Rensen PC

References (7)

Title : Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding - Deng_2017_J.Med.Chem_60_428
Author(s) : Deng H , Kooijman S , van den Nieuwendijk AM , Ogasawara D , van der Wel T , van Dalen F , Baggelaar MP , Janssen FJ , van den Berg RJ , den Dulk H , Cravatt BF , Overkleeft HS , Rensen PC , van der Stelt M
Ref : Journal of Medicinal Chemistry , 60 :428 , 2017
Abstract : Triazole ureas constitute a versatile class of irreversible inhibitors that target serine hydrolases in both cells and animal models. We have previously reported that triazole ureas can act as selective and CNS-active inhibitors for diacylglycerol lipases (DAGLs), enzymes responsible for the biosynthesis of 2-arachidonoylglycerol (2-AG) that activates cannabinoid CB1 receptor. Here, we report the enantio- and diastereoselective synthesis and structure-activity relationship studies. We found that 2,4-substituted triazole ureas with a biphenylmethanol group provided the most optimal scaffold. Introduction of a chiral ether substituent on the 5-position of the piperidine ring provided ultrapotent inhibitor 38 (DH376) with picomolar activity. Compound 38 temporarily reduces fasting-induced refeeding of mice, thereby emulating the effect of cannabinoid CB1-receptor inverse agonists. This was mirrored by 39 (DO34) but also by the negative control compound 40 (DO53) (which does not inhibit DAGL), which indicates the triazole ureas may affect the energy balance in mice through multiple molecular targets.
ESTHER : Deng_2017_J.Med.Chem_60_428
PubMedSearch : Deng_2017_J.Med.Chem_60_428
PubMedID: 27992221

Title : Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise - Catoire_2014_Proc.Natl.Acad.Sci.U.S.A_111_E1043
Author(s) : Catoire M , Alex S , Paraskevopulos N , Mattijssen F , Evers-van Gogh I , Schaart G , Jeppesen J , Kneppers A , Mensink M , Voshol PJ , Olivecrona G , Tan NS , Hesselink MK , Berbee JF , Rensen PC , Kalkhoven E , Schrauwen P , Kersten S
Ref : Proc Natl Acad Sci U S A , 111 :E1043 , 2014
Abstract : Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise encodes angiopoietin-like 4 (ANGPTL4), an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. Using a combination of human, animal, and in vitro data, we show that induction of ANGPTL4 in nonexercising muscle is mediated by elevated plasma free fatty acids via peroxisome proliferator-activated receptor-, presumably leading to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. In contrast, the induction of ANGPTL4 in exercising muscle likely is counteracted via AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles. Our data suggest that nonexercising muscle and the local regulation of ANGPTL4 via AMPK and free fatty acids have key roles in governing lipid homeostasis during exercise.
ESTHER : Catoire_2014_Proc.Natl.Acad.Sci.U.S.A_111_E1043
PubMedSearch : Catoire_2014_Proc.Natl.Acad.Sci.U.S.A_111_E1043
PubMedID: 24591600

Title : Effect of plasma triglyceride metabolism on lipid storage in adipose tissue: studies using genetically engineered mouse models - Voshol_2009_Biochim.Biophys.Acta_1791_479
Author(s) : Voshol PJ , Rensen PC , van Dijk KW , Romijn JA , Havekes LM
Ref : Biochimica & Biophysica Acta , 1791 :479 , 2009
Abstract : The obesity epidemic is associated with an increased incidence of type 2 diabetes, cardiovascular morbidity and various types of cancer. A better insight into the molecular mechanisms that underlie adipogenesis and obesity may result in novel therapeutic handles to fight obesity and these associated diseases. Adipogenesis is determined by the balance between uptake of fatty acids (FA) from plasma into adipocytes, intracellular FA oxidation versus esterification of FA into triglycerides (TG), lipolysis of TG by intracellular lipases, and secretion of FA from adipocytes. Here, we review the mechanisms that are specifically involved in the entry of FA into adipose tissue. In plasma, these originating FA are either present as TG within apoB-containing lipoproteins (i.e. chylomicrons and VLDL) or as free FA bound to albumin. Kinetic studies, however, have revealed that TG are the major source of FA entering adipose tissue, both in the fed and fasted condition. In fact, studies with genetically engineered mice have revealed that the activity of lipoprotein lipase (LPL) is a major determinant for the development of obesity. As a general rule, high fat diet-induced adipogenesis is aggravated by stimulated LPL activity (e.g. by adipose tissue-specific overexpression of LPL or deficiency for apoCIII), and attenuated by inhibited LPL activity (e.g. by adipose-specific deficiency for LPL, overexpression of apoCI or angptl4, or by deficiency for apoE or the VLDL receptor). In addition, we describe that the trans-membrane transport of FA and cytoplasmic binding of FA in adipocytes can also dramatically affect adipogenesis. The relevance of these findings for human pathophysiology is discussed.
ESTHER : Voshol_2009_Biochim.Biophys.Acta_1791_479
PubMedSearch : Voshol_2009_Biochim.Biophys.Acta_1791_479
PubMedID: 19168150

