Trans-Fats Inhibit Autophagy Induced by Saturated Fatty Acids

Abstract

Depending on the length of their carbon backbone and their saturation status, natural fatty acids have rather distinct biological effects. Thus, longevity of model organisms is increased by extra supply of the most abundant natural cis-unsaturated fatty acid, oleic acid, but not by that of the most abundant saturated fatty acid, palmitic acid. Here, we systematically compared the capacity of different saturated, cis-unsaturated and alien (industrial or ruminant) trans-unsaturated fatty acids to provoke cellular stress in vitro, on cultured human cells expressing a battery of distinct biosensors that detect signs of autophagy, Golgi stress and the unfolded protein response. In contrast to cis-unsaturated fatty acids, trans-unsaturated fatty acids failed to stimulate signs of autophagy including the formation of GFP-LC3B-positive puncta, production of phosphatidylinositol-3-phosphate, and activation of the transcription factor TFEB. When combined effects were assessed, several trans-unsaturated fatty acids including elaidic acid (the trans-isomer of oleate), linoelaidic acid, trans-vaccenic acid and palmitelaidic acid, were highly efficient in suppressing autophagy and endoplasmic reticulum stress induced by palmitic, but not by oleic acid. Elaidic acid also inhibited autophagy induction by palmitic acid in vivo, in mouse livers and hearts. We conclude that the well-established, though mechanistically enigmatic toxicity of trans-unsaturated fatty acids may reside in their capacity to abolish cytoprotective stress responses induced by saturated fatty acids.

Graphical Abstract

Highlights

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  The molecular geometry of fatty acids dictates their biological function

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  Saturated fats induce autophagy through a BECN1-dependent pathway

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  Cis fats trigger cytoprotection via the induction of non-canonical autophagy, t rans fats are toxic as they inhibit the stress response induced by saturated fats

Cellular responses to fatty acids are distinct according to their unsaturation status and carbon backbone; saturated & cis fats can induce various cellular stresses, including autophagy (through a BECN1-dependent pathway for the first category only), whereas trans fats are toxic by specifically inhibiting saturated fats-elicited stress responses.