γ-Secretase Inhibition Lowers Plasma Triglyceride-Rich Lipoproteins by Stabilizing the LDL Receptor

Cell Metabolism

Volumn 27, Issue 4, 2018, Pages 816-827.e4

  Kim, KyeongJin ^a   Goldberg, Ira J ^b   Graham, Mark J ^c   Sundaram, Meenakshi ^d   Bertaggia, Enrico ^a   Lee, Samuel X ^a   Qiang, Li ^a   Haeusler, Rebecca A ^a   Metzger, Daniel ^e   Chambon, Pierre ^e   Yao, Zemin ^d   Ginsberg, Henry N ^a   Pajvani, Utpal B ^a  

^a Columbia University ^*  (United States)

^b NEW YORK UNIVERSITY   (United States)

^c ISIS PHARMACEUTICALS   (United States)

^d UNIVERSITY OF OTTAWA   (Canada)

^e INSTITUT DE GÉNÉTIQUE ET DE BIOLOGIE MOLÉCULAIRE ET CELLULAIRE   (France)

Author keywords

ASO; gamma secretase; GSI; LDL; LDLR; Nicastrin; triglyceride; VLDL

Indexed keywords

APOLIPOPROTEIN; GAMMA SECRETASE; GLUCOSE; LIPID; LIPOPROTEIN; LOW DENSITY LIPOPROTEIN; LOW DENSITY LIPOPROTEIN RECEPTOR; MESSENGER RNA; NICASTRIN; NOTCH RECEPTOR; PRESENILIN 1; PRESENILIN 2; PROPROTEIN CONVERTASE 9; TRIACYLGLYCEROL; TRIGLYCERIDE RICH LIPOPROTEIN; UNCLASSIFIED DRUG; VERY LOW DENSITY LIPOPROTEIN; LIPOPROTEIN TRIGLYCERIDE; LOW DENSITY LIPOPROTEIN CHOLESTEROL; SECRETASE; VERY LOW DENSITY LIPOPROTEIN CHOLESTEROL;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; ENDOCYTOSIS; ENZYME DEGRADATION; GLUCOSE HOMEOSTASIS; GLUCOSE INTOLERANCE; HUMAN; HUMAN CELL; HYPERTRIGLYCERIDEMIA; LIVER CELL; LIVER CELL CARCINOMA; METABOLIC SYNDROME X; MOUSE; NONHUMAN; NOTCH SIGNALING; OBESITY; PRIORITY JOURNAL; PROTEIN DEGRADATION; TRIACYLGLYCEROL BLOOD LEVEL; ANIMAL; ANTAGONISTS AND INHIBITORS; BLOOD; C57BL MOUSE; CELL CULTURE; CYTOLOGY; DISEASE MODEL; DRUG EFFECT; LIPID METABOLISM; LIVER; MALE; METABOLISM; PATHOLOGY;

AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; CELLS, CULTURED; CHOLESTEROL, LDL; CHOLESTEROL, VLDL; DISEASE MODELS, ANIMAL; GLUCOSE; GLUCOSE INTOLERANCE; HEPATOCYTES; LIPID METABOLISM; LIPOPROTEINS; LIVER; MALE; METABOLIC SYNDROME; MICE; MICE, INBRED C57BL; RECEPTORS, LDL; TRIGLYCERIDES;

EID: 85042869226     PISSN: 15504131     EISSN: 19327420     Source Type: Journal    
DOI: 10.1016/j.cmet.2018.02.010     Document Type: Article

References (78)

