Chapter Five - Eicosanoids in Metabolic Syndrome
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.
Section snippets
Fatty Acid Transporters
The uptake of essential FFAs, ALA, LA occurs through several transport mechanisms that include caveolins of lipid rafts, FATPs, FABPs, acyl-CoA binding proteins (ACBPs), solute ligand carriers (SLCs), and fatty acid translocases (FATs/CD36) (Table 5.1). The FATPs consist of several integral plasma membrane proteins that show both chain-length and saturation-dependent transport of FFAs (Table 5.1). FATPs have ACS activity and therefore trap FAs inside the cell. FAT/CD36 is expressed in numerous
Metabolism of Eicosanoids in MetS
MetS is a cluster of metabolic and physiological abnormalities that increases an individual’s risk for CVD, type II diabetes, obesity, and NAFLD, which includes symptoms of hyperglycemia, insulin resistance, hypertension, hypertriglyceridemia, hyperlipidemia, and hypercholesterolemia. The causes of these abnormalities are currently believed to be dysfunction in lipid metabolism and persistent subacute inflammation caused by alterations in lipid signaling networks that link the immune system and
Links between Sepsis and MetS
Sepsis or septicemia is defined as systemic inflammatory response syndrome (SIRS) that affects over 750,000 patients annually in the United states with a mortality rate of over 30% (Angus et al., 2001). SIRS is a constellation of both metabolic and inflammatory derangements that ultimately lead to multiple organ failure by increased circulating levels of proinflammatory cytokines, cortisol, acute-phase proteins, and apoptotic immune cells. SIRS patients display many of the symptoms of MetS
Eicosanoids and MetS Diseases
The epidemics of obesity, T2DM, and atherosclerosis in MetS are increasing yearly worldwide. The constellation of diseases associated with MetS, insulin resistance, hypertriglyceridemia, hyperlipidemia, hypertension, and obesity are largely attributed to derangements in lipid and carbohydrate metabolism. The rate of NAFLD is increasing in the United States with 34% of the population displaying many of the symptoms of MetS, thus making NAFLD an additional characteristic of MetS (Anderson &
Therapies in the Treatment of NAFLD
NAFLD is one of the most common causes of chronic liver disease in adults and children worldwide. Even though simple steatosis is initially a benign condition, up to 5% of individuals with NAFLD can progress to chronic diseases of steatohepatitis (NASH), liver fibrosis, liver cirrhosis, and finally either end-stage liver disease or hepatocellular carcinoma. Therefore, early intervention is the key to limit disease progression and realize better outcomes. The cornerstone in the management of
Conclusion
Although, COX, LOX, and P450 eicosanoid mediators elicit their own tissue- and cell-selective biological response, the cross-talk between synergistic and antagonistic lipid mediators within these pathways needs to be better understood in the disease process of MetS to design effective treatment with minimal ADRs. The goal will necessitate understanding the functional role of eicosanoids in the control of tissue-specific intermediary metabolism and in particular lipid and carbohydrate metabolism
Acknowledgments
This work was supported by National Institute of Health Grants HL32788, RO183366, and RCIHL100828 (to W.M.C), RO1DK093774 (to Yoon Kwang Lee), and grants DK44442 and DK58379 (to J.Y.L.C). We also wish to apologize for not to including recognition of excellent studies on MetS and NAFLD by numerous investigator because of limits on references.
Conflict of Interest Statement: The authors have no conflict of interests to declare.
References (269)
- et al.
Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis
Journal of Hepatology
(2012) - et al.
PPARbeta/delta activation blocks lipid-induced inflammatory pathways in mouse heart and human cardiac cells
Biochimica et Biophysica Acta
(2011) - et al.
Liver fatty acid-binding protein and obesity
Journal of Nutritional Biochemistry
(2010) - et al.
Effects of CYP4F2 polymorphism on response to warfarin during induction phase: a prospective, open-label, observational cohort study
Clinical Therapeutics
(2012) - et al.
Re-evaluating lipotoxic triggers in skeletal muscle: relating intramyocellular lipid metabolism to insulin sensitivity
Progress in Lipid Research
(2012) - et al.
Lipid droplets in inflammation and cancer
Prostaglandins Leukotrienes and Essential Fatty Acids
(2010) - et al.
Lipid body function in eicosanoid synthesis: an update
Prostaglandins Leukotrienes and Essential Fatty Acids
(2011) - et al.
Selective versus total insulin resistance: a pathogenic paradox
Cell Metabolism
(2008) - et al.
Hepatic long-chain acyl-CoA synthetase 5 mediates fatty acid channeling between anabolic and catabolic pathways
Journal of Lipid Research
(2010) - et al.
