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1.  Muscle-Derived Angiopoietin-Like Protein 4 Is Induced by Fatty Acids via Peroxisome Proliferator–Activated Receptor (PPAR)-δ and Is of Metabolic Relevance in Humans 
Diabetes  2009;58(3):579-589.
OBJECTIVE— Long-chain fatty acids (LCFAs) contribute to metabolic homeostasis in part via gene regulation. This study's objective was to identify novel LCFA target genes in human skeletal muscle cells (myotubes).
RESEARCH DESIGN AND METHODS— In vitro methods included culture and treatment of human myotubes and C2C12 cells, gene array analysis, real-time RT-PCR, Western blotting, ELISA, chromatin immunoprecipitation, and RNA interference. Human subjects (two cohorts) were characterized by oral glucose tolerance test, hyperinsulinemic-euglycemic clamp, magnetic resonance imaging and spectroscopy, and standard blood analyses (glucose, insulin, C-peptide, and plasma lipids).
RESULTS— We show here that ANGPTL4 (encoding angiopoietin-like protein 4) represents a prominent LCFA-responsive gene in human myotubes. LCFA activated peroxisome proliferator-activated receptor (PPAR)-δ, but not PPAR-α or -γ, and pharmacological activation of PPAR-δ markedly induced ANGPTL4 production and secretion. In C2C12 myocytes, knockdown of PPARD, but not of PPARG, blocked LCFA-mediated ANGPTL4 induction, and LCFA treatment resulted in PPAR-δ recruitment to the ANGPTL4 gene. In addition, pharmacological PPAR-δ activation induced LIPE (encoding hormone-sensitive lipase), and this response crucially depended on ANGPTL4, as revealed by ANGPTL4 knockdown. In a human cohort of 108 thoroughly phenotyped subjects, plasma ANGPTL4 positively correlated with fasting nonesterified fatty acids (P = 0.0036) and adipose tissue lipolysis (P = 0.0012). Moreover, in 38 myotube donors, plasma ANGPTL4 levels and adipose tissue lipolysis in vivo were reflected by basal myotube ANGPTL4 expression in vitro (P = 0.02, both).
CONCLUSIONS— ANGPTL4 is produced by human myotubes in response to LCFA via PPAR-δ, and muscle-derived ANGPTL4 seems to be of systemic relevance in humans.
doi:10.2337/db07-1438
PMCID: PMC2646056  PMID: 19074989
2.  Differential effects of angiopoietin-like 4 in brain and muscle on regulation of lipoprotein lipase activity 
Molecular Metabolism  2014;4(2):144-150.
Objective
Lipoprotein lipase (LPL) is a key regulator of circulating triglyceride rich lipoprotein hydrolysis. In brain LPL regulates appetite and energy expenditure. Angiopoietin-like 4 (Angptl4) is a secreted protein that inhibits LPL activity and, thereby, triglyceride metabolism, but the impact of Angptl4 on central lipid metabolism is unknown.
Methods
We induced type 1 diabetes by streptozotocin (STZ) in whole-body Angptl4 knockout mice (Angptl4-/-) and their wildtype littermates to study the role of Angptl4 in central lipid metabolism.
Results
In type 1 (streptozotocin, STZ) and type 2 (ob/ob) diabetic mice, there is a ~2-fold increase of Angptl4 in the hypothalamus and skeletal muscle. Intracerebroventricular insulin injection into STZ mice at levels which have no effect on plasma glucose restores Angptl4 expression in hypothalamus. Isolation of cells from the brain reveals that Angptl4 is produced in glia, whereas LPL is present in both glia and neurons. Consistent with the in vivo experiment, in vitro insulin treatment of glial cells causes a 50% reduction of Angptl4 and significantly increases LPL activity with no change in LPL expression. In Angptl4-/- mice, LPL activity in skeletal muscle is increased 3-fold, and this is further increased by STZ-induced diabetes. By contrast, Angptl4-/- mice show no significant difference in LPL activity in hypothalamus or brain independent of diabetic and nutritional status.
Conclusion
Thus, Angptl4 in brain is produced in glia and regulated by insulin. However, in contrast to the periphery, central Angptl4 does not regulate LPL activity, but appears to participate in the metabolic crosstalk between glia and neurons.
doi:10.1016/j.molmet.2014.11.003
PMCID: PMC4314546
Angptl4; Lipid metabolism; Lipoprotein lipase; AgRP, agouti-related protein; Angptl4, angiopoietin-like 4; ARC, arcuate nucleus; CART, cocaine-and-amphetamine-regulated transcript; CNS, central nervous system; FFA, free fatty acid; LPL, lipoprotein lipase; NPY, neuropeptide-Y; POMC, pro-opiomelanocortin; STZ, streptozotocin; TG, triglyceride
3.  Linking nutritional regulation of Angptl4, Gpihbp1, and Lmf1 to lipoprotein lipase activity in rodent adipose tissue 
BMC Physiology  2012;12:13.
Background
Lipoprotein lipase (LPL) hydrolyzes triglycerides in lipoproteins and makes fatty acids available for tissue metabolism. The activity of the enzyme is modulated in a tissue specific manner by interaction with other proteins. We have studied how feeding/fasting and some related perturbations affect the expression, in rat adipose tissue, of three such proteins, LMF1, an ER protein necessary for folding of LPL into its active dimeric form, the endogenous LPL inhibitor ANGPTL4, and GPIHBP1, that transfers LPL across the endothelium.
Results
The system underwent moderate circadian oscillations, for LPL in phase with food intake, for ANGPTL4 and GPIHBP1 in the opposite direction. Studies with cycloheximide showed that whereas LPL protein turns over rapidly, ANGPTL4 protein turns over more slowly. Studies with the transcription blocker Actinomycin D showed that transcripts for ANGPTL4 and GPIHBP1, but not LMF1 or LPL, turn over rapidly. When food was withdrawn the expression of ANGPTL4 and GPIHBP1 increased rapidly, and LPL activity decreased. On re-feeding and after injection of insulin the expression of ANGPTL4 and GPIHBP1 decreased rapidly, and LPL activity increased. In ANGPTL4−/− mice adipose tissue LPL activity did not show these responses. In old, obese rats that showed signs of insulin resistance, the responses of ANGPTL4 and GPIHBP1 mRNA and of LPL activity were severely blunted (at 26 weeks of age) or almost abolished (at 52 weeks of age).