Title : Ritonavir impairs lipoprotein lipase-mediated lipolysis and decreases uptake of fatty acids in adipose tissue - den Boer_2006_Arterioscler.Thromb.Vasc.Biol_26_124
Author(s) : den Boer MA , Berbee JF , Reiss P , van der Valk M , Voshol PJ , Kuipers F , Havekes LM , Rensen PC , Romijn JA
Ref : Arterioscler Thromb Vasc Biol , 26 :124 , 2006
Abstract : OBJECTIVE: The use of the HIV protease inhibitor ritonavir (RTV) is frequently associated with hypertriglyceridemia and lipodystrophy. The aim of our study was to determine the mechanism underlying the observed hypertriglyceridemia. METHODS AND
RESULTS: Feeding female APOE*3-Leiden transgenic mice a Western-type diet supplemented with RTV (35 mg/kg per day) for 2 weeks resulted in a 2-fold increase in fasting plasma triglyceride (TG) levels, which was specific for very low-density lipoprotein (VLDL). RTV did not change the hepatic VLDL-TG production. Instead, RTV did increase the postprandial TG response to an oral fat load (area under the curve, 25.5+/-12.1 versus 13.8+/-6.8 mmol/L per hour in controls; P<0.05). Likewise, RTV hampered the plasma clearance of intravenously injected glycerol tri[3H]oleate-labeled VLDL-like emulsion particles (half time, 19.3+/-10.5 versus 5.0+/-1.3 minutes in controls; P<0.05) associated with a decrease of 44% in plasma lipoprotein lipase activity. Accordingly, RTV decreased the uptake of TG-derived fatty acids (FAs) into adipose tissue, as well as the uptake of albumin-bound FA.
CONCLUSIONS: We conclude that RTV causes hypertriglyceridemia via decreased lipoprotein lipase-mediated clearance of VLDL-TG. In addition, RTV specifically impairs the uptake of FA in adipose tissue, which may contribute to the lipodystrophy that is frequently observed in HIV-infected subjects on antiretroviral therapy.
ESTHER : den Boer_2006_Arterioscler.Thromb.Vasc.Biol_26_124
PubMedSearch : den Boer_2006_Arterioscler.Thromb.Vasc.Biol_26_124
PubMedID: 16269669

Title : Apolipoprotein CI causes hypertriglyceridemia independent of the very-low-density lipoprotein receptor and apolipoprotein CIII in mice - van der Hoogt_2006_Biochim.Biophys.Acta_1761_213
Author(s) : van der Hoogt CC , Berbee JF , Espirito Santo SM , Gerritsen G , Krom YD , van der Zee A , Havekes LM , van Dijk KW , Rensen PC
Ref : Biochimica & Biophysica Acta , 1761 :213 , 2006
Abstract : We have recently shown that the predominant hypertriglyceridemia in human apolipoprotein C1 (APOC1) transgenic mice is mainly explained by apoCI-mediated inhibition of the lipoprotein lipase (LPL)-dependent triglyceride (TG)-hydrolysis pathway. Since the very-low-density lipoprotein receptor (VLDLr) and apoCIII are potent modifiers of LPL activity, our current aim was to study whether the lipolysis-inhibiting action of apoCI would be dependent on the presence of the VLDLr and apoCIII in vivo. Hereto, we employed liver-specific expression of human apoCI by using a novel recombinant adenovirus (AdAPOC1). In wild-type mice, moderate apoCI expression leading to plasma human apoCI levels of 12-33 mg/dl dose-dependently and specifically increased plasma TG (up to 6.6-fold, P < 0.001), yielding the same hypertriglyceridemic phenotype as observed in human APOC1 transgenic mice. AdAPOC1 still increased plasma TG in vldlr(-/-) mice (4.1-fold, P < 0.001) and in apoc3(-/-) mice (6.8-fold, P < 0.001) that were also deficient for the low-density lipoprotein receptor (LDLr) and LDLr-related protein (LRP) or apoE, respectively. Thus, irrespective of receptor-mediated remnant clearance by the liver, liver-specific expression of human apoCI causes hypertriglyceridemia in the absence of the VLDLr and apoCIII. We conclude that apoCI is a powerful and direct inhibitor of LPL activity independent of the VLDLr and apoCIII.
ESTHER : van der Hoogt_2006_Biochim.Biophys.Acta_1761_213
PubMedSearch : van der Hoogt_2006_Biochim.Biophys.Acta_1761_213
PubMedID: 16478678

