Disorders of fatty acid homeostasis

Abstract

Humans derive fatty acids (FA) from exogenous dietary sources and/or endogenous synthesis from acetyl-CoA, although some FA are solely derived from exogenous sources ("essential FA"). Once inside cells, FA may undergo a wide variety of different modifications, which include their activation to their corresponding CoA ester, the introduction of double bonds, the 2- and ω-hydroxylation and chain elongation, thereby generating a cellular FA pool which can be used for the synthesis of more complex lipids. The biological properties of complex lipids are very much determined by their molecular composition in terms of the FA incorporated into these lipid species. This immediately explains the existence of a range of genetic diseases in man, often with severe clinical consequences caused by variants in one of the many genes coding for enzymes responsible for these FA modifications. It is the purpose of this review to describe the current state of knowledge about FA homeostasis and the genetic diseases involved. This includes the disorders of FA activation, desaturation, 2- and ω-hydroxylation, and chain elongation, but also the disorders of FA breakdown, including disorders of peroxisomal and mitochondrial α- and β-oxidation.

Keywords: (phospho)lipid metabolism; 2‐hydroxylation; fatty acid elongation; mitochondrial disorders; peroxisomal disorders; sphingolipid metabolism; ω‐hydroxylation.

FIGURE 1

Overview of the essential features of fatty acid (FA) homeostasis in humans. FA may be derived from exogenous, dietary sources, and/or synthesized endogenously from acetyl‐CoA, except for the essential FA which can only be obtained from exogenous sources. The free FA pool thus obtained can then undergo a range of modifications ultimately generating an extended acyl‐CoA ester pool which can then be used for the synthesis of multiple lipid species which serve different roles in human physiology. As part of each lipid species' life cycle, FA are released once again from the different lipid species to reenter the free FA pool where they can be either reutilized or undergo full oxidation to CO₂ and H₂O via FA oxidation in peroxisomes and/or mitochondria. See text for more information.

FIGURE 2

Overview of synthesis and breakdown of different sphingolipids. (A) Biosynthesis of sphingolipids starts with the condensation of serine and palmitoyl‐CoA to generate 3‐keto‐dihydrosphingosine as catalyzed by the enzyme serine palmitoyltransferase which is then converted into ceramide, the unique building block for the synthesis of glucosylceramide and gangliosides, galactosylceramide and sulfatides, and sphingomyelin. These different sphingolipid species are degraded predominantly in lysosomes thereby regenerating ceramide. Ceramide is subsequently broken down by the alkaline ceramidase ACER3 followed by phosphorylation of sphingosine and the other LCB to produce the corresponding LCB‐1‐phosphates which are then cleaved into phosphoethanolamine plus the different long‐chain aldehydes. Finally, ALDH3A2, the enzyme deficient in Sjögren–Larsson syndrome (SLS) will convert the different aldehydes into the corresponding FA for reutilization as is phosphoethanolamine for phospholipid synthesis. (B) Synthesis of ω‐O‐acylceramides: after elongation of VLCFA to ULCFA, CoA is removed and CYP4F22 hydroxylates the FFA at the ω‐position, followed by reactivation to the corresponding ω‐OH‐acyl‐CoA ester by FATP4. This CoA ester then condenses with sphingosine, as catalyzed by CERS3, to form ω‐OH‐dihydroceramide. The sphingoid base of the dihydroceramide can be modified yielding ω‐OH‐forms of 6‐OH‐dihydroceramide or phytoceramide. Desaturation of ω‐OH‐dihydroceramide forms ω‐OH‐ceramide, followed by the PNPLA1‐catalyzed transfer of a linoleyl‐side chain from triacylglycerol to the ω‐OH group of ω‐OH group to for ω‐O‐acylceramides.

FIGURE 3

Overview of the synthesis and elongation of both saturated, monounsaturated and polyunsaturated FA to VLCFA and VLC‐PUFA. Elongation of saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), and polyunsaturated fatty acid (PUFA): The process involves initial activation to CoA derivatives, followed by sequential addition of two carbon units from malonyl‐CoA. For SFA, straightforward chain extension occurs. MUFA elongation involves desaturation before or after elongation steps. PUFA undergoes both elongation and additional desaturations, adding double bonds. The resulting elongated fatty acids vary in chain length and degree of unsaturation, contributing to diverse biological functions. See text for more information.

FIGURE 4

Synthesis and elongation of fatty acids. In the cytoplasm, fatty acids are produced from malonyl‐CoA by the action of the fatty acid synthase complex (FASN), leading to the creation of long‐chain acyl‐CoA (LCFA‐CoA). This LCFA‐CoA is further lengthened in the endoplasmic reticulum (ER), producing an array of very long‐chain fatty acids. The initial phase involves the condensation of malonyl‐CoA with LCFA‐CoA, a process facilitated by a group of enzymes known as elongation of very long‐chain fatty acids (ELOVLs), which exhibit varying patterns of tissue expression and substrate preferences based on the chain length and saturation level of the fatty acid. The 3‐keto group is then converted into a hydroxyl group by 3‐ketoacyl‐CoA‐reductase (KAR). Subsequently, the formed 3‐hydroxyacyl‐CoA undergoes dehydration by a series of 3‐hydroxyacyl‐CoA dehydratases (HACD1‐4), each with distinct patterns of tissue distribution, to produce 2,3‐trans‐enoyl‐CoA. In the final step, the double bond in this molecule is hydrogenated by trans‐2,3‐enoyl‐CoA reductase (TECR), resulting in an acyl‐CoA molecule that is elongated by two carbon units.

FIGURE 5

Schematic representation of the peroxisomal FA α‐ and β‐oxidation systems. Fatty acids such as very long‐chain fatty acids (VLCF‐CoA), di‐ and trihydroxycholestanoic acids (DHCA/THCA), pristanic acid, dicarboxylic acids, as well as tetracosahexaenoic and tetracosapentaenoic acids (C24:6ω3 and C24:5ω3), are imported via ABCD transporters and subsequently shortened in a series of reactions. The initial dehydrogenation step is catalyzed by ACOX1, 2, and 3, each with a different substrate specificity. Further processing involves the bifunctional enzymes LBP/DBP and the thiolases ACAA1 and SCPx. Distinct enzymes of the β‐oxidation system are utilized for different substrates, with 2‐methyl‐acyl‐CoA racemase (AMACR) playing a crucial role in the racemization of pristanic acid as well as DHCA and THCA, the intermediates in bile acid synthesis, preparing them for subsequent β‐oxidation steps. The α‐oxidation pathway is reserved for the conversion of (activated) phytanic acid into pristanic acid allowing the latter to enter the β‐oxidation system.