Docosahexaenoic Acid–Derived Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) With Anti-inflammatory Properties

Kuda, Ondřej; Brezinova, Marie; Rombaldova, Martina; Slavı́ková, Barbora; Pošta, Martin; Beier, Petr; Janovská, Petra; Veleba, Jiri; Kopecký, Jan; Kudová, Eva; Pelikánová, Terezie

doi:10.2337/db16-0385

Cited by 147 publications

(238 citation statements)

References 49 publications

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“…The plasma levels of these unsaturated fatty acids were not influenced by antibiotic treatment. Overall, the changes in plasma fatty acid levels on an HFD reflected an increase in proinflammatory fatty acids, such as adrenic and stearic acid, and a decrease in anti-inflammatory fatty acids, such as eicosopentaenoic and docosohexanoic acids (Kuda et al, 2016; Yamada et al, 2017). However, antibiotic administration had little effect on these changes in free fatty acids in B6J mice despite improving insulin sensitivity, and the changes in free fatty acid (FFA) were similar in the insulin-sensitive 129 substrains, thus disconnecting the FFA levels from the level of insulin resistance.…”

Section: Resultsmentioning

confidence: 99%

Diet, Genetics, and the Gut Microbiome Drive Dynamic Changes in Plasma Metabolites

et al. 2018

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SUMMARY Diet, genetics, and the gut microbiome are determinants of metabolic status, in part through production of metabolites by the gut microbiota. To understand the mechanisms linking these factors, we performed LC-MS-based metabolomic analysis of cecal contents and plasma from C57BL/6J, 129S1/SvImJ, and 129S6/SvEvTac mice on chow or a high-fat diet (HFD) and HFD-treated with vancomycin or metronidazole. Prediction of the functional metagenome of gut bacteria by PICRUSt analysis of 16S sequences revealed dramatic differences in microbial metabolism. Cecal and plasma metabolites showed multifold differences reflecting the combined and integrated effects of diet, antibiotics, host background, and the gut microbiome. Eighteen plasma metabolites correlated positively or negatively with host insulin resistance across strains and diets. Over 1,000 still-unidentified metabolite peaks were also highly regulated by diet, antibiotics, and genetic background. Thus, diet, host genetics, and the gut microbiota interact to create distinct responses in plasma metabolites, which can contribute to regulation of metabolism and insulin resistance.

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Section: Resultsmentioning

confidence: 99%

Diet, Genetics, and the Gut Microbiome Drive Dynamic Changes in Plasma Metabolites

et al. 2018

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“…For a review of the anti-inflammatory effects of FAHFA, see 43 . FAHFAs decrease macrophage activation in vitro following exposure to LPS and IFN-γ and hold promise as potential therapies for inflammatory and metabolic diseases 44 .…”

Section: Macrophage Functions In Lean Tissuementioning

confidence: 99%

Macrophage functions in lean and obese adipose tissue

2017

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Summary Interactions between macrophages and adipocytes influence both metabolism and inflammation. Obesity-induced changes to macrophages and adipocytes lead to chronic inflammation and insulin resistance. This paper reviews the various functions of macrophages in lean and obese adipose tissue and how obesity alters adipose tissue macrophage phenotypes. Metabolic disease and insulin resistance shift the balance between numerous pro- and anti-inflammatory regulators of macrophages and create a feed-forward loop of increasing inflammatory macrophage activation and worsening adipocyte dysfunction. This ultimately leads to adipose tissue fibrosis and diabetes. The molecular mechanisms underlying these processes have therapeutic implications for obesity, metabolic syndrome, and diabetes.

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“…5–6 For instance, palmitic acid esters of hydroxy stearic acids (PAHSAs) and oleic acid esters of hydroxy stearic acid (OAHSAs) are two of the most abundant families that were identified. 4 In addition, for each FAHFA family that has been looked at in detail, different ester regioisomers exist (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…Omega-3 fatty acid FAHFAs, produced after the addition of omega-3-fatty acids to cells, have potent anti-inflammatory activity. 5 …”

Section: Introductionmentioning

confidence: 99%

Stereochemistry of Endogenous Palmitic Acid Ester of 9-Hydroxystearic Acid and Relevance of Absolute Configuration to Regulation

et al. 2017

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Lipids have fundamental roles in the structure, energetics, and signaling of cells and organisms. The recent discovery of fatty acid esters of hydroxy fatty acids (FAHFAs), lipids with potent anti-diabetic and anti-inflammatory activities, indicates that our understanding of the composition of lipidome and the function of lipids is incomplete. The ability to synthesize and test FAHFAs was critical in elucidating the roles of these lipids, but these studies were performed with racemic mixtures, and the role of stereochemistry remains unexplored. Here, we synthesized the R- and S- palmitic acid ester of 9-hydroxystearic acid (R-9-PAHSA, S-9-PAHSA). Access to highly enantioenriched PAHSAs enabled the development of a liquid chromatography-mass spectrometry (LC-MS) method to separate and quantify R- and S-9-PAHSA, and this approach identified R-9-PAHSA as the predominant stereoisomer that accumulates in adipose tissues from transgenic mice where FAHFAs were first discovered. Furthermore, biochemical analysis of 9-PAHSA biosynthesis and degradation indicate that the enzymes and pathways for PAHSA production are stereospecific, with cell lines favoring the production of R-9-PAHSA and carboxyl ester lipase (CEL), a PAHSA degradative enzyme, selectively hydrolyzing S-9-PAHSA. These studies highlight the role of stereochemistry in the production and degradation of PAHSAs and define the endogenous stereochemistry of 9-PAHSA in adipose tissue. This information will be useful in the identification and characterization of the pathway responsible for PAHSA biosynthesis, and access to enantiopure PAHSAs will elucidate the role of stereochemistry in PAHSA activity and metabolism in vivo.

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Docosahexaenoic Acid–Derived Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) With Anti-inflammatory Properties

Cited by 147 publications

References 49 publications

Diet, Genetics, and the Gut Microbiome Drive Dynamic Changes in Plasma Metabolites

Diet, Genetics, and the Gut Microbiome Drive Dynamic Changes in Plasma Metabolites

Macrophage functions in lean and obese adipose tissue

Stereochemistry of Endogenous Palmitic Acid Ester of 9-Hydroxystearic Acid and Relevance of Absolute Configuration to Regulation

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