The Complex Interplay between Lipids, Immune System and Interleukins in Cardio-Metabolic Diseases

Abstract

Lipids and inflammation regulate each other. Early studies on this topic focused on the systemic effects that the acute inflammatory response-and interleukins-had on lipid metabolism. Today, in the era of the obesity epidemic, whose primary complications are cardio-metabolic diseases, attention has moved to the effects that the nutritional environment and lipid derangements have on peripheral tissues, where lipotoxicity leads to organ damage through an imbalance of chronic inflammatory responses. After an overview of the effects that acute inflammation has on the systemic lipid metabolism, this review will describe the lipid-induced immune responses that take place in peripheral tissues and lead to chronic cardio-metabolic diseases. Moreover, the anti-inflammatory effects of lipid lowering drugs, as well as the possibility of using anti-inflammatory agents against cardio-metabolic diseases, will be discussed.

Keywords: cholesterol; free fatty acids; innate immune system; interleukin; lipid; lipotoxicity; triglyceride.

Figure 1

Lipoprotein metabolism. Lipoproteins are classified on the basis of their density as chylomicrons, VLDL, LDL, and HDL. Chylomicrons are low-density lipoproteins that transport dietary lipids from intestinal mucosa to the blood via lymphatic tissue. The associated apolipoproteins include apoA (I, II, IV); apoB48; apoC (I, II, III), and apoE. VLDL transports primarily triglycerides from the liver to the peripheral tissues and its apolipoproteins are apoB100, apoC (I, II; III), and apoE. LDL transports cholesterol esters and its apolipoproteins are apoB100. By contrast, HDL transports cholesterol from the periphery to the liver and it consists of cholesterol esters and its apolipoproteins are apoA (I, II), apoC (I, II, III), and apoE. With respect to the lipoprotein metabolism, after a meal, cholesterol is taken up by the enterocytes via the specific transporter Niemann-Pick C1-Like 1 (NPC1L1). Triglycerides are lipolyzed into free fatty acids (FFA) and taken up either by passive diffusion or by specific transporters such as CD36. Then, cholesterol is esterified by cholesterol acyltransferase and FFA is either re-esterified into triglycerides or released directly into the circulation. Otherwise, cholesterol and triglycerides assemble with apoB48 to form chylomicrons that are released into the circulation. There, they are cleaved by lipoprotein lipase (LPL) into FFA, which is used as an energy source by peripheral tissues. Chylomicron remnants are cleared by liver uptake, through their binding to LDL receptor family members. In parallel, hepatocytes synthesize cholesterol and produce VLDL, which contains triglycerides, cholesterol, and apoB100. VLDL is released into the circulation, where it undergoes lipolysis to release FFA. This becomes LDL and is ultimately cleared away by the hepatic LDL receptor. The reverse cholesterol transport is a process that takes place in the periphery and that is mediated by HDL. Excess cholesterol is transferred to lipid-poor apoAI or to nascent HDL by the specific transporters ATP-binding cassette (ABCA1) and ATP-binding cassette sub-family G member 1 (ABCG1). Next, cholesterol is esterified by lecithin–cholesterol acyltransferase (LCAT). Once HDL is formed, it can directly bind to scavenger receptor class B type 1 (SR-BI) on the liver and transfer cholesterol. Otherwise, cholesteryl esters can be transferred to apoB lipoproteins by cholesteryl ester transfer protein (CEPT), or a small portion of HDL can acquire apoE and bind to LDL receptor.

Figure 2

Interaction between lipids and innate immune receptors. Some lipid products, such as oxidized and modified LDL, cholesterol crystals, and ceramides activate innate immune receptors, such as TLR and NLRP3. FFA activate NLRP3, but not TLR. However, TLR-activation is a prerequisite for FFA to induce inflammation. HMBG1 (High Mobility Group Box 1) and fetuin A mediate TLR4 activation. Upon ligand binding, TLR trigger the activation JNK (c-Jun N-terminal kinase) and IKKβ (inhibitor of nuclear factor kappa-B kinase subunit β), leading to the induction of inflammatory gene transcription factors and the expression of proinflammatory cytokines, such as IL-1β and IL-8. NLRP3 activation leads to the expression of proinflammatory cytokines through the assembly of a large multiprotein complex, the inflammasome. The inflammasome consists of the NLRP3 protein, the adapter apoptosis-associated speck-like protein, and pro-caspase-1. The NLRP3-inflammasome catalyzes the cleavage, activation and secretion of IL-1β and IL-18. Inflammation promotes the development of steatosis in the liver, adipose lipolysis, peripheral insulin resistance, leptin resistance in the central nervous system, it impairs insulin secretion in the pancreas, and it promotes the development and progression of atherosclerosis, leading to obesity, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD).

Figure 3

Cholesterol biosynthesis deficiency syndromes. Schematic representation of the cholesterol pathway and some cholesterol–deficiency syndromes in response to different enzyme defects along the metabolic pathway (indicated with red crosses). Despite different specific causes, all these syndromes share the involvement of the central nervous system, where cholesterol reduction causes NLRP3-inflammosome activation, apoptosis, mitochondrial dysfunctions, autophagy and neuroinflammation with interleukin secretion (IL-1β, IL-18, IL-6 and TNF-α). HMG-CoA: 3-Hydroxy-3-MethylGlutaryl Co-enzyme; MVK: mevalotate kinase gene; MKD: Mevalonate Kinase Deficiency; ALDH3A2: Aldehyde Dehydrogenase 3 Family Member A2 gene; SLS: Sjogren-Larsson syndrome; POR: Cytochrome P450 Oxidoreductase gene; Antley-Bixler syndrome-like phenotype with disordered steroidogenesis; NSDHL: NAD(P) Dependent Steroid Dehydrogenase-Like gene; CHILD: congenital hemidysplasia with ichthyosiform erythroderma and limb defects; SC5DL: Sterol-C5-Desaturase gene; Lathosterolosis; 7DHCR: 7-Dehydrocholesterol Reductase gene; SLO: Smith-Lemli-Opitz) syndrome; IL-1β: Interleukin 1 beta; IL-6: Interleukin 6; IL-18: Interleukin 18; TNF-α: Tumor necrosis factor alpha.