1. Adiels, M., Borén, J., Caslake, M.J., Stewart, P., Soro, A., Westerbacka, J., Wennberg, B., Olofsson, S.O., Packard, C., Taskinen, M.R., Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia. Arterioscler. Thromb. Vasc. Biol. 25 (2005), 1697–1703.
2. Altenburg, M., Arbones-Mainar, J., Johnson, L., Wilder, J., Maeda, N., Human LDL receptor enhances sequestration of ApoE4 and VLDL remnants on the surface of hepatocytes but not their internalization in mice. Arterioscler. Thromb. Vasc. Biol. 28 (2008), 1104–1110.
3. Andersson, E.R., Lendahl, U., Therapeutic modulation of Notch signalling—are we there yet?. Nat. Rev. Drug Discov. 13 (2014), 357–378.
4. Arsenault, B.J., Pelletier-Beaumont, E., Alméras, N., Tremblay, A., Poirier, P., Bergeron, J., Després, J.P., PCSK9 levels in abdominally obese men: association with cardiometabolic risk profile and effects of a one-year lifestyle modification program. Atherosclerosis 236 (2014), 321–326.
5. Aster, J.C., Blacklow, S.C., Targeting the Notch pathway: twists and turns on the road to rational therapeutics. J. Clin. Oncol. 30 (2012), 2418–2420.
6. Ayyobi, A.F., Brunzell, J.D., Lipoprotein distribution in the metabolic syndrome, type 2 diabetes mellitus, and familial combined hyperlipidemia. Am. J. Cardiol. 92 (2003), 27J–33J.
7. Bennett, C.F., Swayze, E.E., RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu. Rev. Pharmacol. Toxicol. 50 (2010), 259–293.
8. Berger, J.M., Loza Valdes, A., Gromada, J., Anderson, N., Horton, J.D., Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice. J. Lipid Res. 58 (2017), 1661–1669.
9. Bi, P., Kuang, S., Notch signaling as a novel regulator of metabolism. Trends Endocrinol. Metab. 26 (2015), 248–255.
10. Bishop, J.R., Stanford, K.I., Esko, J.D., Heparan sulfate proteoglycans and triglyceride-rich lipoprotein metabolism. Curr. Opin. Lipidol. 19 (2008), 307–313.
11. Bretscher, M.S., Lutter, R., A new method for detecting endocytosed proteins. EMBO J. 7 (1988), 4087–4092.
12. Brunkan, A.L., Goate, A.M., Presenilin function and gamma-secretase activity. J. Neurochem. 93 (2005), 769–792.
13. Brunzell, J.D., Clinical practice. Hypertriglyceridemia. N. Engl. J. Med. 357 (2007), 1009–1017.
14. Brunzell, J.D., Ayyobi, A.F., Dyslipidemia in the metabolic syndrome and type 2 diabetes mellitus. Am. J. Med. 115:Suppl 8A (2003), 24S–28S.
15. Choi, S.H., Ginsberg, H.N., Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends Endocrinol. Metab. 22 (2011), 353–363.
16. De Jesus-Acosta, A., Laheru, D., Maitra, A., Arcaroli, J., Rudek, M.A., Dasari, A., Blatchford, P.J., Quackenbush, K., Messersmith, W., A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma. Invest. New Drugs 32 (2014), 739–745.
17. De Strooper, B., Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 38 (2003), 9–12.
18. de Vera Mudry, M.C., Regenass-Lechner, F., Ozmen, L., Altmann, B., Festag, M., Singer, T., Müller, L., Jacobsen, H., Flohr, A., Morphologic and functional effects of gamma secretase inhibition on splenic marginal zone B cells. Int. J. Alzheimers Dis., 2012, 2012, 289412.
19. Denko, N.C., Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat. Rev. Cancer 8 (2008), 705–713.
20. Doody, R.S., Raman, R., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., He, F., Sun, X., Thomas, R.G., et al. Alzheimer's Disease Cooperative Study Steering Committee, Semagacestat Study Group. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N. Engl. J. Med. 369 (2013), 341–350.
21. Dutta, D., Williamson, C.D., Cole, N.B., Donaldson, J.G., Pitstop 2 is a potent inhibitor of clathrin-independent endocytosis. PLoS One, 7, 2012, e45799.
22. Everett, B.M., Smith, R.J., Hiatt, W.R., Reducing LDL with PCSK9 inhibitors—the clinical benefit of lipid drugs. N. Engl. J. Med. 373 (2015), 1588–1591.
