FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity

Abstract

Cellular exposure to free fatty acids (FFA) is implicated in the pathogenesis of obesity-associated diseases. However, studies to date have assumed that a few select FFAs are representative of broad structural categories, and there are no scalable approaches to comprehensively assess the biological processes induced by exposure to diverse FFAs circulating in human plasma. Furthermore, assessing how these FFA-mediated processes interact with genetic risk for disease remains elusive. Here we report the design and implementation of FALCON (Fatty Acid Library for Comprehensive ONtologies) as an unbiased, scalable and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids (MUFAs) with a distinct lipidomic profile associated with decreased membrane fluidity. Furthermore, we developed a new approach to prioritize genes that reflect the combined effects of exposure to harmful FFAs and genetic risk for type 2 diabetes (T2D). Importantly, we found that c-MAF inducing protein (CMIP) protects cells from exposure to FFAs by modulating Akt signaling and we validated the role of CMIP in human pancreatic beta cells. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism.

Stearate-rich diet and oleate restriction directly inhibit tumor growth via the unfolded protein response

“…This phenomenon was directly mitigated by oleate, and impeding the conversion of stearate to oleate ampli ed the cytotoxic effects of stearate. Wieder et al 5 segregated longchain fatty acid-elicited cellular damage into two major pathways, UPR and ROS generation, and showed that the detrimental effects associated with UPR could be rescued by oleate treatment. Our results corroborate the aforementioned ndings.…”

“…However, fatty acids are not universally detrimental, and their effects on cancer cells vary depending on the type of fatty acid 5 .…”

PAQR proteins and the evolution of a superpower: Eating all kinds of fats

“…While many important questions remain, we propose that the PAQR proteins constitute a promising type of target for pharmacological intervention to remedy membrane composition defects that are associated with numerous pathologies, including cancer [ 107 ] and diabetes. [ 110 ]…”

Unravelling neuronal and glial differences in ceramide composition, synthesis, and sensitivity to toxicity

“…In certain disease contexts, astrocytes can take on a reactive state that is toxic to neurons and oligodendrocytes (Liddelow et al, 2017). The precise identity and source of the toxicity remains to be determined and is likely context dependent, but there is evidence that the ceramide synthesis pathway could be involved (Arredondo et al, 2022; Chung et al, 2023; Guttenplan et al, 2021; Victor et al, 2022; Wieder et al, 2023). This is consistent with evidence that glial cells can produce saturated lipids (sphingolipids?)…”