Conclusions
This study demonstrates directly that ANGPTL4 is necessary for rapid modulation of LPL activity in adipose tissue. ANGPTL4 message levels responded very rapidly to changes in the nutritional state. LPL activity always changed in the opposite direction. This did not happen in Angptl4−/− mice. GPIHBP1 message levels also changed rapidly and in the same direction as ANGPTL4, i.e. increased on fasting when LPL activity decreased. This was unexpected because GPIHBP1 is known to stabilize LPL. The plasticity of the LPL system is severely blunted or completely lost in insulin resistant rats.
doi:10.1186/1472-6793-12-13
PMCID: PMC3562520  PMID: 23176178
Gene expression; Insulin; Gene inactivation; Cycloheximide; Actinomycin D; Transcription; Translation; Posttranslational
4.  Silencing of ANGPTL 3 (angiopoietin-like protein 3) in human hepatocytes results in decreased expression of gluconeogenic genes and reduced triacylglycerol-rich VLDL secretion upon insulin stimulation 
Bioscience Reports  2014;34(6):e00160.
Homozygosity of loss-of-function mutations in ANGPTL3 (angiopoietin-like protein 3)-gene results in FHBL2 (familial combined hypolipidaemia, OMIM #605019) characterized by the reduction of all major plasma lipoprotein classes, which includes VLDL (very-low-density lipoprotein), LDL (low-density lipoprotein), HDL (high-density lipoprotein) and low circulating NEFAs (non-esterified fatty acids), glucose and insulin levels. Thus complete lack of ANGPTL3 in humans not only affects lipid metabolism, but also affects whole-body insulin and glucose balance. We used wild-type and ANGPTL3-silenced IHHs (human immortalized hepatocytes) to investigate the effect of ANGPTL3 silencing on hepatocyte-specific VLDL secretion and glucose uptake. We demonstrate that both insulin and PPARγ (peroxisome-proliferator-activated receptor γ) agonist rosiglitazone down-regulate the secretion of ANGPTL3 and TAG (triacylglycerol)-enriched VLDL1-type particles in a dose-dependent manner. Silencing of ANGPTL3 improved glucose uptake in hepatocytes by 20–50% and influenced down-regulation of gluconeogenic genes, suggesting that silencing of ANGPTL3 improves insulin sensitivity. We further show that ANGPTL3-silenced cells display a more pronounced shift from the secretion of TAG-enriched VLDL1-type particles to secretion of lipid poor VLDL2-type particles during insulin stimulation. These data suggest liver-specific mechanisms involved in the reported insulin-sensitive phenotype of ANGPTL3-deficient humans, featuring lower plasma insulin and glucose levels.
We show that silencing of ANGPTL3 in human hepatocytes in addition to reducing secretion of TAG-enriched VLDL upon insulin stimulation enhances glucose uptake and improves insulin response. Thus, our data provide insight into the lower insulin and glucose levels observed in humans with ANGPTL3 loss-of-function mutation.
doi:10.1042/BSR20140115
PMCID: PMC4266921  PMID: 25495645
ANGPTL3 silencing; hypolipidaemia; insulin signalling; liver; rosiglitazone; VLDL; ANGPTL, angiopoietin-like protein; CCD, coiled coil domain; FHBL2, familial combined hypolipidaemia; GLUT2, glucose transporter 2; HDL, high-density lipoprotein; IHH, immortalized human hepatocyte; IR, insulin receptor; IRS, insulin receptor substrate; LDL, low-density lipoprotein; LPL, lipoprotein lipase; NEFA, non-esterified fatty acid; PEPCK, phosphoenolpyruvate carboxykinase; PGC1α, peroxisome proliferator-activated receptor γ co-activator 1-α; PI3K, phosphoinositide 3-kinase; PL, phospholipid; PPAR, peroxisome-proliferator-activated receptor; QPCR, quantitative PCR; shRNA, small hairpin RNA; TAG, triacylglycerol; TRB3, tribbles homologue 3; VLDL, very-low-density lipoprotein
5.  Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans  
The relative activity of lipoprotein lipase (LPL) in different tissues controls the partitioning of lipoprotein-derived fatty acids between sites of fat storage (adipose tissue) and oxidation (heart and skeletal muscle). Here we used a reverse genetic strategy to test the hypothesis that 4 angiopoietin-like proteins (ANGPTL3, -4, -5, and -6) play key roles in triglyceride (TG) metabolism in humans. We re-sequenced the coding regions of the genes encoding these proteins and identified multiple rare nonsynonymous (NS) sequence variations that were associated with low plasma TG levels but not with other metabolic phenotypes. Functional studies revealed that all mutant alleles of ANGPTL3 and ANGPTL4 that were associated with low plasma TG levels interfered either with the synthesis or secretion of the protein or with the ability of the ANGPTL protein to inhibit LPL. A total of 1% of the Dallas Heart Study population and 4% of those participants with a plasma TG in the lowest quartile had a rare loss-of-function mutation in ANGPTL3, ANGPTL4, or ANGPTL5. Thus, ANGPTL3, ANGPTL4, and ANGPTL5, but not ANGPTL6, play nonredundant roles in TG metabolism, and multiple alleles at these loci cumulatively contribute to variability in plasma TG levels in humans.
doi:10.1172/JCI37118
PMCID: PMC2613476  PMID: 19075393
6.  Cardiac lipoprotein lipase activity in the hypertrophied heart may be regulated by fatty acid flux 
Biochimica et Biophysica Acta  2012;1821(4):627-636.
Cardiac hypertrophy is characterised by an imbalance between lipid uptake and fatty acid β-oxidation leading to an accumulation of lipids, particularly triacylglycerol (TAG). It is unclear whether uptake mechanisms such as lipoprotein lipase (LPL) can be attenuated to diminish this uptake. Rats were cold acclimated to induce cardiac hypertrophy and increase cardiac LPL. Lipid uptake and metabolism were altered by feeding a ‘Western-style’ high fat diet (WSD) or feeding oxfenicine (2 g/L) in the drinking water. Diastolic stiffness (increased volume change/unit pressure change) was induced in hypertrophied hearts for rats fed WSD (P < 0.05) or WSD + oxfenicine (P < 0.01), although absolute performance of cardiac muscle, estimated from stress–strain calculations was unchanged. Cold acclimation increased cardiac endothelial LPL (P < 0.05) but this was diminished following oxfenicine. Following WSD LPL was further decreased below WSD-fed control hearts (P < 0.05) with no further decrease by oxfenicine supplementation. A negative correlation was noted between plasma TAG and endothelial LPL (correlation coefficient = − 0.654; P < 0.001) but not cardiac TAG concentration. Transcript levels of angiopoietin-like protein-4 (ANGPTL4) were increased 6-fold by WSD (P < 0.05) and increased 15-fold following WSD + oxfenicine (P < 0.001). For CA-hearts fed WSD or WSD + oxfenicine ANGPTL4 mRNA levels were preserved at chow-fed levels. VLDLR protein levels were increased 10-fold (P < 0.01) by CA. ANGPTL4 protein levels were increased 2-fold (P < 0.05) by WSD, but restored following oxfenicine. For CA-hearts WSD increased ANGPTL4 protein levels 3-fold (P < 0.01) with WSD + oxfenicine increasing ANGPTL4 protein 4-fold (P < 0.01). These data suggest that endothelial LPL levels in the heart are altered to maintain FA flux and may exploit ANGPTL4.
