Peroxisome proliferator-activated receptor δ promotes very low-density lipoprotein-derived fatty acid catabolism in the macrophage

Abstract

Significant attention has focused on the role of low-density lipoprotein (LDL) in the pathogenesis of atherosclerosis. However, recent advances have identified triglyceride-rich lipoproteins [e.g., very LDL (VLDL)] as independent risk predictors for this disease. We have previously demonstrated peroxisome proliferator-activated receptor (PPAR)␦, but not PPAR␥, is the major nuclear VLDL sensor in the macrophage, which is a crucial component of the atherosclerotic lesion. Here, we show that, in addition to ␤-oxidation and energy dissipation, activation of PPAR␦ by VLDL particles induces key genes involved in carnitine biosynthesis and lipid mobilization mediated by a recently identified TG lipase, transport secretion protein 2 (also named desnutrin, iPLA2, and adipose triglyceride lipase), resulting in increased fatty acid catabolism. Unexpectedly, deletion of PPAR␦ results in derepression of target gene expression, a phenotype similar to that of ligand activation, suggesting that unliganded PPAR␦ suppresses fatty acid utilization through active repression, which is reversed upon ligand binding. This unique transcriptional mechanism assures a tight control of the homeostasis of VLDL-derived fatty acid and provides a therapeutic target for other lipid-related disorders, including dyslipidemia and diabetes, in addition to coronary artery disease. At the cellular level, they are indispensable in maintaining cell membrane integrity and serve as signaling molecules regulating metabolic balance. An excessive lipid intake, through the socalled western-style diet, disturbs this balance and is the main cause of obesity-related diseases (or syndrome X) in developed countries (2). The development of drugs that could control circulating lipid levels, such as lowering VLDL TGs and LDL cholesterol and raising high-density lipoprotein cholesterol, has been a major focus for the pharmaceutical industry. These efforts have shown promise in treating diseases, including hyperlipidemia and cardiovascular dysfunctions.Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and are bound and activated by fatty acids (3). There are three subtypes in this subfamily, PPAR␣, PPAR␤͞␦, and PPAR␥, each exhibiting a distinct tissue distribution and regulating different aspects of lipid homeostasis (4, 5). PPAR␣ plays a major role in fatty acid oxidation in liver during fasting (6, 7), whereas PPAR␥ is important for lipid storage, adipocyte functions, and insulin sensitivity (8-12). These important biological activities of PPAR␣ and PPAR␥ have later been proven responsible for the TG-lowering effect of fibrates and the insulin-sensitizing activity of thiazolidinediones, respectively (13-16). The function of ubiquitously expressed PPAR␦ was less defined until the making of genetically modified animals. Transgenic mice expressing an active form of PPAR␦ in adipocytes are resistant to diet-induced obesity due to an increased fatty acid catabolic rate (17). Paradoxically, PPAR␦Ϫ͞Ϫ mice are also lean (18, 19), ...

PPARδ agonists have opposing effects on insulin resistance in high fat‐fed rats and mice due to different metabolic responses in muscle

“…Our findings show an unexpected worsening of muscle insulin resistance and triglyceride accumulation in HF rats after treatment with PPARd agonists. Intriguingly, insulin resistance in HF mice was ameliorated in both muscle and liver along with correction of dyslipidaemia following NNC61-5920 administration, as previously reported for GW501516 (Tanaka et al, 2003;Wang et al, 2003;Lee et al, 2006). Our findings reveal distinct metabolic responses to PPARd agonists between tissues and species and indicate a need for careful selection of preclinical species for characterization of the endpoint metabolic effects of PPARd agonists intended for treatment of patients with the metabolic syndrome.…”

“…In this extended study, rats were started on the HF diet from 4 weeks of age (approx 50 g) to minimize the influence of ageing or overweight on insulin sensitivity. One group of rats were administered GW501516 at 5 mg·kg -1 ·day -1 based on earlier studies in mice (Tanaka et al, 2003;Lee et al, 2006).…”

“…To investigate whether the duration of treatment with NNC61-5920 was not long enough to show beneficial effects as reported in mice (Wang et al, 2003;Lee et al, 2006), we extended the administration of NNC61-5920 by oral gavage for 6 weeks. In this extended study, we also included the well-known PPARd agonist GW501516 to compare its effects with NNC61-5920.…”

“…Activation of PPARd up-regulates carnitine palmitoyltransferase-1 (CPT1), uncoupling protein 3 (UCP3), pyruvate dehydrogenase kinase 4 (PDK4) and peroxisome proliferator-activated receptor g coactivator -1a (PGC1a) and increases palmitate oxidation in muscle cells (Tanaka et al, 2003;Wang et al, 2003;Dimopoulos et al, 2007). Several studies in mice have shown improved glucose tolerance and muscle insulin sensitivity in both genetic and dietary models of insulin resistance after treatment with PPARd agonists (Tanaka et al, 2003;Wang et al, 2003;Lee et al, 2006). Recently, the PPARd agonist GW501516 has also been shown to reverse multiple metabolic abnormalities including reduction in plasma triglyceride, liver triglyceride content and insulin resistance (HOMA-IR) in moderately obese monkeys and men (Oliver et al, 2001;Riserus et al, 2008).…”

Variation in the peroxisome proliferator-activated receptor δ gene in relation to common metabolic traits in 7,495 middle-aged white people

“…In recent years, PPARδ has emerged as a key player in the regulation of energy metabolism and as a potential novel drug target. PPARδ is widely produced and VLDL-derived fatty acids serve as endogenous receptor agonists enhancing the expression of target genes [4,5]. PPARδ acts as a regulator of fatty acid β-oxidation in both adipose tissue and skeletal muscle.…”