Title : CD36 deficiency in mice impairs lipoprotein lipase-mediated triglyceride clearance - Goudriaan_2005_J.Lipid.Res_46_2175
Author(s) : Goudriaan JR , den Boer MA , Rensen PC , Febbraio M , Kuipers F , Romijn JA , Havekes LM , Voshol PJ
Ref : J Lipid Res , 46 :2175 , 2005
Abstract : CD36 is involved in high-affinity peripheral FFA uptake. CD36-deficient (cd36(-)(/)(-)) mice exhibit increased plasma FFA and triglyceride (TG) levels. The aim of the present study was to elucidate the cause of the increased plasma TG levels in cd36(-)(/)(-) mice. cd36(-)(/)(-) mice showed no differences in hepatic VLDL-TG production or intestinal [(3)H]TG uptake compared with wild-type littermates. cd36(-)(/)(-) mice showed a 2-fold enhanced postprandial TG response upon an intragastric fat load (P < 0.05), with a concomitant 2.5-fold increased FFA response (P < 0.05), suggesting that the increased FFA in cd36(-/-) mice may impair LPL-mediated TG hydrolysis. Postheparin LPL levels were not affected. However, the in vitro LPL-mediated TG hydrolysis rate as induced by postheparin plasma of cd36(-)(/)(-) mice in the absence of excess FFA-free BSA was reduced 2-fold compared with wild-type plasma (P < 0.05). This inhibition was relieved upon the addition of excess FFA-free BSA. Likewise, increasing plasma FFA in wild-type mice to the levels observed in cd36(-)(/)(-) mice by infusion prolonged the plasma half-life of glycerol tri[(3)H]oleate-labeled VLDL-like emulsion particles by 2.5-fold (P < 0.05). We conclude that the increased plasma TG levels observed in cd36(-)(/)(-) mice are caused by decreased LPL-mediated hydrolysis of TG-rich lipoproteins resulting from FFA-induced product inhibition of LPL.
ESTHER : Goudriaan_2005_J.Lipid.Res_46_2175
PubMedSearch : Goudriaan_2005_J.Lipid.Res_46_2175
PubMedID: 16024917

Title : ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis - Schaap_2004_J.Biol.Chem_279_27941
Author(s) : Schaap FG , Rensen PC , Voshol PJ , Vrins C , van der Vliet HN , Chamuleau RA , Havekes LM , Groen AK , van Dijk KW
Ref : Journal of Biological Chemistry , 279 :27941 , 2004
Abstract : ApoAV has been discovered recently as a novel modifier of triglyceride (TG) metabolism, but the pathways involved are currently unknown. To gain insight into the function of apoAV, adenovirus-mediated gene transfer of murine apoa5 to C57Bl/6 mice was employed. The injection of low doses of Ad-apoa5 (1-5 x 10(8) plaqueforming units/mouse) dose-dependently reduced plasma very low density lipoprotein (VLDL)-TG levels. First, we evaluated whether a reduced hepatic VLDL production contributed to the TG-lowering effect. Ad-apoa5 treatment dose-dependently diminished (29-37%) the VLDL-TG production rate without affecting VLDL particle production, suggesting that apoAV impairs the lipidation of apoB. Second, Ad-apoa5 treatment dose-dependently reduced (68-88%) the postprandial hypertriglyceridemia following an intragastric fat load, suggesting that apoAV also stimulates the lipoprotein lipase (LPL)-dependent clearance of TG-rich lipoproteins. Indeed, recombinant apoAV was found to dose-dependently stimulate LPL activity up to 2.3-fold in vitro. Accordingly, intravenously injected VLDL-like TG-rich emulsions were cleared at an accelerated rate concomitant with the increased uptake of emulsion TG-derived fatty acids by skeletal muscle and white adipose tissue in Ad-apoa5-treated mice. From these data, we conclude that apoAV is a potent stimulator of LPL activity. Thus, apoAV lowers plasma TG by both reducing the hepatic VLDL-TG production rate and by enhancing the lipolytic conversion of TG-rich lipoproteins.
ESTHER : Schaap_2004_J.Biol.Chem_279_27941
PubMedSearch : Schaap_2004_J.Biol.Chem_279_27941
PubMedID: 15090553