23. Folch, J., Lees, M., Sloane Stanley, G.H., A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226 (1957), 497–509.
24. Foley, E.M., Gordts, P.L.S.M., Stanford, K.I., Gonzales, J.C., Lawrence, R., Stoddard, N., Esko, J.D., Hepatic remnant lipoprotein clearance by heparan sulfate proteoglycans and low-density lipoprotein receptors depend on dietary conditions in mice. Arterioscler. Thromb. Vasc. Biol. 33 (2013), 2065–2074.
25. Fukuda, D., Aikawa, E., Swirski, F.K., Novobrantseva, T.I., Kotelianski, V., Gorgun, C.Z., Chudnovskiy, A., Yamazaki, H., Croce, K., Weissleder, R., et al. Notch ligand delta-like 4 blockade attenuates atherosclerosis and metabolic disorders. Proc. Natl. Acad. Sci. USA 109 (2012), E1868–E1877.
26. Geisler, F., Strazzabosco, M., Emerging roles of Notch signaling in liver disease. Hepatology 61 (2015), 382–392.
27. Ginsberg, H.N., Le, N.A., Goldberg, I.J., Gibson, J.C., Rubinstein, A., Wang-Iverson, P., Norum, R., Brown, W.V., Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J. Clin. Invest. 78 (1986), 1287–1295.
28. Gordts, P.L., Nock, R., Son, N.H., Ramms, B., Lew, I., Gonzales, J.C., Thacker, B.E., Basu, D., Lee, R.G., Mullick, A.E., et al. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J. Clin. Invest. 126 (2016), 2855–2866.
29. Hemming, M.L., Elias, J.E., Gygi, S.P., Selkoe, D.J., Proteomic profiling of gamma-secretase substrates and mapping of substrate requirements. PLoS Biol., 6, 2008, e257.
30. Hernandez, C., Molusky, M., Li, Y., Li, S., Lin, J.D., Regulation of hepatic ApoC3 expression by PGC-1β mediates hypolipidemic effect of nicotinic acid. Cell Metab. 12 (2010), 411–419.
31. Ito, Y., Azrolan, N., O'Connell, A., Walsh, A., Breslow, J.L., Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice. Science 249 (1990), 790–793.
32. Jiang, C., Qu, A., Matsubara, T., Chanturiya, T., Jou, W., Gavrilova, O., Shah, Y.M., Gonzalez, F.J., Disruption of hypoxia-inducible factor 1 in adipocytes improves insulin sensitivity and decreases adiposity in high-fat diet-fed mice. Diabetes 60 (2011), 2484–2495.
33. Johnson, L.A., Arbones-Mainar, J.M., Fox, R.G., Pendse, A.A., Altenburg, M.K., Kim, H.S., Maeda, N., Apolipoprotein E4 exaggerates diabetic dyslipidemia and atherosclerosis in mice lacking the LDL receptor. Diabetes 60 (2011), 2285–2294.
34. Jong, M.C., Hofker, M.H., Havekes, L.M., Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3. Arterioscler. Thromb. Vasc. Biol. 19 (1999), 472–484.
35. Kim, K., Qiang, L., Hayden, M.S., Sparling, D.P., Purcell, N.H., Pajvani, U.B., mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2. Nat. Commun., 7, 2016, 10255.
36. Kim, K., Ryu, D., Dongiovanni, P., Ozcan, L., Nayak, S., Ueberheide, B., Valenti, L., Auwerx, J., Pajvani, U.B., Degradation of PHLPP2 by KCTD17, via a glucagon-dependent pathway, promotes hepatic steatosis. Gastroenterology 153 (2017), 1568–1580.e10.
37. Lagace, T.A., PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Curr. Opin. Lipidol. 25 (2014), 387–393.
38. Lakoski, S.G., Lagace, T.A., Cohen, J.C., Horton, J.D., Hobbs, H.H., Genetic and metabolic determinants of plasma PCSK9 levels. J. Clin. Endocrinol. Metab. 94 (2009), 2537–2543.
39. Lal, M., Caplan, M., Regulated intramembrane proteolysis: signaling pathways and biological functions. Physiology (Bethesda) 26 (2011), 34–44.
40. Le, N.A., Gibson, J.C., Ginsberg, H.N., Independent regulation of plasma apolipoprotein C-II and C-III concentrations in very low density and high density lipoproteins: implications for the regulation of the catabolism of these lipoproteins. J. Lipid Res. 29 (1988), 669–677.
41. Lee, Y.H., Yun, M.R., Kim, H.M., Jeon, B.H., Park, B.C., Lee, B.W., Kang, E.S., Lee, H.C., Park, Y.W., Cha, B.S., Exogenous administration of DLK1 ameliorates hepatic steatosis and regulates gluconeogenesis via activation of AMPK. Int. J. Obes. 40 (2016), 356–365.