Thematic review series: proteomics. an integrated omics analysis of eicosanoid biology
Journal of Lipid Research
(2009)
Epoxyeicosatrienoic acids and heme oxygenase-1 interaction attenuates diabetes and metabolic syndrome complications
Prostaglandins and Other Lipid Mediators
Effects of leukotriene B4 and prostaglandin E2 on the differentiation of murine Foxp3+ T regulatory cells and Th17 cells
Prostaglandins Leukotrienes and Essential Fatty Acids
Cytochrome P450 epoxygenase CYP2J2 attenuates nephropathy in streptozotocin-induced diabetic mice
Prostaglandins and Other Lipid Mediators
JNK regulation of hepatic manifestations of the metabolic syndrome
Trends in Endocrinology and Metabolism
Effect of montelukast and MK-886 on hepatic ischemia-reperfusion injury in rats
Journal of Surgical Research
Steatohepatitis: a tale of two “hits”?
Gastroenterology
Inhibition of soluble epoxide hydrolase reduces food intake and increases metabolic rate in obese mice
Nutrition, Metabolism, and Cardiovascular Diseases
Differential expression and localization of 12/15 lipoxygenases in adipose tissue in human obese subjects
Biochemical and Biophysical Research
Effects of steatosis on drug-metabolizing capability of primary human hepatocytes
Toxicology In Vitro
Saturated fatty acid and TLR signaling link beta cell dysfunction and islet inflammation
Cell Metabolism
Improvement of hepatic fibrosis by leukotriene inhibition in cholestatic rats
Annals of Hepatology
Characterization of an arachidonic acid-deficient (Fads1 knockout) mouse model
Journal of Lipid Research
The functional variant V433M of the CYP4F2 and the metabolic syndrome in Swedes
Prostaglandins and Other Lipid Mediators
Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
Journal of Lipid Research
Metabolism of eicosapentaenoic and docosahexaenoic acids by recombinant human cytochromes P450
Archives of Biochemistry and Biophysics
Aldo-keto reductase 1B7 is a target gene of FXR and regulates lipid and glucose homeostasis
Journal of Lipid Research
Interfacial kinetic and binding properties of mammalian group IVB phospholipase A2 (cPLA2beta) and comparison with the other cPLA2 isoforms
Journal of Biological Chemistry
Cyclooxygenase-2 deficiency attenuates adipose tissue differentiation and inflammation in mice
Journal of Biological Chemistry
Inflammation and lipid signaling in the etiology of insulin resistance
Cell Metabolism
Group IVA phospholipase A2 is necessary for the biogenesis of lipid droplets
Journal of Biological Chemistry
Peroxisomal and microsomal lipid pathways associated with resistance to hepatic steatosis and reduced pro-inflammatory state
Journal of Biological Chemistry
Evidence for regulated monoacylglycerol acyltransferase expression and activity in human liver
Journal of Lipid Research
Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases
Biochemical Pharmacology
A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis
Journal of Biological Chemistry
Proteomic insights into an expanded cellular role for cytoplasmic lipid droplets
Journal of Lipid Research
Adipose overexpression of desnutrin promotes fatty acid use and attenuates diet-induced obesity
Diabetes
A switch in hepatic cortisol metabolism across the spectrum of non alcoholic fatty liver disease
PLoS One
Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis
Pharmacological Reviews
Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care
Critical Care Medicine
Insulin induces fatty acid desaturase expression in human monocytes
Scandinavian Journal of Clinical and Laboratory Investigation
Genetic analysis of expression profile involved in retinoid metabolism in non-alcoholic fatty liver disease
Hepatology Research
Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long-chain fatty Acyl-CoAs and insulin action in type 2 diabetic patients
Diabetes
Bioinformatics-driven identification and examination of candidate genes for non-alcoholic fatty liver disease
PLoS One
20-Hydroxyeicosatetraenoic acid induces apoptosis in neonatal rat cardiomyocytes through mitochondrial-dependent pathways
Journal of Cardiovascular Pharmacology
Epoxyeicosatrienoic acids function as selective, endogenous antagonists of native thromboxane receptors: identification of a novel mechanism of vasodilation
Journal of Pharmacology and Experimental Therapeutics
SNARE proteins mediate fusion between cytosolic lipid droplets and are implicated in insulin sensitivity
Nature Cell Biology
A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis
Nature
Sepsis-associated changes of the arachidonic acid metabolism and their diagnostic potential in septic patients
Critical Care Medicine
Human CYP2S1 metabolizes cyclooxygenase- and lipoxygenase-derived eicosanoids
Drug Metabolism and Disposition
Heme oxygenase (HO-1) rescue of adipocyte dysfunction in HO-2 deficient mice via recruitment of epoxyeicosatrienoic acids (EETs) and adiponectin
Cellular Physiology and Biochemistry
Cited by (74)
Berberine prevents NAFLD and HCC by modulating metabolic disorders
2024, Pharmacology and TherapeuticsThe CYP/20-HETE/GPR75 axis in hypertension
2022, Advances in Pharmacology20-HETE interferes with insulin signaling and contributes to obesity-driven insulin resistance
2021, Prostaglandins and Other Lipid Mediators2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters hepatic polyunsaturated fatty acid metabolism and eicosanoid biosynthesis in female Sprague-Dawley rats
2020, Toxicology and Applied Pharmacology