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Functional Characterization of the PPAR Targets ANGPTL4 and HILPDA in Lipid Metabolism

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Functional Characterization of the PPAR Targets ANGPTL4 and HILPDA in Lipid Metabolism Functional characterization of the PPAR targets ANGPTL4 and HILPDA in lipid metabolism Frits Mattijssen Thesis committee Promotor Prof. Dr A.H. Kersten Personal chair at the Division of Human Nutrition Wageningen University Other members Prof. Dr M.K. Hesselink, Maastricht University Dr J.W. Jonker, University Medical Center Groningen Prof. Dr P.C.N. Rensen, Leiden University Medical Center Prof. Dr D. Weijers, Wageningen University This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). Functional characterization of the PPAR targets ANGPTL4 and HILPDA in lipid metabolism Frits Mattijssen Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. Dr M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Thursday 15 May 2014 at 11 a.m. in the Aula. Frits Mattijssen Functional characterization of the PPAR targets ANGPTL4 and HILPDA in lipid metabolism 194 pages PhD thesis, Wageningen University, Wageningen, The Netherlands (2014) With references, with summaries in Dutch and English ISBN: 978-94-6173-908-7 Abstract The peroxisomal proliferator activator receptors (PPARs) are ligand-activated transcription factors that play important roles in the regulation of lipid metabolism. Three PPAR isoforms have been identified: PPARα, PPARβ/δ, and PPARγ. Each isoform has specific functions determined by their relative abundance in a cell and regulation of specific target genes. A highly sensitive PPAR target gene is represented by Angiopoietin-like 4 (ANGPTL4), which was discovered by three independent groups in 2000. ANGPTL4 is produced in a number of organs including liver and adipose tissue, where its expression is governed by PPARα and PPARγ, respectively. Upon secretion, ANGPTL4 is cleaved into N- and C-terminal fragments that have divergent functions. nANGPTL4 is known to function as an inhibitor of lipoprotein lipase, whereas cANGPTL4 is involved in a number of processes including tumorigenesis and wound healing, and is known to interact with integrins β1 and β5. In this thesis we set out to expand our knowledge on the molecular function of ANGPTL4 in the regulation of lipid metabolism. We performed animal experiments, cell culture, biochemical assays, and other functional measurements to zoom in on previously unexplored aspects of ANGPTL4. Feeding mice deficient in ANGPLT4 a diet rich in long-chain saturated fatty acids elicited a complex phenotype and Angptl4–/– mice ultimately died from fibrinopurulent peritonitis. In contrast, the lethal phenotype was not observed when the fat component of the high-fat diet was changed to medium-chain fatty acids, suggesting a role for increased chyle flow via the lymphatic system. Indeed, Angptl4–/– mice had dramatically enlarged mesenteric lymph nodes which contained numerous lipid laden macrophages. In vitro experiments showed that PPARβ/δ-mediated induction of ANGPTL4 results in inhibition of macrophage LPL. In the absence of ANGPTL4, lipid uptake in mesenteric lymph node resident macrophages is increased, leading to ER stress and subsequent pro-inflammatory response. Additionally, Angptl4–/– mice initially gain more weight when fed a high-fat diet. The increased body weight and adiposity was unrelated to food intake, activity, or energy expenditure. Remarkably, we observed decreased fecal lipid excretion in Angptl4–/– mice, which coincided with increased lipase activity in the intestinal lumen. Using biochemical assays we reveal that ANGPTL4 inhibits pancreatic lipase. In the second part of this thesis we identify a novel PPAR target gene named hypoxia inducible lipid droplet associated (HILPDA). We observed Hilpda expression to be increased in liver slices exposed to a synthetic PPARα ligand. Additionally, oral dosing of similar ligand induced a marked increase in HILPDA expression in livers of wild-type mice but not Ppara–/– mice. Induction of HILPDA expression by PPAR was found to be mediated by a conserved and functional PPAR response element located 1200 base pair upstream of the transcription start site of Hilpda. Functional characterization of HILPDA in liver was performed via adeno-associated virus-mediated overexpression. Interestingly, increased hepatic expression of HILPDA was associated with the development of a fatty liver, which could be attributed to a decrease in hepatic very low-density lipoprotein (VLDL) production. HILPDA was also found to be highly expressed in both human and mouse adipose tissue, where its expression is under the control of PPARγ and β-adrenergic receptor. Moreover, adipose tissue HILPDA