Alterations in Plasma and Tissue Lipids Associated with Obesity and Metabolic Syndrome
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Clinical Science (2008) 114, 183–193 (Printed in Great Britain) doi:10.1042/CS20070115 183 REVIEW Alterations in plasma and tissue lipids associated with obesity and metabolic syndrome Concepcion´ M. AGUILERA∗, Mercedes GIL-CAMPOS†, Ramon´ CANETE˜ † and Angel´ GIL∗ ∗Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology, School of Pharmacy, University of Granada, Campus de Cartuja 18071 Granada, Spain, and †Unit of Pediatric Endocrinology, Reina Sofia University Hospital, Avda Men´endez Pidal s/n, Cordoba,´ Spain ABSTRACT The MS (metabolic syndrome) is a cluster of clinical and biochemical abnormalities charac- terized by central obesity, dyslipidaemia [hypertriglyceridaemia and decreased HDL-C (high- density lipoprotein cholesterol)], glucose intolerance and hypertension. Insulin resistance, hyperleptinaemia and low plasma levels of adiponectin are also widely related to features of the MS. This review focuses on lipid metabolism alterations associated with the MS, paying special attention to changes in plasma lipids and cellular fatty acid oxidation. Lipid metabolism alterations in liver and peripheral tissues are addressed, with particular reference to adipose and muscle tissues, and the mechanisms by which some adipokines, namely leptin and adiponectin, mediate the regulation of fatty acid oxidation in those tissues. Activation of the AMPK (AMP- dependent kinase) pathway, together with a subsequent increase in fatty acid oxidation, appear to constitute the main mechanism of action of these hormones in the regulation of lipid metabolism. Decreased activation of AMPK appears to have a role in the development of features of the MS. In addition, alteration of AMPK signalling in the hypothalamus, which may function as a sensor of nutrient availability, integrating multiple nutritional and hormonal signals, may have a key role in the appearance of the MS. INTRODUCTION released through the action of LPL (lipoprotein lipase), an insulin-stimulated enzyme. In addition, glucose provides White adipose tissue, the body’s major energy store, is the glycerol backbone for TAG. In humans, FAs can composed of TAGs (triacylglycerols), produced mainly also be synthesized from glucose, although the rate of by FAs (fatty acids) derived from chylomicrons and cir- synthesis is lower than in rodents. Adipose tissue is also culating VLDLs [very-LDL (low density lipoproteins)], able to release NEFAs [non-esterified FAs (‘free FAs’)]; Key words: AMP-dependent kinase (AMPK), fatty acid oxidation, hypothalamus, lipid, metabolic syndrome, non-esterified fatty acid (NEFA), obesity. Abbreviations: ACC, acetyl-CoA carboxylase; AgRP, agouti protein; AMPK, AMP-activated protein kinase; apo, apolipoprotein; CE, cholesterol ester; CETP,CE transfer protein; CPT-1, carnitine-palmitoyl transferase-1; D6D, 6 desaturase; FA, fatty acid; FAS, FA synthase; HDL, high-density lipoprotein; HDL-C, HDL cholesterol; HL, hepatic lipase; HSL, hormone-sensitive lipase; IR, insulin resistance; LC-CoA, long-chain acyl-CoA; LCFA, long-chain FA; LDL, low-density lipoprotein; LPL, lipoprotein lipase; MS , metabolic syndrome; MUFA, monounsaturated FA; NEFA, non-esterified FA; NPY, neuropeptide Y; PI3K, phosphoinositide 3-kinase; PL, phospholipid; PPAR, peroxisome-proliferator-activated receptor; PUFA, polyunsaturated FA; SFA, saturated FA; TAG, triacylglycerol; Tri-C, triacsin C; VLDL, very-LDL. Correspondence: Professor Angel´ Gil (email [email protected]). C The Authors Journal compilation C 2008 Biochemical Society 184 C. M. Aguilera and others during lipolysis, TAGs are hydrolysed in a reaction liver, adipose tissue and muscle tissue. Attention is also catalysed by HSL (hormone-sensitive lipase), which is, paid to the LCFA (long-chain FA)-mediated mechani- in turn, regulated by numerous factors and hormones. sms by which the hypothalamus controls energy homo- Catecholamines, by binding to β-adrenergic receptors, eostasis, and to alterations linked to obesity and the MS. stimulate lipolysis, whereas insulin inhibits this pro- cess [1]. TAG accumulation is enhanced by the preferential PLASMA LIPOPROTEINS AND THE MS channelling of nutrients into adipose tissue, rather than into muscle or other tissues for fairly immediate The MS can best be explained by viewing abdominal oxidation. Overall, it would seem reasonable to assume adipose tissue as an endocrine organ that releases that alterations which limit lipolysis and oxidation of FAs, excess NEFAs and adipokines into the circulation. First, and those which stimulate lipogenesis (the two processes increased blood NEFAs inhibit the uptake of glucose are often linked), are the cause of, or at least are related to, by muscle [19]. Although