Highlights
► Cardiac endothelial LPL inversely correlates with plasma triacylglycerol. ► Heart TAG levels do not relate to tissue LPL levels. ► Cardiac ANGPTL4 protein levels increased in response to high plasma lipids. ► LPL in the heart may be controlled to maintain fatty acid flux.
doi:10.1016/j.bbalip.2011.12.004
PMCID: PMC3793859  PMID: 22226882
Lipoprotein lipase; Very-low-density lipoprotein; Cardiac hypertrophy; ANGPTL4
7.  Regulation of angiopoietin‐like protein 4 production during and after exercise 
Physiological Reports  2014;2(8):e12109.
Abstract
Angiopoietin‐like protein 4 (ANGPTL4) may regulate lipoprotein lipase‐dependent plasma clearance of triacylglycerol from skeletal muscle during exercise. The aim of this study was to examine the importance of muscle in regulating ANGPTL4 in response to exercise. We sampled muscle biopsies and serum before, immediately after, and 2 h after 45 min of ergometer cycling. Sampling was done before and after a 12‐week training intervention in controls and dysglycemic subjects. Moreover, fat biopsies were taken before and after the training intervention. The regulation of ANGPTL4 was also investigated in several tissues of exercising mice, and in cultured myotubes. ANGPTL4 levels in serum and expression in muscle were highest 2 h after exercise in both groups. Whereas ANGPTL4 was higher in muscle of exercising controls as compared to dysglycemic subjects, the opposite was observed in serum. In exercising mice, Angptl4 mRNA showed both higher basal expression and induction in liver compared to muscle. Angptl4 mRNA was much higher in adipose tissue than muscle and was also induced by exercise. We observed two mRNA isoforms of ANGPTL4 in muscle and fat in humans. Both were induced by exercise in muscle; one isoform was expressed 5‐ to 10‐fold higher than the other. Studies in mice and cultured myotubes showed that both fatty acids and cortisol have the potential to increase ANGPTL4 expression in muscle during exercise. In conclusion, ANGPTL4 is markedly induced in muscle in response to exercise. However, liver and adipose tissue may contribute more than muscle to the exercise‐induced increase in circulating ANGPTL4.
The Production of ANGPTL4 is markedly induced in skeletal muscle in response to exercise. However, liver and adipose tissue may contribute more than skeletal muscle to the exercise‐induced increase in circulatory ANGPTL4.
doi:10.14814/phy2.12109
PMCID: PMC4246580  PMID: 25138789
Adipose tissue; ANGPTL4; exercise; skeletal muscle
8.  Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome 
Nature medicine  2013;20(1):37-46.
The molecular link between proteinuria and hyperlipidemia in nephrotic syndrome is not known. We show in the present study that plasma angiopoietin-like 4 (Angptl4) links proteinuria with hypertriglyceridemia through two negative feedback loops. In previous studies in a rat model that mimics human minimal change disease, we observed localized secretion by podocytes of hyposialylated Angptl4, a pro-proteinuric form of the protein. But in this study we noted high serum levels of Angptl4 (presumably normosialylated based on a neutral isoelectric point) in other glomerular diseases as well. Circulating Angptl4 was secreted by extrarenal organs in response to an elevated plasma ratio of free fatty acids (FFAs) to albumin when proteinuria reached nephrotic range. In a systemic feedback loop, these circulating pools of Angptl4 reduced proteinuria by interacting with glomerular endothelial αvβ5 integrin. Blocking the Angptl4–β5 integrin interaction or global knockout of Angptl4 or β5 integrin delayed recovery from peak proteinuria in animal models. But at the same time, in a local feedback loop, the elevated extrarenal pools of Angptl4 reduced tissue FFA uptake in skeletal muscle, heart and adipose tissue, subsequently resulting in hypertriglyceridemia, by inhibiting lipoprotein lipase (LPL)-mediated hydrolysis of plasma triglycerides to FFAs. Injecting recombinant human ANGPTL4 modified at a key LPL interacting site into nephrotic Buffalo Mna and Zucker Diabetic Fatty rats reduced proteinuria through the systemic loop but, by bypassing the local loop, without increasing plasma triglyceride levels. These data show that increases in circulating Angptl4 in response to nephrotic-range proteinuria reduces the degree of this pathology, but at the cost of inducing hypertriglyceridemia, while also suggesting a possible therapy to treat these linked pathologies.
doi:10.1038/nm.3396
PMCID: PMC4114723  PMID: 24317117
9.  Inflammation increases plasma angiopoietin-like protein 4 in patients with the metabolic syndrome and type 2 diabetes 
Background
Angiopoietin-like protein 4 (ANGPTL4) inhibits lipoprotein lipase and associates with dyslipidemia. The expression of ANGPTL4 is regulated by free fatty acids (FFA) that activate lipid-sensing peroxisome proliferator-activated receptors (PPARs), but FFA can also activate pattern recognition receptors including Toll-like receptor 4 (TLR4) in macrophages.
Objective
To assess whether systemic low-grade inflammation is a determinant for plasma ANGPTL4 levels in patients with the metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM).
Design
We studied 335 male participants: healthy controls (Controls), patients with the MetS without inflammation (MetS−I) and with low-grade inflammation (MetS+I), and patients with T2DM. All patients without diabetes included in the present study were initially matched for waist circumference. In plasma, ANGPTL4, C reactive protein (CRP) and metabolic parameters were determined. Underlying mechanisms were examined using human macrophages in vitro.
