Disrupted Lipid Metabolism in Multiple Sclerosis: A Role for Liver X Receptors?

Abstract

Multiple sclerosis (MS) is a chronic neurological disease driven by autoimmune, inflammatory and neurodegenerative processes leading to neuronal demyelination and subsequent degeneration. Systemic lipid metabolism is disturbed in people with MS, and lipid metabolic pathways are crucial to the protective process of remyelination. The lipid-activated transcription factors liver X receptors (LXRs) are important integrators of lipid metabolism and immunity. Consequently, there is a strong interest in targeting these receptors in a number of metabolic and inflammatory diseases, including MS. We have reviewed the evidence for involvement of LXR-driven lipid metabolism in the dysfunction of peripheral and brain-resident immune cells in MS, focusing on human studies, both the relapsing remitting and progressive phases of the disease are discussed. Finally, we discuss the therapeutic potential of modulating the activity of these receptors with existing pharmacological agents and highlight important areas of future research.

Keywords: cholesterol; lipid metabolism; liver X receptor; multiple sclerosis; nuclear receptor.

Figure 1

Potential therapeutic roles of LXR activation in MS. (A) Intracellular cholesterol levels in the brain are tightly regulated by two transcription factors (61): 1. Liver-X-receptor (LXR) and sterol response element binding-protein 2 (SREBP-2). SREBP2 upregulates genes involved in cholesterol biosynthesis. Cholesterol in the brain is produced de novo mainly by glial cells such as astrocytes using the Bloch pathway. Neurons which have a high cholesterol requirement produce less cholesterol via the Kandutsch-Russell pathway. 2. LXR is activated by by-products of cholesterol synthesis (oxysterols). 3. LXR activation promotes cholesterol export via intracellular cholesterol transporter Niemann Pick Type C1 and 2 (NPC1/NPC2), and ATP binding cassette (ABC) A1 and ABCG1 which efflux cholesterol from the plasma membrane to high density lipoprotein (HDL)-like lipoproteins including apolipoprotein-E (Apo-E). 4. Cholesterol is taken up by cells via lipoprotein receptors. Excess cellular cholesterol (potentially generated by neurodegeneration processes) is stored in lipid droplets or converted into oxysterols. 24-S hydroxycholesterol is the most abundant oxysterol in the brain and its production is catalyzed by the enzyme Cyp46A1 (cholesterol 24S-hydroxylase). 24-S hydroxycholesterol is able to cross the blood brain barrier to the periphery where it is degraded in the liver. 5. LXR also promotes fatty acid synthesis through its target genes SREBP1c, fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD). Plasma membrane levels of cholesterol and fatty acids can influence lipid rafts-membrane microdomains important for immune synapse formation and immune cell activation and function. Fatty acid (glycosphingolipid) abundance and composition can also influence plasma membrane fluidity (64). (B) LXRβ expression is elevated in peripheral blood mononuclear cells from MS patients potentially due to increased levels of oxysterols including 24S-hydroxycholesterol. Increased LXR activation can also be triggered by myelin uptake by glial cells in the central nervous system (CNS). LXR activation induces reverse cholesterol transport (A, 4). Patients with MS have altered lipoprotein profiles which may reflect defects in the efficacy of this process. MS progression is associated with reduced levels of high density lipoproteins (HDL)- responsible for effective cholesterol efflux. LXR activation also induces fatty acid and glycosphingolipid biosynthesis (A, 5). Changes in cellular cholesterol and glycosphingolipids can alter immune cell function by altering cell signaling and downstream functions including proliferation and cytokine production. In T-cells LXR activation reduces T-cell infiltration into the CNS (65) and inhibits naïve CD4+ T-cell differentiation towards an inflammatory Th17 phenotype (66) and suppressed IL-9 producing CD8+ T cells during anti-tumor responses (67). LXR activation is crucial for Treg function (68). LXR activation stimulates oligodendrocyte myelin production and remyelination processes (69). Mechanisms include stimulation of reverse cholesterol transport and fatty acid synthesis. LXR activation leads to the repression of inflammatory responses through the downregulation of pro-inflammatory genes including inducible nitric oxide synthase (NO), interleukin (IL)-1β, IL-6 and tumor necrosis factor-α. Myelin uptake by macrophages activates LXR and suppresses the production these pro-inflammatory mediators These myelin-laden macrophages, express high levels of anti-inflammatory IL-1-receptor-α, IL-10, CC-chemokine ligand-18 and transforming growth factor-β (70).