CD36 maintains lipid homeostasis via selective uptake of monounsaturated fatty acids during matrix detachment and tumor progression.

Abstract

A high-fat diet (HFD) promotes metastasis through increased uptake of saturated fatty acids (SFAs). The fatty acid transporter CD36 has been implicated in this process, but a detailed understanding of CD36 function is lacking. During matrix detachment, endoplasmic reticulum (ER) stress reduces SCD1 protein, resulting in increased lipid saturation. Subsequently, CD36 is induced in a p38- and AMPK-dependent manner to promote preferential uptake of monounsaturated fatty acids (MUFAs), thereby maintaining a balance between SFAs and MUFAs. In attached cells, CD36 palmitoylation is required for MUFA uptake and protection from palmitate-induced lipotoxicity. In breast cancer mouse models, CD36-deficiency induced ER stress while diminishing the pro-metastatic effect of HFD, and only a palmitoylation-proficient CD36 rescued this effect. Finally, AMPK-deficient tumors have reduced CD36 expression and are metastatically impaired, but ectopic CD36 expression restores their metastatic potential. Our results suggest that, rather than facilitating HFD-driven tumorigenesis, CD36 plays a supportive role by preventing SFA-induced lipotoxicity.

• Authors: Alexander R Terry, Veronique Nogueira, Hyunsoo Rho, Gopalakrishnan Ramakrishnan, Jing Li, Soeun Kang, Koralege C Pathmasiri, Sameer Ahmed Bhat, Liping Jiang, Shafi Kuchay, Stephanie M Cologna, Nissim Hay
• Journal: Cell metabolism (Cell Metab) Vol. 35 Issue 11 Pg. 2060-2076.e9 (11 07 2023) ISSN: 1932-7420 [Electronic] United States
• PMID: 37852255 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Fatty Acids, Monounsaturated
• AMP-Activated Protein Kinases
• Fatty Acids

Topics

• Animals
• Mice
• Fatty Acids, Monounsaturated (metabolism)
• AMP-Activated Protein Kinases (metabolism)
• Fatty Acids (metabolism)
• Biological Transport
• Homeostasis