Results
As compared with Controls, plasma ANGPTL4 levels were increased in patients with MetS−I, MetS+I, and T2DM. Furthermore, ANGPTL4 was increased in T2DM compared with MetS−I. In fact, plasma CRP correlated positively with plasma ANGPTL4. In vitro studies showed that TLR 3/4 activation largely increased the expression and release of ANGPTL4 by macrophages.
Conclusions
Plasma ANGPTL4 levels in humans are predicted by CRP, a marker of inflammation, and ANGPTL4 expression by macrophages is increased by inflammatory stimuli.
doi:10.1136/bmjdrc-2014-000034
PMCID: PMC4265148  PMID: 25512873
Inflammatory Process in Diabetes; Metabolic Syndrome
10.  Angiopoietin-Like 4 Is Involved in the Poor Angiogenic Potential of High Glucose-Insulted Bone Marrow Stem Cells 
Korean Circulation Journal  2014;44(3):177-183.
Background and Objectives
Diabetes is reported to reduce the function or number of progenitor cells. We compared the gene expression patterns of bone marrow-derived mesenchymal stem cells from diabetic (DM-BMCs) and healthy (non-DM-BMCs) rats and suggested Angiopoietin-like 4 (Angptl4) could be a responsible factor for impaired angiogenesis of DM-BMCs.
Subjects and Methods
BMCs were isolated from DM or non-DM rat, and in vitro angiogenesis activity was compared by tube formation assay on Matrigel and complementary deoxyribonucleic acid expression was analyzed by microarray with or without oxytocin treatment. Human BMCs (hBMCs) were treated with high glucose, and were performed polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. Angptl4 plasmid DNA and micro ribonucleic acid-132 (miR-132) were transfected to immortalized hBMCs.
Results
In vitro angiogenesis assay showed the impaired tube formation in DM-BMCs, and slightly recovery by oxytocin treatment. Angptl4, an adipokine, was upregulated in DM-BMCs compared to non-DM-BMCs. Oxytocin treatment reduced Angptl4 in DM-BMCs. In hBMCs, overexpression of Angptl4 attenuated the tube formation. In addition to Angptl4, miR-132 was increased by high glucose treatment. Collectively, high glucose resulted in impaired tube formation through miR-132 induction and Angptl4 upregulation in BMCs.
Conclusion
Our results show that the angiogenic activity of BMCs is impaired by high glucose stress, which would be mediated by Angptl4 and miR-132.
doi:10.4070/kcj.2014.44.3.177
PMCID: PMC4037640  PMID: 24876859
Stem cells; Diabetes mellitus; ANGPTL4 protein, rat; MicroRNAs
11.  Severity of Diabetes Governs Vascular Lipoprotein Lipase by Affecting Enzyme Dimerization and Disassembly 
Diabetes  2011;60(8):2041-2050.
OBJECTIVE
In diabetes, when glucose consumption is restricted, the heart adapts to use fatty acid (FA) exclusively. The majority of FA provided to the heart comes from the breakdown of circulating triglyceride (TG), a process catalyzed by lipoprotein lipase (LPL) located at the vascular lumen. The objective of the current study was to determine the mechanisms behind LPL processing and breakdown after moderate and severe diabetes.
RESEARCH DESIGN AND METHODS
To induce acute hyperglycemia, diazoxide, a selective, ATP-sensitive K+ channel opener was used. For chronic diabetes, streptozotocin, a β-cell–specific toxin was administered at doses of 55 or 100 mg/kg to generate moderate and severe diabetes, respectively. Cardiac LPL processing into active dimers and breakdown at the vascular lumen was investigated.
RESULTS
After acute hyperglycemia and moderate diabetes, more LPL is processed into an active dimeric form, which involves the endoplasmic reticulum chaperone calnexin. Severe diabetes results in increased conversion of LPL into inactive monomers at the vascular lumen, a process mediated by FA-induced expression of angiopoietin-like protein 4 (Angptl-4).
CONCLUSIONS
In acute hyperglycemia and moderate diabetes, exaggerated LPL processing to dimeric, catalytically active enzyme increases coronary LPL, delivering more FA to the heart when glucose utilization is compromised. In severe chronic diabetes, to avoid lipid oversupply, FA-induced expression of Angptl-4 leads to conversion of LPL to inactive monomers at the coronary lumen to impede TG hydrolysis. Results from this study advance our understanding of how diabetes changes coronary LPL, which could contribute to cardiovascular complications seen with this disease.
doi:10.2337/db11-0042
PMCID: PMC3142087  PMID: 21646389
12.  Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention? 
All fibrates are peroxisome proliferators-activated receptors (PPARs)-alpha agonists with ability to decrease triglyceride and increase high density lipoprotein- cholesterol (HDL-C). However, bezafibrate has a unique characteristic profile of action since it activates all three PPAR subtypes (alpha, gamma and delta) at comparable doses. Therefore, bezafibrate operates as a pan-agonist for all three PPAR isoforms. Selective PPAR gamma agonists (thiazolidinediones) are used to treat type 2 diabetes mellitus (T2DM). They improve insulin sensitivity by up-regulating adipogenesis, decreasing free fatty acid levels, and reversing insulin resistance. However, selective PPAR gamma agonists also cause water retention, weight gain, peripheral edema, and congestive heart failure. The expression of PPAR beta/ delta in essentially all cell types and tissues (ubiquitous presence) suggests its potential fundamental role in cellular biology. PPAR beta/ delta effects correlated with enhancement of fatty acid oxidation, energy consumption and adaptive thermogenesis. Together, these data implicate PPAR beta/delta in fuel combustion and suggest that pan-PPAR agonists that include a component of PPAR beta/delta activation might offset some of the weight gain issues seen with selective PPAR gamma agonists, as was demonstrated by bezafibrate studies. Suggestively, on the whole body level all PPARs acting as one orchestra and balanced pan-PPAR activation seems as an especially attractive pharmacological goal. Conceptually, combined PPAR gamma and alpha action can target simultaneously insulin resistance and atherogenic dyslipidemia, whereas PPAR beta/delta properties may prevent the development of overweight. Bezafibrate, as all fibrates, significantly reduced plasma triglycerides and increased HDL-C level (but considerably stronger than other major fibrates). Bezafibrate significantly decreased prevalence of small, dense low density lipoproteins particles, remnants, induced atherosclerotic plaque regression in thoracic and abdominal aorta and improved endothelial function. In addition, bezafibrate has important fibrinogen-related properties and anti-inflammatory effects. In clinical trials bezafibrate was highly effective for cardiovascular risk reduction in patients with metabolic syndrome and atherogenic dyslipidemia. The principal differences between bezafibrate and other fibrates are related to effects on glucose level and insulin resistance. Bezafibrate decreases blood glucose level, HbA1C, insulin resistance and reduces the incidence of T2DM compared to placebo or other fibrates. Currently statins are the cornerstone of the treatment and prevention of cardiovascular diseases related to atherosclerosis. However, despite the increasing use of statins as monotherapy for low density lipoprotein- cholesterol (LDL-C) reduction, a significant residual cardiovascular risk is still presented in patients with atherogenic dyslipidemia and insulin resistance, which is typical for T2DM and metabolic syndrome. Recently, concerns were raised regarding the development of diabetes in statin-treated patients. Combined bezafibrate/statin therapy is more effective in achieving a comprehensive lipid control and residual cardiovascular risk reduction. Based on the beneficial effects of pan-PPAR agonist bezafibrate on glucose metabolism and prevention of new-onset diabetes, one could expect a neutralization of the adverse pro-diabetic effect of statins using the strategy of a combined statin/fibrate therapy.
