Direct sensing of dietary ω-6 linoleic acid through FABP5-mTORC1 signaling

Nikos Koundouros, Michal J. Nagiec, Nayah Bullen, Evan K. Noch, Guillermo Burgos-Barragan, Zhongchi Li, Long He, Sungyun Cho, Bobak Parang, Dominique Leone, Eleni Andreopoulou, John Blenis

Science3/14/2025·DOI·Read paper

Abstract

Diet influences macronutrient availability to cells, and although mechanisms of sensing dietary glucose and amino acids are well characterized, less is known about sensing lipids. We defined a nutrient signaling mechanism involving fatty acid–binding protein 5 (FABP5) and mechanistic target of rapamycin complex 1 (mTORC1) that is activated by the essential polyunsaturated fatty acid (PUFA) ω-6 linoleic acid (LA). FABP5 directly bound to the regulatory-associated protein of mTOR (Raptor) to enhance formation of functional mTORC1 and substrate binding, ultimately converging on increased mTOR signaling and proliferation. The amounts of FABP5 protein were increased in tumors and serum from triple-negative compared with those from receptor-positive breast cancer patients, which highlights its potential role as a biomarker that mediates cellular responses to ω-6 LA intake in this disease subtype.

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