoshana Spring⁵, Sabrina Robichaud¹, Shaza Asif¹, Derrick Gibbings⁶, Kathryn J Moore⁷, John G Sled⁸, Matthieu Ruiz⁹, Mathieu Lavallée-Adam³, Stephen S G Ferguson¹⁰, Baptiste Lacoste¹⁰, Diane C Lagace¹⁰, Mireille Ouimet¹¹

Affiliations

¹ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada.
² Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
³ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON.
⁴ Montreal Heart Institute Research Center, Montreal, QC, Canada.
⁵ Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada.
⁶ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
⁷ Department of Medicine, Cardiovascular Research Center, New York University School of Medicine, New York, NY.
⁸ Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁹ Montreal Heart Institute Research Center, Montreal, QC, Canada; Département de Nutrition, Université de Montréal, Montreal, QC, Canada.
¹⁰ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada.
¹¹ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada. Electronic address: mireille.ouimet@uottawa.ca.

Abstract

The mammalian brain is the most cholesterol-rich organ of the body, relying on in situ de novo cholesterol synthesis. Maintaining cholesterol homeostasis is crucial for normal brain function. Oxysterol-binding protein (OSBP)-related proteins (ORPs) are highly conserved cytosolic proteins that coordinate lipid homeostasis by regulating cell signaling, interorganelle membrane contact sites, and non-vesicular transport of cholesterol. Here, we show that ORP6 is highly enriched in the mammalian brain, particularly within neurons and astrocytes, with widespread expression across distinct brain regions, including the hippocampus, which is essential for learning and memory. Whole-body ablation of ORP6 (Osbpl6^-/-) in mice resulted in dysregulation of systemic and brain lipid homeostasis, with elevated levels of brain desmosterol and amyloid-beta oligomers (AβOs). Mechanistically, ORP6 knockdown in astrocytes altered the expression of cholesterol metabolism genes, promoting the accumulation of esterified cholesterol in lipid droplets, reducing cholesterol efflux and plasma membrane cholesterol content, and increasing amyloid-beta precursor protein (APP) processing. Our findings underscore the role of ORP6 in systemic and brain lipid homeostasis, highlighting its importance in maintaining overall brain health.

Keywords: amyloid beta; astrocyte; cholesterol efflux; high-density lipoprotein; lipid droplet; lipid metabolism; oxysterol-binding protein-like 6.

MeSH terms

Amyloid beta-Peptides* / biosynthesis
Amyloid beta-Peptides* / metabolism
Animals
Astrocytes / metabolism
Brain* / diagnostic imaging
Brain* / metabolism
Cholesterol / metabolism
Female
Gene Expression Regulation
Lipid Metabolism* / physiology
Magnetic Resonance Imaging
Male
Mice
Mice, Inbred C57BL
Oxysterol Binding Proteins* / genetics
Oxysterol Binding Proteins* / metabolism
Oxysterols* / metabolism
Protein Binding
Receptors, Steroid / metabolism

Substances

Oxysterols
Amyloid beta-Peptides
Oxysterol Binding Proteins
Cholesterol
Receptors, Steroid