doi:10.1186/1475-2840-11-140
PMCID: PMC3502168  PMID: 23150952
Atherogenic dyslipidemia; Bezafibrate; Combined fibrate/statin therapy; Metabolic syndrome; PPAR; Prevention; Residual cardiovascular risk; Type 2 diabetes
13.  Angiopoietin-like 4 (Angptl4) 
Adipocyte  2012;1(3):182-187.
Angiopoietin-like 4 (Angptl4) is a secreted protein modulating triacylglycerol homeostasis. Its transcription is induced by glucocorticoids, which act to elevate circulating Angptl4 levels during fasting. In investigating the role of Angptl4 in glucocorticoid action, we identified that in addition to its known ability to inhibit lipoprotein lipase, Angptl4 stimulates intracellular adipocyte lipolysis. Fatty acid release by murine adipocytes following fasting or treatment with glucocorticoids or catecholamines is highly Angptl4-dependent. In fact, Angptl4 can directly stimulate cAMP-dependent PKA signaling and lipolysis when added to adipocytes. Here, we detail this novel Angptl4-dependent lipolytic regulatory mechanism and discuss its physiological and therapeutic implications.
doi:10.4161/adip.20787
PMCID: PMC3609093  PMID: 23700531
Angptl4; adipocyte; cAMP; catecholamine; fasting; glucocorticoids; lipolysis
14.  Intronic Cis-Regulatory Modules Mediate Tissue-Specific and Microbial Control of angptl4/fiaf Transcription 
PLoS Genetics  2012;8(3):e1002585.
The intestinal microbiota enhances dietary energy harvest leading to increased fat storage in adipose tissues. This effect is caused in part by the microbial suppression of intestinal epithelial expression of a circulating inhibitor of lipoprotein lipase called Angiopoietin-like 4 (Angptl4/Fiaf). To define the cis-regulatory mechanisms underlying intestine-specific and microbial control of Angptl4 transcription, we utilized the zebrafish system in which host regulatory DNA can be rapidly analyzed in a live, transparent, and gnotobiotic vertebrate. We found that zebrafish angptl4 is transcribed in multiple tissues including the liver, pancreatic islet, and intestinal epithelium, which is similar to its mammalian homologs. Zebrafish angptl4 is also specifically suppressed in the intestinal epithelium upon colonization with a microbiota. In vivo transgenic reporter assays identified discrete tissue-specific regulatory modules within angptl4 intron 3 sufficient to drive expression in the liver, pancreatic islet β-cells, or intestinal enterocytes. Comparative sequence analyses and heterologous functional assays of angptl4 intron 3 sequences from 12 teleost fish species revealed differential evolution of the islet and intestinal regulatory modules. High-resolution functional mapping and site-directed mutagenesis defined the minimal set of regulatory sequences required for intestinal activity. Strikingly, the microbiota suppressed the transcriptional activity of the intestine-specific regulatory module similar to the endogenous angptl4 gene. These results suggest that the microbiota might regulate host intestinal Angptl4 protein expression and peripheral fat storage by suppressing the activity of an intestine-specific transcriptional enhancer. This study provides a useful paradigm for understanding how microbial signals interact with tissue-specific regulatory networks to control the activity and evolution of host gene transcription.
Author Summary
Recent studies have revealed that the community of microorganisms residing in the intestine regulates fat storage. Microbes evoke this response in part by suppressing expression of the Angptl4 gene, which encodes a secreted inhibitor of fat storage. Although Angptl4 is expressed in multiple tissues, microbial suppression occurs only in the intestine. To determine how microbes control fat storage, we must elucidate the mechanisms underlying intestine-specific and microbial regulation of Angptl4 expression. Here, we take advantage of the unique features of the zebrafish model to define the regulatory DNA sequences controlling angptl4 expression. Our results reveal that different DNA regulatory regions within the angptl4 gene mediate expression of angptl4 in the intestine and other tissues. By assessing the evolution of angptl4 regulatory regions and subjecting them to structure-function analyses, we identify discrete DNA sequences that are required for intestinal expression. Strikingly, microbes suppress the activity of the intestine-specific regulatory region similar to the endogenous angptl4 gene. Therefore, intestinal microbes might regulate angptl4 production by suppressing the signaling pathway interpreted by an intestine-specific transcriptional regulatory region. Our results provide new mechanistic insights into how intestinal microbes might influence fat storage and contribute to the development of obesity.
doi:10.1371/journal.pgen.1002585
PMCID: PMC3315460  PMID: 22479192
15.  Hypothalamic Angptl4/Fiaf Is a Novel Regulator of Food Intake and Body Weight 
Diabetes  2010;59(11):2772-2780.
OBJECTIVE
The angiopoietin-like protein 4 (Angptl4)/fasting-induced adipose factor (Fiaf) is known as a regulator of peripheral lipid and glucose metabolism. In the present study, we investigated the physiological role of Angptl4 in central regulation of body weight homeostasis.
RESEARCH DESIGN AND METHODS
Hypothalamic Angptl4 expression levels were measured using immunoblot assay during feeding manipulation or after administration of leptin, insulin, and nutrients. The effects of Angptl4 on food intake, body weight, and energy expenditure were determined following intracerebroventricular (ICV) administration of Angptl4 in C57BL/6 mice. Food intake, energy metabolism, and feeding responses to leptin, insulin, and nutrients were compared between Angptl4-null mice and their wild littermates. Finally, the relationship of hypothalamic AMP-activated protein kinase (AMPK) and Angptl4 was studied.