42. Li, X., Zhu, M., Penfold, M.E., Koenen, R.R., Thiemann, A., Heyll, K., Akhtar, S., Koyadan, S., Wu, Z., Gremse, F., et al. Activation of CXCR7 limits atherosclerosis and improves hyperlipidemia by increasing cholesterol uptake in adipose tissue. Circulation 129 (2014), 1244–1253.
43. MacArthur, J.M., Bishop, J.R., Stanford, K.I., Wang, L., Bensadoun, A., Witztum, J.L., Esko, J.D., Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members. J. Clin. Invest. 117 (2007), 153–164.
44. Maeda, N., Li, H., Lee, D., Oliver, P., Quarfordt, S.H., Osada, J., Targeted disruption of the apolipoprotein C-III gene in mice results in hypotriglyceridemia and protection from postprandial hypertriglyceridemia. J. Biol. Chem. 269 (1994), 23610–23616.
45. Mamo, J.C., Watts, G.F., Barrett, P.H., Smith, D., James, A.P., Pal, S., Postprandial dyslipidemia in men with visceral obesity: an effect of reduced LDL receptor expression?. Am. J. Physiol. Endocrinol. Metab. 281 (2001), E626–E632.
46. Masucci-Magoulas, L., Goldberg, I.J., Bisgaier, C.L., Serajuddin, H., Francone, O.L., Breslow, J.L., Tall, A.R., A mouse model with features of familial combined hyperlipidemia. Science 275 (1997), 391–394.
47. Millar, J.S., Cromley, D.A., McCoy, M.G., Rader, D.J., Billheimer, J.T., Determining hepatic triglyceride production in mice: comparison of poloxamer 407 with Triton WR-1339. J. Lipid Res. 46 (2005), 2023–2028.
48. Nishina, P.M., Lowe, S., Wang, J., Paigen, B., Characterization of plasma lipids in genetically obese mice: the mutants obese, diabetes, fat, tubby, and lethal yellow. Metabolism 43 (1994), 549–553.
49. Nordestgaard, B.G., Benn, M., Schnohr, P., Tybjaerg-Hansen, A., Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 298 (2007), 299–308.
50. Norum, R.A., Lakier, J.B., Goldstein, S., Angel, A., Goldberg, R.B., Block, W.D., Noffze, D.K., Dolphin, P.J., Edelglass, J., Bogorad, D.D., Alaupovic, P., Familial deficiency of apolipoproteins A-I and C-III and precocious coronary-artery disease. N. Engl. J. Med. 306 (1982), 1513–1519.
51. Pajvani, U.B., Shawber, C.J., Samuel, V.T., Birkenfeld, A.L., Shulman, G.I., Kitajewski, J., Accili, D., Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. Nat. Med. 17 (2011), 961–967.
52. Pajvani, U.B., Qiang, L., Kangsamaksin, T., Kitajewski, J., Ginsberg, H.N., Accili, D., Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability. Nat. Med. 19 (2013), 1054–1060.
53. Pollin, T.I., Damcott, C.M., Shen, H., Ott, S.H., Shelton, J., Horenstein, R.B., Post, W., McLenithan, J.C., Bielak, L.F., Peyser, P.A., et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 322 (2008), 1702–1705.
54. Real, P.J., Ferrando, A.A., NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia 23 (2009), 1374–1377.
55. Real, P.J., Tosello, V., Palomero, T., Castillo, M., Hernando, E., de Stanchina, E., Sulis, M.L., Barnes, K., Sawai, C., Homminga, I., et al. Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat. Med. 15 (2009), 50–58.
56. Robinson, J.G., Farnier, M., Krempf, M., Bergeron, J., Luc, G., Averna, M., Stroes, E.S., Langslet, G., Raal, F.J., El Shahawy, M., et al., ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372 (2015), 1489–1499.
57. Schonfeld, G., George, P.K., Miller, J., Reilly, P., Witztum, J., Apolipoprotein C-II and C-III levels in hyperlipoproteinemia. Metabolism 28 (1979), 1001–1010.
58. Schuler, M., Dierich, A., Chambon, P., Metzger, D., Efficient temporally controlled targeted somatic mutagenesis in hepatocytes of the mouse. Genesis 39 (2004), 167–172.
59. Selkoe, D.J., Alzheimer's disease: genes, proteins, and therapy. Physiol. Rev. 81 (2001), 741–766.
60. Shih, IeM., Wang, T.L., Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res. 67 (2007), 1879–1882.