the pancreas manufactures obesity [2–4]. A number of published findings point to a extra insulin, there is not enough to counter the hyper- link between human obesity and genetic defects affecting glycaemia, thus explaining the paradox of fasting the lipolytic pathway [5]. Oxidation of FAs depends hyperglycaemia despite increased plasma insulin levels, on the availability of substrates and on co-adjuvant which is known as IR [20]. Hyperglycaemia and increased mechanisms for their transport into mitochondria. In circulating NEFAs provide the correct substrates for obese subjects with a predominance of visceral fat, increased manufacture of TAGs by the liver [21]. Release increased lipolytic activity triggers the release of NEFAs, of NEFAs by adipocytes is greater in central obesity prompting the subsequent hormonal and metabolic than in lower-body obesity, with no concomitant increase changes observed in obesity, such as hyperinsulinaemia, in oxidation by peripheral tissues [22,23]. The ‘portal hypoadiponectinaemia and hypertriglyceridaemia [6]. theory’ posits one of the major mechanisms behind the However, as stated by Smith et al. [7], sustained changes dyslipidaemia, which is the increased flux of NEFAs in lipolysis could never occur dissociated from sustained from adipose tissue to the liver via the portal vein when changes in synthesis. Otherwise, the mass of TAGs within visceral TAG stores are increased, which is related to the adipocyte would soon be depleted. IR and the lack of inhibition of HSL [24]. Individuals Obesity is associated with the so-called MS (metabolic afflicted by the MS are often viscerally obese and insulin- syndrome) [6] characterized by hyperinsulinaemia and resistant. Under these circumstances, the failure of insulin peripheral resistance to the action of insulin, glucose to suppress HSL stimulates the release of NEFAs from intolerance or Type 2 diabetes, hypertriglyceridaemia, lipolytically active visceral fat. This increased flux of decreased HDL-C [HDL (high-density lipoprotein) NEFAs, channelled to the liver via the portal circulation, cholesterol] and other changes associated with risks stimulates hepatic TAG synthesis, apoB100 formation of cardiovascular disease, such as arterial hypertension and, ultimately, the assembly and secretion of VLDL [25]. [8–10]. IR (insulin resistance) would appear to be NEFAs promote increased TAG synthesis in the liver, the major common finding in subjects with obesity, which can lead to the secretion of VLDL (Figure 1). glucose intolerance or Type 2 diabetes, hypertension or In peripheral tissues, VLDL particles are exposed to dyslipidaemia, and it has been claimed to be the initial LPL, which hydrolyses the TAG of VLDL particles, factor triggering a metabolic cascade which is also in- generating NEFAs. Under normal conditions, these fluenced by genetic and environmental factors [8,11–13]. NEFAs are taken up by muscle and adipose tissue for The combination of IR and hyperinsulinaemia greatly energy use or storage. The resulting remnant particles are increases the likelihood of developing a cluster of closely hydrolysed further by HL (hepatic lipase) to form LDL. related abnormalities, and the resulting clinical diagnoses In contrast, in individuals afflicted by the MS, the failure can be considered to make up the IR syndrome [8]. of insulin to activate LPL favours the accumulation of Findings common to central obesity and the MS TAG-rich lipoproteins in the circulation [23,26], which include, in addition to increased VLDL and indeed TAG, in turn enhances the exchange of TAG from TAG- the presence of small-dense LDL particles, increased rich lipoproteins to LDL and HDL, with a reciprocal apoB (apolipoprotein B), decreased apoA-I (apolipopro- transfer of cholesteryl esters to TAG-rich lipoproteins. tein A-I) and impaired haemostasis due to increased TAG-enriched cholesteryl ester-depleted LDL are better fibrinogen and PAI-1 (plasminogen-activator inhibitor) substrates for HL-mediated TAG lipolysis, which in [14-17]. Likewise, the cholesterol content of HDL turn leads to the formation of small-dense LDL declines, whereas that of VLDL and LDL increases [18]. (Figure 2). Mechanistically, small-dense LDL particles The present review focuses on some of the major enter the arterial wall more easily, bind to arterial wall alterations in plasma lipids in obesity and their involve- proteoglycans more avidly and are highly susceptible to ment in the MS, and also addresses the main cellular oxidative modification, leading to macrophage uptake, all lipid alterations, especially FA oxidation, occurring in of which may contribute to increased atherogenesis [27]. C The Authors Journal compilation C 2008 Biochemical Society Alterations in plasma and tissue lipids associated with obesity and metabolic syndrome 185 Figure