RESULTS
Hypothalamic Angptl4 expression levels were increased upon food intake or administration of leptin, insulin, and nutrients. Furthermore, central administration of Angptl4 suppressed food intake and body weight gain but enhanced energy expenditure. These effects were mediated via suppression of hypothalamic AMPK activities. Consistently, Angptl4-null mice displayed increased body weight and hypothalamic AMPK activity but reduced energy expenditure. Food intake following a fast was significantly greater in Angptl4-null mice, which was normalized by centrally administered Angptl4. Moreover, anorectic responses to leptin, insulin, and glucose were diminished in Angptl4-null mice. In contrast, Angptl4-null mice were resistant to diet-induced obesity, indicating obesity-promoting effects of Angptl4 under the condition of fat-enriched diet.
CONCLUSIONS
We have demonstrated that hypothalamic Angptl4 is regulated by physiological appetite regulators and mediates their anorexigenic effects via inhibition of hypothalamic AMPK activity. Therefore, Angptl4 appears to have an important role in central regulation of energy metabolism.
doi:10.2337/db10-0145
PMCID: PMC2963535  PMID: 20798332
16.  Lack of Relationship between Cord Serum Angiopoietin-Like Protein 4 (ANGPTL4) and Lipolytic Activity in Human Neonates Born by Spontaneous Delivery 
PLoS ONE  2013;8(12):e81201.
Background
Ligands of peroxisome-proliferator activated receptors (PPARs), such as non-esterified fatty acids (NEFAs), induce expression of angiopoietin-like protein 4 (ANGPTL4). Recently ANGPTL4 has been reported to be a mediator of intracellular adipose lipolysis induced by glucocorticoids.
Objective
To determine the concentrations of ANGPTL4 in cord serum of neonates born by spontaneous vaginal delivery (SVD) and by pre-labor cesarean section (CS) from healthy women, and to relate them to parameters of neonatal lipolytic activity at birth.
Measurements
In 54 neonates born by SVD and in 56 neonates born by CS, arterial cord blood was drawn to determine insulin, cortisol, triacylglycerols (TAGs), glycerol, non-esterified fatty acids (NEFAs), individual fatty acids, ANGPTL4, adiponectin, retinol binding protein 4 (RBP4) and leptin.
Results
Birth weight and neonatal fat mass in SVD and CS showed no difference, but the concentrations of glycerol, adiponectin, RBP4, NEFAs and most individual fatty acids were higher in cord serum of neonates born by SVD compared to CS, indicating a higher adipose tissue breakdown in the SVD group. The concentrations of TAG and cortisol were also higher and that of insulin was lower in cord serum of SVD compared to the CS group. However, the concentration in cord serum of ANGPTL4 did not differ between the two groups and no positive correlation with either NEFA or glycerol concentrations were detected.
Conclusion
ANGPTL4 is known to stimulate lipolysis in adults, but does not appear to mediate the increased activity in SVD, indicating the presence of different regulatory inputs.
doi:10.1371/journal.pone.0081201
PMCID: PMC3852178  PMID: 24324678
17.  Decreased Fat Storage by Lactobacillus Paracasei Is Associated with Increased Levels of Angiopoietin-Like 4 Protein (ANGPTL4) 
PLoS ONE  2010;5(9):e13087.
Background
Intervention strategies for obesity are global issues that require immediate attention. One approach is to exploit the growing consensus that beneficial gut microbiota could be of use in intervention regimes. Our objective was to determine the mechanism by which the probiotic bacteria Lactobacillus paracasei ssp paracasei F19 (F19) could alter fat storage. Angiopoietin-like 4 (ANGPTL4) is a circulating lipoprotein lipase (LPL) inhibitor that controls triglyceride deposition into adipocytes and has been reported to be regulated by gut microbes.
Methodology/Principal Findings
A diet intervention study of mice fed high-fat chow supplemented with F19 was carried out to study potential mechanistic effects on fat storage. Mice given F19 displayed significantly less body fat, as assessed by magnetic resonance imaging, and a changed lipoprotein profile. Given that previous studies on fat storage have identified ANGPTL4 as an effector, we also investigated circulating levels of ANGPTL4, which proved to be higher in the F19-treated group. This increase, together with total body fat and triglyceride levels told a story of inhibited LPL action through ANGPTL4 leading to decreased fat storage. Co-culture experiments of colonic cell lines and F19 were set up in order to monitor any ensuing alterations in ANGPTL4 expression by qPCR. We observed that potentially secreted factors from F19 can induce ANGPTL4 gene expression, acting in part through the peroxisome proliferator activated receptors alpha and gamma. To prove validity of in vitro findings, germ-free mice were monocolonized with F19. Here we again found changes in serum triglycerides as well as ANGPTL4 in response to F19.
Conclusions/Significance
Our results provide an interesting mechanism whereby modifying ANGPTL4, a central player in fat storage regulation, through manipulating gut flora could be an important gateway upon which intervention trials of weight management can be based.
doi:10.1371/journal.pone.0013087
PMCID: PMC2948012  PMID: 20927337
18.  Genetic Variation in ANGPTL4 Provides Insights into Protein Processing and Function*S⃞ 
The Journal of Biological Chemistry  2009;284(19):13213-13222.
Angiopoietin-like protein 4 (ANGPTL4) is a secreted protein that modulates the disposition of circulating triglycerides (TG) by inhibiting lipoprotein lipase (LPL). Here we examine the steps involved in the synthesis and post-translational processing of ANGPTL4, and the effects of a naturally occurring sequence variant (E40K) that is associated with lower plasma TG levels in humans. Expression of the wild-type and mutant proteins in HEK-293A cells indicated that ANGPTL4 formed dimers and tetramers in cells prior to secretion and cleavage of the protein. After cleavage at a canonical proprotein convertase cleavage site (161RRKR164), the oligomeric structure of the N-terminal domain was retained whereas the C-terminal fibrinogen-like domain dissociated into monomers. Inhibition of cleavage did not interfere with oligomerization of ANGPTL4 or with its ability to inhibit LPL, whereas mutations that prevented oligomerization severely compromised the capacity of the protein to inhibit LPL. ANGPTL4 containing the E40K substitution was synthesized and processed normally, but no monomers or oligomers of the N-terminal fragments accumulated in the medium; medium from these cells failed to inhibit LPL activity. Parallel experiments performed in mice recapitulated these results. Our findings indicate that oligomerization, but not cleavage, of ANGPTL4 is required for LPL inhibition, and that the E40K substitution destabilizes the protein after secretion, preventing the extracellular accumulation of oligomers and abolishing the ability of the protein to inhibit LPL activity.
doi:10.1074/jbc.M900553200
PMCID: PMC2676053  PMID: 19270337
19.  Activation of Peroxisome Proliferator–Activated Receptor-β/-δ (PPAR-β/-δ) Ameliorates Insulin Signaling and Reduces SOCS3 Levels by Inhibiting STAT3 in Interleukin-6–Stimulated Adipocytes 
Diabetes  2011;60(7):1990-1999.