61. Sparling, D.P., Yu, J., Kim, K., Zhu, C., Brachs, S., Birkenfeld, A.L., Pajvani, U.B., Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity. Mol. Metab. 5 (2015), 113–121.
62. Stanford, K.I., Bishop, J.R., Foley, E.M., Gonzales, J.C., Niesman, I.R., Witztum, J.L., Esko, J.D., Syndecan-1 is the primary heparan sulfate proteoglycan mediating hepatic clearance of triglyceride-rich lipoproteins in mice. J. Clin. Invest. 119 (2009), 3236–3245.
63. Sundaram, M., Zhong, S., Bou Khalil, M., Links, P.H., Zhao, Y., Iqbal, J., Hussain, M.M., Parks, R.J., Wang, Y., Yao, Z., Expression of apolipoprotein C-III in McA-RH7777 cells enhances VLDL assembly and secretion under lipid-rich conditions. J. Lipid Res. 51 (2010), 150–161.
64. Tabuchi, K., Chen, G., Südhof, T.C., Shen, J., Conditional forebrain inactivation of nicastrin causes progressive memory impairment and age-related neurodegeneration. J. Neurosci. 29 (2009), 7290–7301.
65. Tomita, T., Watabiki, T., Takikawa, R., Morohashi, Y., Takasugi, N., Kopan, R., De Strooper, B., Iwatsubo, T., The first proline of PALP motif at the C terminus of presenilins is obligatory for stabilization, complex formation, and gamma-secretase activities of presenilins. J. Biol. Chem. 276 (2001), 33273–33281.
66. Tveten, K., Strøm, T.B., Berge, K.E., Leren, T.P., PCSK9-mediated degradation of the LDL receptor generates a 17 kDa C-terminal LDL receptor fragment. J. Lipid Res. 54 (2013), 1560–1566.
67. Valenti, L., Mendoza, R.M., Rametta, R., Maggioni, M., Kitajewski, C., Shawber, C.J., Pajvani, U.B., Hepatic notch signaling correlates with insulin resistance and nonalcoholic fatty liver disease. Diabetes 62 (2013), 4052–4062.
68. van Driel, I.R., Davis, C.G., Goldstein, J.L., Brown, M.S., Self-association of the low density lipoprotein receptor mediated by the cytoplasmic domain. J. Biol. Chem. 262 (1987), 16127–16134.
69. van Es, J.H., van Gijn, M.E., Riccio, O., van den Born, M., Vooijs, M., Begthel, H., Cozijnsen, M., Robine, S., Winton, D.J., Radtke, F., Clevers, H., Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435 (2005), 959–963.
70. Villa, J.C., Chiu, D., Brandes, A.H., Escorcia, F.E., Villa, C.H., Maguire, W.F., Hu, C.J., de Stanchina, E., Simon, M.C., Sisodia, S.S., et al. Nontranscriptional role of Hif-1α in activation of γ-secretase and notch signaling in breast cancer. Cell Rep. 8 (2014), 1077–1092.
71. von Kleist, L., Stahlschmidt, W., Bulut, H., Gromova, K., Puchkov, D., Robertson, M.J., MacGregor, K.A., Tomilin, N., Pechstein, A., Chau, N., et al. Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition. Cell 146 (2011), 471–484.
72. Vujovic, S., Henderson, S.R., Flanagan, A.M., Clements, M.O., Inhibition of gamma-secretases alters both proliferation and differentiation of mesenchymal stem cells. Cell Prolif. 40 (2007), 185–195.
73. Wang, Y., Tran, K., Yao, Z., The activity of microsomal triglyceride transfer protein is essential for accumulation of triglyceride within microsomes in McA-RH7777 cells. A unified model for the assembly of very low density lipoproteins. J. Biol. Chem. 274 (1999), 27793–27800.
74. Wei, P., Walls, M., Qiu, M., Ding, R., Denlinger, R.H., Wong, A., Tsaparikos, K., Jani, J.P., Hosea, N., Sands, M., et al. Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Mol. Cancer Ther. 9 (2010), 1618–1628.
75. Wolfe, M.S., The gamma-secretase complex: membrane-embedded proteolytic ensemble. Biochemistry 45 (2006), 7931–7939.
76. Wolfe, M.S., Kopan, R., Intramembrane proteolysis: theme and variations. Science 305 (2004), 1119–1123.
77. Zelcer, N., Hong, C., Boyadjian, R., Tontonoz, P., LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325 (2009), 100–104.
78. Zheng, C., Updates on apolipoprotein CIII: fulfilling promise as a therapeutic target for hypertriglyceridemia and cardiovascular disease. Curr. Opin. Lipidol. 25 (2014), 35–39.