Determination of Major Endogenous FAHFAs in Healthy Human Circulation: The Correlations with Several Circulating Cardiovascular-Related Biomarkers and Anti-Inflammatory Effects on RAW 264.7 Cells

Dongoran, Rachmad Anres; Lin, Tsung-Jen; Byekyet, Akhsholphan; Tang, Sheau‐Chung; Yang, Jen‐Hung; Liu, Chin‐Hung

doi:10.3390/biom10121689

Cited by 29 publications

(23 citation statements)

References 49 publications

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“…FAHFAs, a new class of endogenous lipids derived from DHA, were first discovered in 2014 and have antidiabetic and anti-inflammatory effects in mammals [ 32 , 33 , 34 ]. Additionally, recent studies have determined that FAHFAs also have cardiovascular protective effects [ 35 ]. Although evidence for the direct interaction between alcohol and FAHFAs is deficient, downregulated FAHFA levels in the ACM group are speculated to be associated with the pathogenesis of myocardial injury induced by chronic alcohol consumption.…”

Section: Discussionmentioning

confidence: 99%

A Pilot Metabolomic Study on Myocardial Injury Caused by Chronic Alcohol Consumption—Alcoholic Cardiomyopathy

et al. 2021

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Chronic alcohol consumption leads to myocardial injury, ventricle dilation, and cardiac dysfunction, which is defined as alcoholic cardiomyopathy (ACM). To explore the induced myocardial injury and underlying mechanism of ACM, the Liber-DeCarli liquid diet was used to establish an animal model of ACM and histopathology, echocardiography, molecular biology, and metabolomics were employed. Hematoxylin-eosin and Masson’s trichrome staining revealed disordered myocardial structure and local fibrosis in the ACM group. Echocardiography revealed thinning wall and dilation of the left ventricle and decreased cardiac function in the ACM group, with increased serum levels of brain natriuretic peptide (BNP) and expression of myocardial BNP mRNA measured through enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction (PCR), respectively. Through metabolomic analysis of myocardium specimens, 297 differentially expressed metabolites were identified which were involved in KEGG pathways related to the biosynthesis of unsaturated fatty acids, vitamin digestion and absorption, oxidative phosphorylation, pentose phosphate, and purine and pyrimidine metabolism. The present study demonstrated chronic alcohol consumption caused disordered cardiomyocyte structure, thinning and dilation of the left ventricle, and decreased cardiac function. Metabolomic analysis of myocardium specimens and KEGG enrichment analysis further demonstrated that several differentially expressed metabolites and pathways were involved in the ACM group, which suggests potential causes of myocardial injury due to chronic alcohol exposure and provides insight for further research elucidating the underlying mechanisms of ACM.

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Section: Discussionmentioning

confidence: 99%

A Pilot Metabolomic Study on Myocardial Injury Caused by Chronic Alcohol Consumption—Alcoholic Cardiomyopathy

et al. 2021

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“…Also, we used glucose and clinical diagnosis to classify our study subjects. Of note, another recent study reported even negative correlation of 9-POHSA and 9-OAHSA with blood glucose in healthy subjects (16). An interpretation of all those studies might be complicated by the fact that different experimental set ups were used and confirmatory experimental studies with a similar design over a longer period are needed to clarify the role of FAHFAs in diabetes and insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

“…The recent discovery of FAHFAs has evoked growing interest, as studies have shown that these bioactive lipids might have potent anti-inflammatory properties (3,4,(14)(15)(16). Moreover, they are considered to mediate anti-diabetic effects by stimulating insulin secretion and increasing insulin-stimulated glucose uptake into the adipocyte (3,15).…”

Section: Introductionmentioning

confidence: 99%

Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) Are Associated With Diet, BMI, and Age

