Eicosanoids in Metabolic Syndrome

Abstract

Chronic persistent inflammation plays a significant role in disease pathology of cancer, cardiovascular disease, and metabolic syndrome (MetS). MetS is a constellation of diseases that include obesity, diabetes, hypertension, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia. Nonalcoholic fatty liver disease (NAFLD) is associated with many of the MetS diseases. These metabolic derangements trigger a persistent inflammatory cascade, which includes production of lipid autacoids (eicosanoids) that recruit immune cells to the site of injury and subsequent expression of cytokines and chemokines that amplify the inflammatory response. In acute inflammation, the transcellular synthesis of antiinflammatory eicosanoids resolve inflammation, while persistent activation of the autacoid-cytokine-chemokine cascade in metabolic disease leads to chronic inflammation and accompanying tissue pathology. Many drugs targeting the eicosanoid pathways have been shown to be effective in the treatment of MetS, suggesting a common linkage between inflammation, MetS and drug metabolism. The cross-talk between inflammation and MetS seems apparent because of the growing evidence linking immune cell activation and metabolic disorders such as insulin resistance, dyslipidemia, and hypertriglyceridemia. Thus modulation of lipid metabolism through either dietary adjustment or selective drugs may become a new paradigm in the treatment of metabolic disorders. This review focuses on the mechanisms linking eicosanoid metabolism to persistent inflammation and altered lipid and carbohydrate metabolism in MetS.

Introduction

Eicosanoids represent a diverse group of bioactive lipids synthesized from polyunsaturated fatty acids (PUFA) to either proinflammatory omega-6 arachidonic acid (AA) or anti-inflammatory omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Fig. 5.1). These eicosanoids are synthesized from two essential fatty acids (FAs), ω-6 linoleic acid (C18:2n6) and ω-3 linolenic acid (LA) (C18:3n3), by a series of desaturase and elongase enzymes. Both eicosanoids and FAs are partitioned to different organelles by fatty acid transport proteins (FATPs), which transport fatty acid-coenzyme A (CoA) (FA-CoA) or fatty acid binding protein (FABP) that transports free fatty acid (FFA). The FFA is esterified by a group of organelles and FA chain-length-selective acyl-CoA synthetase (ACS) and then incoproation of saturated FA into the sn-1 position or unsaturated FA into sn-2 position of triacylglycerol (TAG) or phospholipids (PLs) by acyltransferase. These bioactive FAs are stored in membranes as PLs [e.g. phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidylglycerol] or in the endoplasmic reticulum (ER) or lipid droplets (LDs) as TAG. PLs are polar ionic lipids composed of 1,2-diacylglycerol and sn-3 phosphodiester bridge that links the glycerol backbone to usually a nitrogenous base, choline, serine, ethanolamine inositol or glycerol, while TAG has FAs located at all positions of the glycerol backbone. The release of both saturated and unsaturated FAs from PL or TAG are performed by a group of phospholipases. Phospholipidase A1 (PLA₁) releases saturated palmitic acid (C16:0) from the sn-1 producing 2-acyl lysophospholipid. Phospholipase A₂ releases unsaturated fatty acid (uSFA) either oleic acid (C18:1n9) or AA from the sn-2 position forming 1-acylphospholipid. Phospholipase C (PLC) hydrolyzes inositol PLs to yield inositol phosphates and diacylglycerol (DAG) as secondary messengers, while phospholipase D produces phosphatidic acid (PA), which is acted upon by PA phosphohydrolase to produce DAG. Lipid peroxidation of membrane PL uSFAs at the sn-2 is removed by PLA₂ producing sn-2-lysoPL that is reacylated by either arachidonyl-CoA transacylase or by an exchange reaction catalyzed by lysolecithin:lecithin acyltransferase, which is a major mechanism in membrane remodeling.

