Branched and linear fatty acid esters of hydroxy fatty acids (FAHFA) relevant to human health
Graphical abstract
Introduction
FAHFAs belong to a family of estolides that are defined as oligomers of a hydroxy fatty acid and a fatty acid. Hence, FAHFA is a monoestolide in which the carboxylic acid group of a fatty acid (FA) is esterified to the hydroxyl group of a hydroxy fatty acid (HFA). Depending on the length and saturation of their acyl chains and the position of the branching carbon, they are grouped into various super−/sub-families (Brejchova et al., 2020; Yore et al., 2014). For instance, 5-PAHSA common abbreviation expands to 16:0-(5-O-18:0), where “5” defines the ester position relative to carboxylic acid, 16:0 stands for palmitic acid (PA), and (5-O-18:0) stands for hydroxy stearic acid (HSA) (Ma et al., 2015; Yore et al., 2014).
We can divide FAHFAs related to human health into two main superfamilies based on the estolide bond position. These superfamilies include 1) in-chain “branched” FAHFAs, involved in the regulation of metabolism and immune reactions, and 2) “linear” (ω-hydroxylated) FAHFAs serving mainly as biosurfactants and skin barrier matrix (Fig. 1). The first superfamily contains several hundred members (Brejchova et al., 2020; Zhu et al., 2020) and the latter even more species (Butovich, 2017; Khanal et al., 2021; Vavrusova et al., 2020).
The biochemical difference between the families is also the origin of HFA. Only little is known about the branched saturated HFA synthesis that happens mainly in adipose tissue (Yore et al., 2014). More is known about unsaturated HFA synthesis that is driven mainly by enzymatic reactions (Hajeyah et al., 2020), while enzymes oxidizing the ω‑carbon in sebaceous and meibomian glands are known (see below). Free FAHFAs can also be incorporated into complex lipids. Branched FAHFAs, mainly saturated, are stored in triacylglycerol (TAG) estolides (Brejchova et al., 2021; Brezinova et al., 2020; Paluchova, Oseeva, et al., 2020; Tan et al., 2019) and the ω-hydroxylated FAHFAs were found in the form of cholesteryl esters (Butovich, 2017; Butovich et al., 2009; Kaluzikova et al., 2017).
In this review, we discuss the endogenous and exogenous levels and potential sources of FAHFAs in humans. Next, we briefly summarize FAHFA biological effects related to human diseases for the most studied species. To transfer the therapeutic potential of FAHFAs into a drug, we need to identify the potential pharmacologic targets within the metabolic pathways. We review metabolic pathways of FAHFA synthesis and degradation, speculate on the missing parts, and summarize the small molecule inhibitors used in the literature. Strategies for total organic synthesis of FAHFA and optimal detection methods have been reviewed elsewhere (Balas et al., 2018; Brejchova et al., 2020; Hancock et al., 2018; Kokotou, 2020).
Section snippets
Sources of FAHFAs
FAHFAs are synthesized endogenously in specialized tissues (e.g. adipose tissue or meibomian glands) and the branched FAHFAs also circulate in the blood (Table 1). Therefore, branched FAHFAs can be detected in organs that do not produce them independently (e.g. lungs, thymus, heart) and which are exposed to FAHFAs in the blood (Yore et al., 2014; Zhu et al., 2017). Besides endogenous synthesis, nutrition is another important source of FAHFAs as was recently shown in a cohort of vegans and
FAHFA biological effects
FAHFA lipid class is very diverse and theoretically, any combination of an FA and an HFA is conceivable. Therefore, there are probably bioactive species with positive or negative effects on target receptors as well as species that exert their effects as amphiphilic structural lipids. We reviewed branched FAHFA biological effects in cell and animal models recently (Brejchova et al., 2020) and here we focus on the FAHFA effect related to human health and FAHFA therapeutic potential.
Potential pharmacologic targets
The biology of FAHFAs is complex and we still do not know which FAHFAs are beneficial and which could be detrimental. It is clear that the family of PAHSAs and PAHPAs, and the polyunsaturated FAHFAs exert positive effects and that their levels are lower in pathophysiological states (Benlebna, Balas, Bonafos, Pessemesse, Fouret, et al., 2020; Kuda et al., 2016; Yore et al., 2014). Characterization of metabolic pathways, key enzymes, and regulation of FAHFA metabolism is critical for the
Pathway intersection
The synthesis of FAHFAs can be divided into three steps: 1) formation of an HFA; 2) synthesis of an FA, and 3) HFA esterification with an FA.
First, the regioisomer distribution of hydroxyl positions on the acyl chain among the FAHFA kingdom suggests that a) branched HFA and ω-HFA are synthesized by different pathways, and b) branched saturated HFA are formed by different processes than branched unsaturated HFAs, reviewed in (Brejchova et al., 2020).
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Regarding the “linear” ω-HFA, Butovich and
FAHFA degradation
Several FAHFA hydrolases including androgen-induced gene 1 (AIG1) protein, androgen-dependent TFPI regulating protein (ADTRP), carboxyl ester lipase (CEL), ATGL, and HSL have already been identified as potential FAHFA hydrolases (Brejchova et al., 2021; Erikci Ertunc et al., 2020; Kolar et al., 2016; Parsons et al., 2016). Induced mutant mouse models proved that AIG1, ADTRP, and HSL are active FAHFA estolide bond hydrolases in vivo (Brejchova et al., 2021; Erikci Ertunc et al., 2020). Aig1 and
Potential pharmacologic tools in FAHFA research
Nowadays, basic research in FAHFA metabolism focuses on the identification of new biological effects and the exploration of potential metabolic pathways. Mainly tools based on gene modifications (knock out mice, siRNA) and FAHFA administration (gavage, osmotic mini-pumps, supplemented diet) are used. However, several FAHFA-related proteins were targeted with small molecule inhibitors (Table 3). G-protein coupled receptors GPR120 and GPR40 are two membrane receptors involved in PAHSA signaling
Conclusion and future perspectives
FAHFA kingdom is very diverse and only selected highly abundant molecules were characterized in detail. We can estimate that the number of FAHFAs in humans is close to 1000 species, while their role, presence, and composition change during the lifespan (Brejchova et al., 2020; Brezinova et al., 2020; Khanal et al., 2021; Vavrusova et al., 2020; Zhu et al., 2020). Our understanding of FAHFA signaling potency and its integration with parallel regulations of metabolic pathways is very limited to
Declaration of Competing Interest
The authors declare no competing interests.
Acknowledgments
This work was supported by grants from the Ministry of Education, Youth and Sport of the Czech Republic project no. LTAUSA18104 and the Czech Academy of Sciences (Lumina quaeruntur LQ200111901). Images were designed using resources from Flaticon.com
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2023, American Journal of PathologyCitation Excerpt :TG-estolides are TG-bound FA esters of hydroxy FA and represent a major storage form of bioactive free FA esters of hydroxy FA.55 FA esters of hydroxy FA represent a large family of lipids with poorly understood biological functions, including immunomodulatory activities.56 It is plausible that the presence of these lipids reflected the need of the hepatocytes to cope with increased hepatic lipid load and/or to induce liver inflammation, causing the onset of NASH.