expression was increased with fasting but decreased with high-fat feeding. HILPDA did not affect 3T3-L1 adipogenesis. Furthermore, adipose tissue specific Hilpda knock-out mice showed no major metabolic perturbations upon fasting. However, overexpression of HILPDA in adipocytes significantly reduced the release of NEFAs upon β-adrenergic receptor activation. Induction of HILPDA by β-adrenergic receptor stimulation may be part of feedback mechanism to regulate adipocyte lipolysis. In conclusion, in thesis we have extended the current knowledge on the function of ANGPTL4. We show that ANGPTL4 serves as an important regulator in the process of lipid digestion and in the protection of macrophages that reside in mesenteric lymph nodes. HILPDA is a novel PPAR target that is involved in hepatic VLDL secretion and adipocyte lipolysis. Future research will focus on elucidating the mechanistic aspects of the regulation and function of HILPDA in liver and adipose tissue. Contents Chapter 1 General introduction 9 Chapter 2 Regulation of triglyceride metabolism by Angiopoietin-like 21 proteins Chapter 3 ANGPTL4 protects against severe proinflammatory effects of 43 saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages Chapter 4 ANGPTL4 serves as an endogenous inhibitor of intestinal lipid 83 digestion Chapter 5 Hypoxia inducible lipid droplet associated (HILPDA) is a novel 105 PPAR target involved in hepatic triglyceride secretion Chapter 6 Hypoxia inducible lipid droplet associated (HILPDA) is a PPARγ 135 and β-adrenergic receptor target gene involved in adipose tissue lipolysis Chapter 7 General discussion 165 Nederlandse samenvatting 181 Dankwoord 185 About the author 189 1 General introduction Chapter 1 Lipid digestion Our diet contains three major macronutrients that can provide energy: carbohydrates, lipids, and proteins. Carbohydrates and proteins yield 4 kcal of energy per gram whereas lipids contribute 9 kcal of energy per gram. Around 34% of the energy in the current diet of the Dutch population is derived from lipids, which corresponds to 70-105 gram of fat per day, depending on age and gender (1). Dietary fat mainly consists of triglycerides (TGs) (95%), with minor fractions of phospholipids and cholesteryl esters. The human body is able to extract > 90% of these TGs with the aid of several lipases. Digestion of TGs starts in the mouth by the enzyme lingual lipase followed by contractions of the stomach to mix lipids with water, gastric acid, and gastric lipase secreted by the chief cells of the stomach (2). However, the major fraction of dietary lipids is digested in the small intestine (3). In the duodenum, the predigested food is emulsified with bile acids to allow for efficient digestion. At the same time, the pancreas releases several digestive enzymes including lipases such as pancreatic lipase (PL), carboxyl ester hydrolase, and pancreatic lipase-related protein 2 (3). Among those PL is the major lipase involved in the digestion of dietary lipids and hydrolyzes the ester bonds at the sn-1 and sn-3 positions of TGs (3). PL is a carboxyl esterase that is part of the family of extracellular lipases that includes lipoprotein lipase (LPL), hepatic lipase, and endothelial lipase (4). Inhibition of PL by pharmacological inhibitors such as Orlistat lowers the amount of lipid that is digested and subsequently absorbed by 30% and is used in the treatment of obesity (5). Similarly, many plant-derived components have been found to inhibit PL (6). Following PL mediated hydrolysis, 2-monoacylglycerol (2-MG) and fatty acids mix with bile acids to form micelles that subsequently migrate to the apical membrane of enterocytes (7). The precise mechanisms by which 2-MG and fatty acids enter enterocytes are not completely understood and several mechanism including passive diffusion and active transport via transporters such as CD36 and fatty acid binding proteins (FABPs) have been postulated (7, 8). Chylomicron formation and secretion Once taken up by enterocytes, 2-MG and fatty acids are re-esterified into TGs catalyzed by several monoacylglycerol acyltransferase (MGAT) and acyl-coenzyme A: diacylglycerol acyltransferase (DGAT) enzymes localized at the surface of the endoplasmic reticulum (ER) (9-11). Within the rough ER, apolipoprotein B48 (APOB48) is lipidated by the enzyme microsomal triglyceride transfer protein (MTTP) to form a primordial particle 10 General introduction (12, 13). These particles fuse with intraluminal ER-associated lipid droplets to form pre-chylomicrons that are subsequently transported to the Golgi via transport vesicles (14). After maturation in the Golgi, the chylomicrons are subsequently secreted into 1 intercellular space by exocytosis after which the chylomicrons
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