OBJECTIVE
It has been suggested that interleukin (IL)-6 is one of the mediators linking obesity-derived chronic inflammation with insulin resistance through activation of STAT3, with subsequent upregulation of suppressor of cytokine signaling 3 (SOCS3). We evaluated whether peroxisome proliferator–activated receptor (PPAR)-β/-δ prevented activation of the IL-6-STAT3-SOCS3 pathway and insulin resistance in adipocytes.
RESEARCH DESIGN AND METHODS
Adipocytes and white adipose tissue from wild-type and PPAR-β/-δ-null mice were used to evaluate the effect of PPAR-β/-δ on the IL-6-STAT3-SOCS3 pathway.
RESULTS
First, we observed that the PPAR-β/-δ agonist GW501516 prevented both IL-6–dependent reduction in insulin-stimulated Akt phosphorylation and glucose uptake in adipocytes. In addition, this drug treatment abolished IL-6–induced SOCS3 expression in differentiated 3T3-L1 adipocytes. This effect was associated with the capacity of the drug to prevent IL-6–induced STAT3 phosphorylation on Tyr705 and Ser727 residues in vitro and in vivo. Moreover, GW501516 prevented IL-6–dependent induction of extracellular signal–related kinase (ERK)1/2, a serine-threonine-protein kinase involved in serine STAT3 phosphorylation. Furthermore, in white adipose tissue from PPAR-β/-δ–null mice, STAT3 phosphorylation (Tyr705 and Ser727), STAT3 DNA-binding activity, and SOCS3 protein levels were higher than in wild-type mice. Several steps in STAT3 activation require its association with heat shock protein 90 (Hsp90), which was prevented by GW501516 as revealed in immunoprecipitation studies. Consistent with this finding, the STAT3-Hsp90 association was enhanced in white adipose tissue from PPAR-β/-δ–null mice compared with wild-type mice.
CONCLUSIONS
Collectively, our findings indicate that PPAR-β/-δ activation prevents IL-6–induced STAT3 activation by inhibiting ERK1/2 and preventing the STAT3-Hsp90 association, an effect that may contribute to the prevention of cytokine-induced insulin resistance in adipocytes.
doi:10.2337/db10-0704
PMCID: PMC3121427  PMID: 21617181
20.  Angiopoietin-like 4 promotes melanoma cell invasion and survival through aldolase A 
Oncology Letters  2014;8(1):211-217.
In the present study, the association between angiopoietin-like 4 (ANGPTL4) and aldolase A (ALDOA) in human melanoma cell invasion and survival was investigated. Overexpression and knockdown of ANGPTL4 were respectively performed in WM-115 and WM-266-4 cells. ALDOA expression at both the mRNA and the protein levels as well as the ALDOA gene promoter activities were increased and decreased in parallel with overexpression and knockdown of ANGPTL4 in the melanoma cells, which was blocked by selective protein kinase C (PKC) inhibitor and restored by PKC agonist, respectively. ANGPTL4 overexpression significantly increased cell invasion and matrix metalloproteinase-2 (MMP-2) expression and decreased cell apoptosis against cisplatin in WM-115 cells, which was reversed by knocking down ALDOA. In WM-266-4 cells, knockdown of ANGPTL4 decreased cell invasion and MMP-2 expression and increased cell apoptosis against cisplatin, which was reversed by overexpression of ALDOA. In conclusion, this study demonstrates that ANGPTL4 upregulates ALDOA expression in human melanoma cells at the ALDOA gene promoter/transcriptional level through a PKC-dependent mechanism, and that ALDOA is a critical mediator of the promoting effect of ANGPTL4 on melanoma cell invasion, likely through upregulating the MMP-2 expression. Additionally, our results suggest that ALDOA plays an important role in ANGPTL4-enhanced melanoma cell survival against apoptotic stress, which implicates ANGPTL4 and ALDOA in the development of melanoma chemoresistance.
doi:10.3892/ol.2014.2071
PMCID: PMC4063564  PMID: 24959248
angiopoietin-like 4; aldolase A; melanoma; cell invasion; cell survival; protein kinase C; matrix metalloproteinase-2
21.  Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons 
There are three peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL) cholesterol synthesis, stimulates "reverse" cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Until recently, the biological role of PPAR beta/delta remained unclear. However, treatment of obese animals by specific PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies "pure" PPAR gamma ligands. The new generation of dual-action PPARs – the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) are on deck in late-stage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including ragaglitazar and farglitazar). The old and well known lipid-lowering fibric acid derivative bezafibrate is the first clinically tested pan – (alpha, beta/delta, gamma) PPAR activator. It is the only pan-PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore, bezafibrate could be considered (indeed, as a "post hoc" understanding) as an "archetype" of a clinically tested pan-PPAR ligand. Bezafibrate leads to considerable raising of HDL cholesterol and reduces triglycerides, improves insulin sensitivity and reduces blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients with features of metabolic syndrome. Clinical evidences obtained from bezafibrate-based studies strongly support the concept of pan-PPAR therapeutic approach to conditions which comprise the metabolic syndrome. However, from a biochemical point of view, bezafibrate is a PPAR ligand with a relatively low potency. More powerful new compounds with pan-PPAR activity and proven long-term safety should be highly effective in a clinical setting of patients with coexisting relevant lipid and glucose metabolism disorders.
doi:10.1186/1475-2840-4-14
PMCID: PMC1236941  PMID: 16168052
22.  ANGPTL4 variants E40K and T266M are associated with lower fasting triglyceride levels in Non-Hispanic White Americans from the Look AHEAD Clinical Trial 
BMC Medical Genetics  2011;12:89.
