Branched and linear fatty acid esters of hydroxy fatty acids (FAHFA) relevant to human health

Abstract

Fatty acid esters of hydroxy fatty acids (FAHFAs) represent a complex lipid class that contains both signaling mediators and structural components of lipid biofilms in humans. The majority of endogenous FAHFAs share a common chemical architecture, characterized by an estolide bond that links the hydroxy fatty acid (HFA) backbone and the fatty acid (FA). Two structurally and functionally distinct FAHFA superfamilies are recognized based on the position of the estolide bond: omega-FAHFAs and in-chain branched FAHFAs. The existing variety of possible HFAs and FAs combined with the position of the estolide bond generates a vast quantity of unique structures identified in FAHFA families.

In this review, we discuss the anti-diabetic and anti-inflammatory effects of branched FAHFAs and the role of omega-FAHFA-derived lipids as surfactants in the tear film lipid layer and dry eye disease. To emphasize potential pharmacological targets, we recapitulate the biosynthesis of the HFA backbone within the superfamilies together with the degradation pathways and the FAHFA regioisomer distribution in human and mouse adipose tissue. We propose a theoretical involvement of cytochrome P450 enzymes in the generation and degradation of saturated HFA backbones and present an overview of small-molecule inhibitors used in FAHFA research.

The FAHFA lipid class is huge and largely unexplored. Besides the unknown biological effects of individual FAHFAs, also the enigmatic enzymatic machinery behind their synthesis could provide new therapeutic approaches for inflammatory metabolic or eye diseases. Therefore, understanding the mechanisms of (FA)HFA synthesis at the molecular level should be the next step in FAHFA research.

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).