Saturated Hydroxy Fatty Acids Exhibit a Cell Growth Inhibitory Activity and Suppress the Cytokine-Induced β-Cell Apoptosis

Abstract

The field of bioactive lipids is ever expanding with discoveries of novel lipid molecules that promote human health. Adopting a lipidomic-assisted approach, two new families of previously unrecognized saturated hydroxy fatty acids (SHFAs), namely, hydroxystearic and hydroxypalmitic acids, consisting of isomers with the hydroxyl group at different positions, were identified in milk. Among the various regio-isomers synthesized, those carrying the hydroxyl at the 7- and 9-positions presented growth inhibitory activities against various human cancer cell lines, including A549, Caco-2, and SF268 cells. In addition, 7- and 9-hydroxystearic acids were able to suppress β-cell apoptosis induced by proinflammatory cytokines, increasing the possibility that they can be beneficial in countering autoimmune diseases, such as type 1 diabetes. 7-(R)-Hydroxystearic acid exhibited the highest potency both in cell growth inhibition and in suppressing β-cell death. We propose that such naturally occurring SHFAs may play a role in the promotion and protection of human health.

Saturated Oxo Fatty Acids (SOFAs): A Previously Unrecognized Class of Endogenous Bioactive Lipids Exhibiting a Cell Growth Inhibitory Activity

“…As mentioned in the introduction, we have most recently studied the cell growth inhibitory activity of various HSAs and HPAs, and we have found that 7RHSA exhibited the highest potency on epithelial lung carcinoma (A549) cell line with an IC 50 value of 38 μM. 13 In the present work, we studied the effect of a number of synthesized OPAs and OSAs on the proliferation of three human cancer cell lines: epithelial lung carcinoma (A549), colorectal adenocarcinoma (Caco-2), and astrocytoma (SF268). The MTT assay was employed to assess viable cell numbers.…”

“…Following a suspect analysis approach involving an LC-HRMS technique, we successfully identified new families of bioactive SHFAs in milk. 13 In the present work, our aim was to explore if families of SOFAs are present in human plasma and cow milk.…”

“…12 Most recently, in milk, we have identified new families of previously unrecognized saturated hydroxy fatty acids (SHFAs), namely, hydroxystearic acids (HSAs) and hydroxypalmitic acids (HPAs), which exhibit cell growth inhibitory activity and the ability to inhibit the cytokine-induced β-cell apoptosis. 13 Among the various positional isomers of HPAs and HSAs, 7-(R)-hydroxystearic acid (3, 7HSA, Figure 1a) exhibited the highest potency both in cell growth inhibition and in suppressing β-cell death. 13 Due to their potential role in the promotion and protection of human health, an analytical liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method was developed for the quantitation of these new bioactive lipids in cow and goat milk.…”

“…13 Among the various positional isomers of HPAs and HSAs, 7-(R)-hydroxystearic acid (3, 7HSA, Figure 1a) exhibited the highest potency both in cell growth inhibition and in suppressing β-cell death. 13 Due to their potential role in the promotion and protection of human health, an analytical liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method was developed for the quantitation of these new bioactive lipids in cow and goat milk. 14 An unexplored up-to-date class of naturally occurring fatty acids is that of saturated oxo (keto) fatty acids (SOFAs).…”

“…Inspired by our most recent research that led to the discovery of bioactive SHFAs, 13 where we followed a research workflow involving: (a) "suspect" LC-HRMS analysis in a food matrix, (b) organic synthesis, (c) targeted LC-HRMS analysis using reference compounds in a natural matrix, and (d) a study of in vitro bioactivities; the aim of the present study was to apply the same successful strategy to investigate SOFAs (Figure 1c) and to uncover their potential bioactivities. Thus, first, we adopted a lipidomic approach to identify previously unrecognized SOFAs existing in natural sources.…”