Fat for fuel: lipid metabolism in haematopoiesis

Abstract

The importance of metabolic regulation in the immune system has launched back into the limelight in recent years. Various metabolic pathways have been examined in the context of their contribution to maintaining immune cell homeostasis and function. Moreover, this regulation is also important in the immune cell precursors, where metabolism controls their maintenance and cell fate. This review will discuss lipid metabolism in the context of haematopoiesis, that is blood cell development. We specifically focus on nonoxidative lipid metabolism which encapsulates the synthesis and degradation of the major lipid classes such as phospholipids, sphingolipids and sterols. We will also discuss how these metabolic processes are affected by haematological malignancies such as leukaemia and lymphoma, which are known to have altered metabolism, and how these different pathways contribute to the pathology.

Keywords: cellular metabolism; haematopoiesis; lipid metabolism.

Figure 1

A brief overview of lipid metabolism in immune cells. Acetyl‐CoA can be derived either from glycolysis or from extracellular FAs that can be used to fuel B‐oxidation or can be converted into fatty acyl‐CoAs, committing them to nonoxidative lipid metabolism. Fatty acyl‐CoAs are further processed in the endoplasmic reticulum where they produce lipids such as phospholipids, glycerolipids, sterols and sphingolipids. Fatty acyl‐CoAs can also be redirected to the peroxisome where they are converted to fatty alcohols, the rate‐limiting step in plasmalogen biosynthesis where they finish processing in the endoplasmic reticulum.

Figure 2

Representative chemical structures of the main lipid classes in eukaryotic cells. (a) Fatty acids: Consisting of a hydrocarbon chain connected to a carboxyl group. The hydrocarbon chain can either be saturated or be unsaturated, indicated by the presence of a carbon–carbon double bond (unsaturated). (b) Sphingolipids: An acyl chain is connected to a sphingoid base (typically sphinganine) to produce ceramide. Through further metabolic reactions, the head group region can change to yield complex sphingolipids such as sphingomyelin and glycosylated ceramides. (c) Glycerolipids: Fatty acids can be attached at the sn‐1, sn‐2 and sn‐3 positions of the glycerol backbone to produce monoacylglycerol (MAG) [1 fatty acid], DAG [2 fatty acids] and TAG [3 fatty acids]. (d) Sterols: An isoprenoid‐based lipid with four hydrocarbon rings where a hydroxyl group located on one end and a hydrocarbon chain attached at another. (e) Phospholipids: Two fatty acids connected to a glycerol backbone at the sn‐1 and sn‐2 position. At the sn‐3 position is a variable head group which produces the major phospholipid species in eukaryotes. Further, the sn‐1 linkage defines can alter the phospholipid species.

Figure 3

Nonoxidative lipid metabolism in haematopoiesis. (a) Sphingolipids: (i) TNF‐α activates sphingomyelin hydrolysis through sphingomyelinase (SMase), changing erythroid progenitors towards a myeloid phenotype. (ii) Ganglioside‐expressing stromal cells (presumably a subset of the leptin receptor⁺ stromal cell population) differentiate into adipocytes and osteoblasts. (iii) Stromal cell‐derived gangliosides support both myelopoiesis and lymphopoiesis directly or by supporting the BM niche. (b) Glycerolipids: (i) Budding lipid droplets from BMAT interact with erythroblast island macrophages, supporting myelopoiesis and erythropoiesis and the egress of their mature cells from the BM. (ii) HSCs utilise lipolysis through LPL and LAL to regulate HSC differentiation. (c) Cholesterol: (i) Increasing cholesterol levels through LDL uptake and inflammatory signalling‐induced cholesterol biosynthesis promotes myelopoiesis. (ii) Oestrogen and 27HC‐induced activation of the oestrogen receptor promotes erythropoiesis. (d) Phospholipids: (i) Phospholipid catabolism liberates polyunsaturated FAs for eicosanoid synthesis which maintains HSC self‐renewal and regulates myelopoiesis and erythropoiesis. (ii) PLCβ2‐mediated GPI cleavage induces HSPC egress from the BM. (iii) Plasmalogen synthesis is observed during monocyte‐to‐macrophage differentiation.

Figure 4

Lipid metabolism in myeloproliferative neoplasms. (a) Membrane remodelling at the plasma membrane and mitochondrial levels induces chemotherapeutic resistance and increases stemness. (b) Alterations in sphingolipid metabolism by shifting the metabolic flux towards S1P synthesis inhibit apoptosis. (c) Mitochondrial membrane remodelling occurs because of an increase in Taz activity leading to an increase in leukaemic stem cell stemness. (d) Increased cholesterol uptake and biosynthesis along with defective cholesterol efflux promote lipid raft formation, which houses raft‐dependent receptors such as c‐MPL enhancing cell proliferation.