Abstract
Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are a recently discovered class of biologically active lipids with anti-inflammatory and anti-diabetic properties. Despite the possible link between endogenous FAHFA levels and nuclear factor erythroid 2-related factor 2 (Nrf2), their possible function as antioxidants and the mechanisms involved in this are unknown. Here, we investigate FAHFAs’ plausible antioxidant potential with reference to their effect on the Nrf2 levels, oxidative stress, and lipid droplet oxidation in human hepatocytes (C3A). Six authentic FAHFAs were chemically synthesized and performed activity-based screening by reporter gene assay. Among them, eicosapentaenoic acid (EPA) esterified 12-hydroxy stearic acid (12-HSA) and 12-hydroxy oleic acid (12-HOA) FAHFAs showed less cytotoxicity compared to their free fatty acids and potent activators of Nrf2. To define their mode of action, relative levels of nuclear Nrf2 were determined, which found a higher amount of Nrf2 in nucleus of cells treated with 12-EPAHSA compared to the control. Furthermore, 12-EPAHSA increased the expression of Nrf2-dependent antioxidant enzyme genes (NQO1, GCLM, GCLC, SOD-1, and HO-1). Fluorescence imaging analysis of linoleic-acid-induced lipid droplets (LDs) in C3A cells treated with 12-EPAHSA revealed the strong inhibition of small-size LD oxidation. These results suggest that EPA-derived FAHFAs as a new class of lipids with less cytotoxicity, and strong Nrf2 activators with plausible antioxidant effects via the induction of cytoprotective proteins against oxidative stress, induced cellular damage.
Highlights
Fatty acid esters of hydroxy fatty acids (FAHFAs) are a new class of endogenous lipids with beneficial biological effects, including antidiabetic and anti-inflammatory properties [1]
The cellular transporters of FAHFAs are still unknown, but our results revealed that 12unknown, but our results revealed that 12-EPAHSA could activate the nuclear nuclear factor erythroid 2-related factor 2 (Nrf2) and induce the EPAHSA could activate the nuclear Nrf2 and induce the activation of Nrf2-targeted genes to protect activation of Nrf2-targeted genes to protect cells against oxidative-stress-related damages
Our findings demonstrate that eicosapentaenoic acid (EPA)-derived FAHFAs are a novel class of lipids with less cytotoxicity compared to their free fatty acids and potent Nrf2 activators
Summary
Fatty acid esters of hydroxy fatty acids (FAHFAs) are a new class of endogenous lipids with beneficial biological effects, including antidiabetic and anti-inflammatory properties [1]. To date, their biosynthesis and metabolism are not well elucidated [2]. Palmitic acid esters of hydroxy stearic acid (PAHSAs) are the major esters in human and mice. PAHSAs received considerable attention because their levels were significantly decreased in serum of insulin-resistant patients [4], breast cancer patients [5], and the milk of obese women compared to lean mothers [6], as well as suppressing inflammatory markers [7], decreasing T-cell activation in ulcerative colitis [8], and improving glucose tolerance by stimulating insulin secretion via GPR120 signaling [1].
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