Background
Elevated triglyceride levels are a risk factor for cardiovascular disease. Angiopoietin-like protein 4 (Angptl4) is a metabolic factor that raises plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). In non-diabetic individuals, the ANGPTL4 coding variant E40K has been associated with lower plasma triglyceride levels while the T266M variant has been associated with more modest effects on triglyceride metabolism. The objective of this study was to determine whether ANGPTL4 E40K and T266M are associated with triglyceride levels in the setting of obesity and T2D, and whether modification of triglyceride levels by these genetic variants is altered by a lifestyle intervention designed to treat T2D.
Methods
The association of ANGPTL4 E40K and T266M with fasting triglyceride levels was investigated in 2,601 participants from the Look AHEAD Clinical Trial, all of whom had T2D and were at least overweight. Further, we tested for an interaction between genotype and treatment effects on triglyceride levels.
Results
Among non-Hispanic White Look AHEAD participants, ANGPTL4 K40 carriers had mean triglyceride levels of 1.61 ± 0.62 mmol/L, 0.33 mmol/L lower than E40 homozygotes (p = 0.001). Individuals homozygous for the minor M266 allele (MAF 30%) had triglyceride levels of 1.75 ± 0.58 mmol/L, 0.24 mmol/L lower than T266 homozygotes (p = 0.002). The association of the M266 with triglycerides remained significant even after removing K40 carriers from the analysis (p = 0.002). There was no interaction between the weight loss intervention and genotype on triglyceride levels.
Conclusions
This is the first study to demonstrate that the ANGPTL4 E40K and T266M variants are associated with lower triglyceride levels in the setting of T2D. In addition, our findings demonstrate that ANGPTL4 genotype status does not alter triglyceride response to a lifestyle intervention in the Look AHEAD study.
doi:10.1186/1471-2350-12-89
PMCID: PMC3146919  PMID: 21714923
23.  Angptl4 serves as an endogenous inhibitor of intestinal lipid digestion☆ 
Molecular Metabolism  2013;3(2):135-144.
Dietary triglycerides are hydrolyzed in the small intestine principally by pancreatic lipase. Following uptake by enterocytes and secretion as chylomicrons, dietary lipids are cleared from the bloodstream via lipoprotein lipase. Whereas lipoprotein lipase is inhibited by several proteins including Angiopoietin-like 4 (Angptl4), no endogenous regulator of pancreatic lipase has yet been identified. Here we present evidence that Angptl4 is an endogenous inhibitor of dietary lipid digestion. Angptl4−/− mice were heavier compared to their wild-type counterparts without any difference in food intake, energy expenditure or locomotor activity. However, Angptl4−/− mice showed decreased lipid content in the stools and increased accumulation of dietary triglycerides in the small intestine, which coincided with elevated luminal lipase activity in Angptl4−/− mice. Furthermore, recombinant Angptl4 reduced the activity of pancreatic lipase as well as the lipase activity in human ileostomy output. In conclusion, our data suggest that Angptl4 is an endogenous inhibitor of intestinal lipase activity.
doi:10.1016/j.molmet.2013.11.004
PMCID: PMC3953698  PMID: 24634819
Angptl4; Pancreatic lipase; Intestine; Obesity
24.  Short-Chain Fatty Acids Stimulate Angiopoietin-Like 4 Synthesis in Human Colon Adenocarcinoma Cells by Activating Peroxisome Proliferator-Activated Receptor γ 
Molecular and Cellular Biology  2013;33(7):1303-1316.
Angiopoietin-like protein 4 (ANGPTL4/FIAF) has been proposed as a circulating mediator between the gut microbiota and fat storage. Here, we show that transcription and secretion of ANGPTL4 in human T84 and HT29 colon adenocarcinoma cells is highly induced by physiological concentrations of short-chain fatty acids (SCFA). SCFA induce ANGPTL4 by activating the nuclear receptor peroxisome proliferator activated receptor γ (PPARγ), as demonstrated using PPARγ antagonist, PPARγ knockdown, and transactivation assays, which show activation of PPARγ but not PPARα and PPARδ by SCFA. At concentrations required for PPARγ activation and ANGPTL4 induction in colon adenocarcinoma cells, SCFA do not stimulate PPARγ in mouse 3T3-L1 and human SGBS adipocytes, suggesting that SCFA act as selective PPARγ modulators (SPPARM), which is supported by coactivator peptide recruitment assay and structural modeling. Consistent with the notion that fermentation leads to PPAR activation in vivo, feeding mice a diet rich in inulin induced PPAR target genes and pathways in the colon. We conclude that (i) SCFA potently stimulate ANGPTL4 synthesis in human colon adenocarcinoma cells and (ii) SCFA transactivate and bind to PPARγ. Our data point to activation of PPARs as a novel mechanism of gene regulation by SCFA in the colon, in addition to other mechanisms of action of SCFA.
doi:10.1128/MCB.00858-12
PMCID: PMC3624264  PMID: 23339868
25.  Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity 
Oncogene  2006;25(8):1225-1241.
Peroxisome proliferator–activated receptors (PPARs) are transcription factors that strongly influence molecular events in normal and cancer cells. PPAR-beta/delta overexpression suppresses the activity of PPAR-gamma and -alpha. This interaction has been questioned, however, by studies with synthetic ligands of PPARs in PPAR-beta/delta–null cells, and it is not known whether an interaction between PPAR-beta/delta and -gamma exists, especially in relation to the signaling by natural PPAR ligands. Oxidative metabolites of linoleic and arachidonic acids are natural ligands of PPARs. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), the main product of 15-lipoxygenase-1 (15-LOX-1) metabolism of linoleic acid, downregulates PPAR-beta/delta. We tested (a) whether PPAR-beta/delta expression modulates PPAR-gamma activity in experimental models of the loss and gain of PPAR-beta/delta function in colon cancer cells and (b) whether 15-LOX-1 formation of 13-S-HODE influences the interaction between PPAR-beta/delta and PPAR-gamma. We found that (a) 15-LOX-1 formation of 13-S-HODE promoted PPAR-gamma activity, (b) PPAR-beta/delta expression suppressed PPAR-gamma activity in models of both loss and gain of PPAR-beta/delta function, (c) 15-LOX-1 activated PPAR-gamma by downregulating PPAR-beta/delta , and (d) 15-LOX-1 expression induced apoptosis in colon cancer cells via modulating PPAR-beta/delta suppression of PPAR-gamma. These findings elucidate a novel mechanism of the signaling by natural ligands of PPARs, which involves modulating the interaction between PPAR-beta/delta and PPAR-gamma.
doi:10.1038/sj.onc.1209160
PMCID: PMC1432095  PMID: 16288226

Results 1-25 (947853)