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

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. (c) 2021 Elsevier Inc. All rights reserved.

Automated summary

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a complex lipid class that play important roles as signaling mediators and structural components. Two structurally and functionally distinct FAHFA superfamilies are recognized based on the position of the estolide bond. The combination of different hydroxy fatty acids and fatty acids, along with the position of the estolide bond, generates a wide variety of unique FAHFA structures. This review highlights the anti-diabetic and anti-inflammatory effects of branched FAHFAs, the role of omega-FAHFA-derived lipids in tear film lipid layer and dry eye disease, and provides insights into the biosynthesis, degradation pathways, and distribution of FAHFAs in adipose tissue.