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WIREs Syst Biol Med
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Lipid‐sensing nuclear receptors in the pathophysiology and treatment of the metabolic syndrome

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Abstract Metabolic syndrome (MS) is a cluster of different diseases, namely central obesity, hypertension, hyperglycemia, and dyslipidemia, together with a pro‐thrombotic and pro‐inflammatory state. These metabolic abnormalities are often associated with an increased risk for cardiovascular disease (CVD) and cancer. Dietary and lifestyle modifications are currently believed more effective than pharmacological therapies in the management of MS patients. Nevertheless, the relatively low grade of compliance of patients to these recommendations, as well as the failure of current therapies, highlights the need for the discovery of new pharmacological and nutraceutic approaches. A deeper knowledge of the patho‐physiological events that initiate and support the MS is mandatory. Lipid‐sensing nuclear receptors (NRs) are the master transcriptional regulators of lipid and carbohydrate metabolism and inflammatory responses, thus standing as suitable targets. This review focuses on the physiological relevance of the NRs (peroxisome proliferator‐activated receptors, liver X receptors, and farnesoid X receptor) in the control of whole‐body homeostasis, with a special emphasis on lipid and glucose metabolism, and on the relationships between metabolic unbalances, systemic inflammation, and the onset of CVD. Future perspectives and possible clinical applications are also presented. WIREs Syst Biol Med 2011 3 562–587 DOI: 10.1002/wsbm.137 This article is categorized under: Biological Mechanisms > Cell Signaling

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Schematic representation of liver X receptors (LXRs) transcriptional activation (left): as a heterodimer of retinoid X receptors (RXR), LXRs bind the LXR response elements (LXREs), containing direct repeats (DR) of hexameric sequences AGGTCA, interspaced by four nucleotide spacers (DR‐4). Effects of LXRs activation in tissues involved in metabolic homeostasis (right): LXRs are the master regulators of cholesterol metabolism. In the liver, LXRs promote cholesterol secretion in bile and its conversion to bile acids (BA), whereas inhibiting low‐density lipoprotein (LDL) cholesterol uptake. In the intestine, LXRs inhibit cholesterol absorption while promoting its secretion. LXRs also promote reverse cholesterol transport (RCT) via an integrated mechanism involving the liver and intestine [increased high‐density lipoprotein (HDL) biogenesis], macrophages (increased efflux of cholesterol), and serum (enhanced RCT and lipoprotein remodeling). The activation of LXRs also reduces glucose concentrations in blood (inhibiting hepatic gluconeogenesis, whereas increasing glucose uptake in muscle and adipose tissue), and enhances triglyceridemia [promoting hepatic fatty acid (FA) synthesis]. Finally, LXRs negatively modulate inflammatory pathways in macrophages.

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Schematic representation of peroxisome proliferator‐activated receptor (PPAR)γ transcriptional activation (left): as a heterodimer of retinoid X receptors (RXR), PPARγ binds the PPAR response elements (PPREs), containing direct repeats (DR) of hexameric sequences AGGTCA, interspaced only by a single nucleotide spacer (DR‐1). Effects of PPARγ activation in tissues involved in metabolic homeostasis (right): PPARγ activation improves glucose metabolism, inducing insulin sensitivity (in the liver, skeletal muscle, and adipose tissue), increasing glucose uptake from the muscle and reducing hepatic gluconeogenesis. In the adipose tissue, PPARγ also induces fatty acid (FA) uptake, adipogenesis, increased fat storage, and a better lipid repartition into adipocytes, leading to the formation of small, newly formed, and active adipocytes. Nevertheless, PPARγ increases the production of adiponectin from adipocytes, which is negatively correlated to metabolic unbalances and MS. In macrophages, PPARγ also induces an increased M2/M1 ratio (thus inhibiting inflammation) and contributes to an enhanced uptake of oxidized low‐density lipoprotein (LDL). In addition, PPARγ regulates the transcription of the liver X receptor (LXR), lipoprotein lipase (LPL), and apolipoprotein E (apoE), further preventing atherosclerosis.

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Schematic representation of peroxisome proliferator‐activated receptor (PPAR)β/δ transcriptional activation (left): as a heterodimer of retinoid X receptors (RXR), PPARβ/δ binds the PPAR response elements (PPREs), containing direct repeats (DR) of hexameric sequences AGGTCA, interspaced only by a single nucleotide spacer (DR‐1). Effects of PPARβ/δ activation in tissues involved in metabolic homeostasis (right): in adipose tissue and muscle, PPARβ/δ induces fatty acid (FA) transport and oxidation, mitochondrial activity, and thermogenesis, thus increasing energy expenditure. In muscle, PPARβ/δ activation ameliorates the endurance capacity. In the liver, PPARβ/δ inhibits glucose output, thereby contributing to the peripheral glucose homeostasis. PPARβ/δ also induces increased serum high‐density lipoprotein (HDL) levels, leading to enhanced reverse cholesterol transport (RCT), and reduced inflammation in the macrophages. These effects could further promote a PPARβ/δ‐mediated cardiovascular prevention.

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Schematic representation of peroxisome proliferator‐activated receptor (PPAR)α transcriptional activation (left): as a heterodimer of retinoid X receptors (RXR), PPARα binds the PPAR response elements (PPREs), containing direct repeats (DR) of hexameric sequences AGGTCA, interspaced only by a single nucleotide spacer (DR‐1). Effects of PPARα activation in tissues involved in metabolic homeostasis (right): PPARα reduces plasma triglycerides (TG) by inducing fatty acid (FA) transport and oxidation in liver, adipose tissue, and muscle. In addition, PPARα induces lipolysis in adipocytes and hepatocytes. PPARα also modulates lipoprotein metabolism both in the liver, where PPARα induces ApoAI expression and clearance of TG‐rich lipoproteins, and in macrophages, where PPARα promotes the efflux of cholesterol, the uptake of oxidized LDL, and the expression of lipoprotein lipase (LPL), thus promoting lipoprotein remodeling. In the endothelium, PPARα exerts athero‐protective properties, inhibiting the release of adhesion molecules and inflammatory cytokines, while enhancing vascular remodeling.

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Schematic representation of farnesoid X receptor (FXR) transcription activation (left): as a heterodimer of retinoid X receptors (RXR), FXR binds the FXR response elements (FXREs). The most common FXRE motif consists of inverted repeats (IR) of hexameric sequences AGGTCA, interspaced only by a single nucleotide spacer (IR‐1). Effects of FXR activation in tissues involved in metabolic homeostasis (right): FXR plays the key role in bile acid (BA) metabolism, reducing hepatic BA synthesis, increasing BA secretion into bile, and inhibiting intestinal BA reabsorption. FXR additionally modulates cholesterol metabolism [increasing the hepatic uptake of low‐density lipoprotein (LDL) cholesterol, reducing the conversion of cholesterol to BA, and promoting high‐density lipoprotein (HDL) remodeling], reduces the circulating levels of glucose (promoting glycogen synthesis and inhibiting gluconeogenesis), free fatty acids (FFA), and triglycerides (TG; promoting FA oxidation while inhibiting FFA and TG synthesis). The reduction of the cholesterol conversion to BA can be achieved directily (activating FXR in the liver), or indirectly via an intestinal FXR mediated increase of FGF 15 (see asterisks).

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