Unbound free fatty acid profiles in human plasma and the unexpected absence of unbound palmitoleate

Huber, Andrew H.; Kleinfeld, Alan M.

doi:10.1194/jlr.m074260

Cited by 37 publications

(32 citation statements)

References 29 publications

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“…FFA concentrations that elicit observed responses are around 100 nmol/L, which is typical for what is determined for unbound FFAs in the plasma (as opposed to millimolar concentration of albumin bound FFAs; ref. 48). In addition, a recent study, targeting the fatty acid receptor CD36 showed that metastasis-initiating cells rely on free fatty acids to promote metastasis (49).…”

Section: Discussionmentioning

confidence: 99%

Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling

et al. 2019

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Obesity is a risk factor for postmenopausal estrogen receptor alpha (ERa)-positive (ER þ) breast cancer. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERa signaling have yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in plasma samples from women at high risk for breast cancer, which led us to focus on factors that were differentially present in plasma of obese versus nonobese postmenopausal women. These studies, combined with in vitro assays, identified free fatty acids (FFA) as circulating plasma factors that correlated with increased proliferation and aggressiveness in ER þ breast cancer cells. FFAs activated both the ERa and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which targets ERa and mTOR sig-naling, was able to block changes induced by FFA and was more effective in the presence of FFA. Collectively, these data suggest a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ER þ breast cancer in postmenopausal women. Furthermore, they provide a basis for preclinical and clinical trials where the impact of agents that target ERa and mTOR signaling cross-talk would be tested to prevent ER þ breast cancers in obese postmenopausal women. Significance: These findings show that obesity-associated changes in certain blood metabolites rewire metabolic programs in cancer cells, influence mammary epithelial cell tumorigenicity and aggressiveness, and increase breast cancer risk.

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Section: Discussionmentioning

confidence: 99%

Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling

et al. 2019

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“…non-protein bound) concentration of FAs in blood [87]. The concentration of unbound FAs was found to be 7.5 + 2.5 nM in humans [88] and increases exponentially with a rise in the total plasma FA concentration [89]. Unfortunately, no studies report on kinetics of hepatic FA uptake in humans, thus a comparison of the plasma (unbound) FA concentration to the K M value of hepatic FA uptake is not possible at present.…”

Section: Discussionmentioning

confidence: 99%

Zonation of hepatic fat accumulation: insights from mathematical modelling of nutrient gradients and fatty acid uptake

Schleicher

Dahmen

Guthke

et al. 2017

J. R. Soc. Interface.

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Intrinsic of non-alcoholic fatty liver diseases is an aberrant accumulation of triglycerides (steatosis), which occurs inhomogeneously within lobules. To improve our understanding of the mechanisms involved in this zonation patterning, we developed a mathematical multicompartment model of hepatic fatty acid metabolism accompanied by blood flow simulations. A model analysis determines the influence of the uptake process of fatty acids, the porto-central gradient of plasma fatty acid concentration, and the oxygen supply via blood on the zonation of triglyceride accumulation. From this theoretical perspective, the plasma oxygen gradient, but not the fatty acid gradient, leads the way to a zonated triglyceride accumulation by its decisive role in oxidative processes. In addition, the uptake mechanism of fatty acids seems to be fundamental for a pericentral dominance of steatosis. However, the mechanism of cellular fatty acid uptake from the blood is still under debate. Our theoretical approach supports the transporter-mediated uptake mechanism and reveals that the maximal velocity of fatty acid uptake affects the switching between a periportal and a pericentral triglyceride accumulation. Further research on hepatic fatty acid uptake is needed to push forward our understanding of aberrant triglyceride accumulation in diet-induced steatosis.

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“…Many of these epidemiologic studies are obscured by various forms and sources of palmitoleate present in the serum. In addition, palmitoleate may exist almost exclusively in an inactive, protein-bound form, so the level of bioactive palmitoleate may not correlate with serum levels [32]. Further research is necessary to characterize how much the adipose tissue contributes to circulating palmitoleate and its role in human metabolic health.…”

Section: Palmitoleic Acidmentioning

confidence: 97%

Adipose crosstalk with other cell types in health and disease

Choi

Cohen

2017

Experimental Cell Research

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Unbound free fatty acid profiles in human plasma and the unexpected absence of unbound palmitoleate

Cited by 37 publications

References 29 publications

Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling

Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling

Zonation of hepatic fat accumulation: insights from mathematical modelling of nutrient gradients and fatty acid uptake

Adipose crosstalk with other cell types in health and disease

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