Fatty Acid 2-Hydroxylase and 2-Hydroxylated Sphingolipids: Metabolism and Function in Health and Diseases

Abstract

Sphingolipids containing acyl residues that are hydroxylated at C-2 are found in most, if not all, eukaryotes and certain bacteria. 2-hydroxylated sphingolipids are present in many organs and cell types, though they are especially abundant in myelin and skin. The enzyme fatty acid 2-hydroxylase (FA2H) is involved in the synthesis of many but not all 2-hydroxylated sphingolipids. Deficiency in FA2H causes a neurodegenerative disease known as hereditary spastic paraplegia 35 (HSP35/SPG35) or fatty acid hydroxylase-associated neurodegeneration (FAHN). FA2H likely also plays a role in other diseases. A low expression level of FA2H correlates with a poor prognosis in many cancers. This review presents an updated overview of the metabolism and function of 2-hydroxylated sphingolipids and the FA2H enzyme under physiological conditions and in diseases.

Global Analysis of 2-Hydroxy Fatty Acids by Gas Chromatography-Tandem Mass Spectrometry Reveals Species-Specific Enrichment in Echinoderms

“…1 They are also required for the normal physiological functions of the nervous system and skin barrier 7−10 and their deficiency plays important roles in many diseases. 3 Our previous studies demonstrated that FA2H plays key roles in adipocyte metabolism 11 and metabolic reprogramming in gastric and colorectal cancer. 12,13 Moreover, oral supplementation of 2-hydroxy oleic acid decreases blood pressure by modulating the levels and activities of membrane signaling proteins.…”

“…A broad range of hydroxylation enzymes from animals, plants, and microorganisms produce thousands of hydroxy fatty acids differing in the number and locations of hydroxylation sites, as well as double bonds, branches, and chain length of the carbon backbonds. − In mammals, fatty acid 2-hydroxylase (FA2H) produces 2-hydroxyl fatty acids (2-OH FAs), , which are subsequently incorporated into sphingolipids. , Sphingolipids bearing 2-OH FAs (2-OH SPLs) are important components of plasma membrane lipid rafts, which host a variety of signaling and trafficking events . They are also required for the normal physiological functions of the nervous system and skin barrier − and their deficiency plays important roles in many diseases . Our previous studies demonstrated that FA2H plays key roles in adipocyte metabolism and metabolic reprogramming in gastric and colorectal cancer. , Moreover, oral supplementation of 2-hydroxy oleic acid decreases blood pressure by modulating the levels and activities of membrane signaling proteins .…”

“…1−3 In mammals, fatty acid 2-hydroxylase (FA2H) produces 2-hydroxyl fatty acids (2-OH FAs), 4,5 which are subsequently incorporated into sphingolipids. 3,6 Sphingolipids bearing 2-OH FAs (2-OH SPLs) are important components of plasma membrane lipid rafts, which host a variety of signaling and trafficking events. 1 They are also required for the normal physiological functions of the nervous system and skin barrier 7−10 and their deficiency plays important roles in many diseases.…”

The fatty acid 2-hydroxylase CsSCS7 is a key hyphal growth factor and potential control target in Colletotrichum siamense

“…Sphingolipids are ubiquitous and abundant components of eukaryotic plasma membranes and play multiple important roles in signal transduction, intracellular trafficking, apoptosis, cell differentiation, and other processes ( 3 , 4 ). Fungal sphingolipids play a pivotal role in growth, morphogenesis, and virulence and have potential as targets in future antifungal therapies ( 5 , 6 ).…”

“…The structural diversity of sphingolipids has been extensively studied, and the studies have focused on their tree building blocks, the headgroup, the acyl chain, and the sphingoid base ( 16 ). Hydroxylation of the sphingoid base can add structural diversity that appears to be important for the physiological function of sphingolipids ( 4 ). Hydroxylation can occur at C-2, C-3, and ω-C of the acyl residue and at C-4 of the sphingoid base and is catalyzed by fatty acid hydroxylase ( 17 , 18 ).…”