The release of AA, EPA or DHA by PLA₂ is the initial rate-limiting step in the synthesis of bioactive eicosanoids, prostaglandins (PGs), leukotrienes (LTs), and cytochrome P450 metabolites. Although the cyclooxygenase and lipoxygenase (LOX) pathways that produce prostanoids and LTs, respectively, have profound roles in inflammation and regulation of metabolism, the cytochrome P450 epoxygenase and FA omega hydroxylase P450 produce unique eicosanoids that also play a significant role in inflammation and recently, in the regulation of metabolism. The interrelationship between eicosanoid metabolic enzymes and drug-metabolizing enzymes is evident from: 1) many of the same transports for drug metabolites are also used in the trans-cellular synthesis of bioactive eicosanoids, 2) conjugation of drugs with glutathione for transport and synthesis of LTs conjugate to glutathione are performed by glutathione-S-transferase as well as glutathione being necessary for the synthesis of eicosanoids and epoxide hydrolase function in both pathways, and 3) both thromboxane synthase (TXAS) (CYP5), prostacyclin synthase (CYP8), epoxygenase CYP2 and FA omega hydrolase (CYP4) cytochrome P450 enzymes participate in drug metabolism and eicosanoid pathways.

The functional role of eicosanoids in the inflammatory etiology of diseases of metabolic syndrome (MetS) has been extensively studied in relation to immune cell recruitment and cytokine, chemokine production and their activation of inflammatory pathways in cancer, diabetes, and cardiovascular disease (CVD). However, the role of eicosanoids in the regulation of metabolic pathways of lipid and carbohydrate metabolism in obesity, hyperlipidemia, hypertriglyceridemia, hypertension, and insulin resistance has only recently been studied with the use of eicosanoid metabolic enzyme transgenic and global knockout mouse models. These studies in PLA₂, 5-lipooxygenase, and 12/15-LOX pathways and knockout mice of fatty acid desaturase (FADS) and elongase (Elovl) in the formation of AA from α-linoleic acid (ALA) have strongly supported eicosanoids as key regulatory molecules in MetS and the progression of hepatic steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD). Furthermore, it is uncertain whether these knockout mice will show alterations in drug-metabolizing enzyme function and regulation. This will be of particular interest with respect to drugs that target inflammation through inhibition of eicosanoid metabolism. These same drugs also target key enzymes in intermediary metabolism and are metabolized by drug-metabolizing cytochrome P450s. The future challenges will include construction of floxed tissue-specific knockout animals to study the role of eicosanoid metabolism in regulation of adipose tissue lipogenesis and lipolysis, in the regulation of pancreas hyperinsulinemia and β-cell destruction, and in progression of steatosis to steatohepatitis and fibrosis in NAFLD.

Finally, we can learn much from patients with sepsis, glucocorticoid disorders and MetS in understanding how eicosanoids link inflammation, drug metabolism and diseases of MetS. The cardinal signs of acute inflammation of dolar (heat), calor (pain), rubor (redness), and tumor (edema) are initiated by a cascade of eicosanoid lipid autacoids, cytokines, and chemokines. Normally, the resolution of inflammation begins with the transcellular synthesis of antiinflammatory lipoxins (LX) and resolvins between different cell types. However, in chronic inflammation, the persistent cellular damage by foreign agents amplifies the inflammatory cascade, which initiates a poorly calibrated immune response that progresses from a local to a systemic response involving multiple organs, leading to immune system repression of drug metabolism and deregulation of basic metabolism. This anomaly is observed in sepsis and septicemia with multiple organ failure, which is the leading cause of surgical deaths, with a death rate equal to that of myocardial infarction. Sepsis is characterized by multiple and systemic changes in several organs that lead to insulin resistance, dyslipidemia, cholestasis, hyperbilirubinemia and vasodilation, vascular leakage, hypovolemia and coagulopathy. These symptoms are also observed in patients with Cushing syndrome and individuals with MetS. Recent studies have revealed alterations in eicosanoid metabolism in septic patients and a downregulation of the major drug-metabolizing cytochrome P450s such as CYP1, CYP2, and CYP3 families that metabolize more than 90% of known drugs, thereby making sepsis a challenge to manage from a therapeutic perspective. It is of interest that CYPs involved in the metabolism of endogenous lipids and eicosanoids have not been characterized with respect to sepsis and metabolic alterations.

The purpose of this review is not to recapitulate the several excellent reviews on eicosanoid metabolism and inflammation but to attempt to link the eicosanoids as pivotal lipid mediators in the control of inflammation and intermediary and drug metabolism in diseases such as MetS, dyslipidemia, hypertriglyceridemia, hypertension, insulin resistance and obesity. We hope that this review will provide insight into the function of eicosanoid metabolites in the regulatory control of lipid and carbohydrate metabolism in adipose tissue, pancreas, liver, and cardiovascular system under MetS.