et al. 2021

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Background: Fatty acid esters of hydroxy fatty acids (FAHFAs) are a group of fatty acids with potential anti-inflammatory and anti-diabetic effects. The blood levels of FAHFAs and their regulation in humans have hardly been studied.Objective: We aimed to investigate serum FAHFA levels in well-characterized human cohorts, to evaluate associations with age, sex, BMI, weight loss, diabetic status, and diet.Methods: We analyzed levels of stearic-acid-9-hydroxy-stearic-acid (9-SAHSA), oleic-acid-9-hydroxy-stearic-acid (9-OAHSA) and palmitic-acid-9-hydroxy-palmitic-acid (9-PAHPA) as well as different palmitic acid-hydroxy-stearic-acids (PAHSAs) by HPLC-MS/MS with the use of an internal standard in various cohorts: A cohort of different age groups (18–25y; 40–65y; 75–85y; Σn = 60); severely obese patients undergoing bariatric surgery and non-obese controls (Σn = 36); obese patients with and without diabetes (Σn = 20); vegetarians/vegans (n = 10) and omnivores (n = 9); and young men before and after acute overfeeding with saturated fatty acids (SFA) (n = 15).Results: Omnivores had substantially higher FAHFA levels than vegetarians/vegans [median (25th percentile; 75th percentile) tFAHFAs = 12.82 (7.57; 14.86) vs. 5.86 (5.10; 6.71) nmol/L; P < 0.05]. Dietary overfeeding by supplementation of SFAs caused a significant increase within 1 week [median tFAHFAs = 4.31 (3.31; 5.27) vs. 6.96 (6.50; 7.76) nmol/L; P < 0.001]. Moreover, obese patients had lower FAHFA levels than non-obese controls [median tFAHFAs = 3.24 (2.80; 4.30) vs. 5.22 (4.18; 7.46) nmol/L; P < 0.01] and surgery-induced weight loss increased 9-OAHSA level while other FAHFAs were not affected. Furthermore, significant differences in some FAHFA levels were found between adolescents and adults or elderly, while no differences between sexes and between diabetic and non-diabetic individuals were detected.Conclusions: FAHFA serum levels are strongly affected by high SFA intake and reduced in severe obesity. Age also may influence FAHFA levels, whereas there was no detectable relation with sex and diabetic status. The physiological role of FAHFAs in humans remains to be better elucidated.Trial Registration: All studies referring to these analyses were registered in the German Clinical Trial Register (https://www.drks.de/drks_web/) with the numbers DRKS00009008, DRKS00010133, DRKS00006211, and DRKS00009797.

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“…Exercise training induces serum and WAT PAHSA levels in elderly women 11 . Levels of circulating palmitoleic acid ester of 9-HSA (9-POHSA) and oleic acid ester of 9-HSA (9-OAHSA) correlate with protective cardiovascular biomarkers in healthy humans 12 . Thus, FAHFAs have the potential to be important in many physiological and pathophysiological states in humans.…”

Section: Mainmentioning

confidence: 99%

ATGL is a biosynthetic enzyme for fatty acid esters of hydroxy fatty acids

Patel

Santoro

Hofer

et al. 2022

Nature

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Branched fatty acid (FA) esters of hydroxy FAs (HFAs; FAHFAs) are recently discovered lipids that are conserved from yeast to mammals1,2. A subfamily, palmitic acid esters of hydroxy stearic acids (PAHSAs), are anti-inflammatory and anti-diabetic1,3. Humans and mice with insulin resistance have lower PAHSA levels in subcutaneous adipose tissue and serum1. PAHSA administration improves glucose tolerance and insulin sensitivity and reduces inflammation in obesity, diabetes and immune-mediated diseases1,4–7. The enzyme(s) responsible for FAHFA biosynthesis in vivo remains unknown. Here we identified adipose triglyceride lipase (ATGL, also known as patatin-like phospholipase domain containing 2 (PNPLA2)) as a candidate biosynthetic enzyme for FAHFAs using chemical biology and proteomics. We discovered that recombinant ATGL uses a transacylation reaction that esterifies an HFA with a FA from triglyceride (TG) or diglyceride to produce FAHFAs. Overexpression of wild-type, but not catalytically dead, ATGL increases FAHFA biosynthesis. Chemical inhibition of ATGL or genetic deletion of Atgl inhibits FAHFA biosynthesis and reduces the levels of FAHFA and FAHFA-TG. Levels of endogenous and nascent FAHFAs and FAHFA-TGs are 80–90 per cent lower in adipose tissue of mice in which Atgl is knocked out specifically in the adipose tissue. Increasing TG levels by upregulating diacylglycerol acyltransferase (DGAT) activity promotes FAHFA biosynthesis, and decreasing DGAT activity inhibits it, reinforcing TGs as FAHFA precursors. ATGL biosynthetic transacylase activity is present in human adipose tissue underscoring its potential clinical relevance. In summary, we discovered the first, to our knowledge, biosynthetic enzyme that catalyses the formation of the FAHFA ester bond in mammals. Whereas ATGL lipase activity is well known, our data establish a paradigm shift demonstrating that ATGL transacylase activity is biologically important.

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Determination of Major Endogenous FAHFAs in Healthy Human Circulation: The Correlations with Several Circulating Cardiovascular-Related Biomarkers and Anti-Inflammatory Effects on RAW 264.7 Cells

Cited by 29 publications

References 49 publications

A Pilot Metabolomic Study on Myocardial Injury Caused by Chronic Alcohol Consumption—Alcoholic Cardiomyopathy

A Pilot Metabolomic Study on Myocardial Injury Caused by Chronic Alcohol Consumption—Alcoholic Cardiomyopathy

Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) Are Associated With Diet, BMI, and Age

ATGL is a biosynthetic enzyme for fatty acid esters of hydroxy fatty acids

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