PCSK9 mediates dyslipidemia induced by olanzapine treatment in schizophrenia patients.
Dyslipidemia
LDL-C
Olanzapine
PCSK9
SREBP-1c
SREBP-2
Schizophrenia
Journal
Psychopharmacology
ISSN: 1432-2072
Titre abrégé: Psychopharmacology (Berl)
Pays: Germany
ID NLM: 7608025
Informations de publication
Date de publication:
Jan 2022
Jan 2022
Historique:
received:
30
08
2021
accepted:
02
12
2021
pubmed:
15
1
2022
medline:
22
1
2022
entrez:
14
1
2022
Statut:
ppublish
Résumé
It is controversial whether dyslipidemia induced by antipsychotics in schizophrenia patients is due to weight gain or direct effects of drug treatment. However, recent evidence showed that olanzapine can cause acute dyslipidemia independent of weight change, and the underlying mechanism remains unclear. To study the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in olanzapine-induced dyslipidemia, we analyzed in schizophrenic patients and in experimental models involving mice and cells to understand the mechanism. Disturbances in lipid homeostasis caused by 8-week olanzapine treatment were prospectively evaluated in first-episode schizophrenic patients. Additionally, mice were administered olanzapine for 5 or 8 weeks to delineate liver actions for PCSK9 contributing to olanzapine-induced dyslipidemia. Olanzapine directly affected lipid metabolism, suggesting dyslipidemia is independent of weight gain in schizophrenia patients. Olanzapine administration significantly increased plasma PCSK9, which was positively correlated with the increment in low-density lipoprotein cholesterol (LDL-C) (r=0.77, p<0.001). Increased expression of PCSK9 in liver tissue of olanzapine-treated mice occurred prior to olanzapine-induced LDL-C abnormality. Hepatic sterol regulatory element binding protein-2 (SREBP-2) protein levels increased in mice treated with olanzapine but largely declined in olanzapine (10μM) treated HepG2 cells, which suggested high concentration of olanzapine-induced PCSK9 increase was not SREBP-2-dependent. However, expressions of sterol regulatory element binding protein-1c (SREBP-1c) significantly increased in the higher dose treated groups, which was consistent with PCSK9 increases. Activation of SREBP-1c after high-dose olanzapine treatment promotes PSCK9 expression, and consequently the degradation of low-density lipoprotein receptors results in LDL-C increase. Lipid disturbances caused by olanzapine are independent of weight gain. The study explored the relationship between SREBP-1c and PCSK9 in regulating lipoprotein metabolism after olanzapine treatment in vitro and in vivo. Further exploration of olanzapine-induced PCSK9 regulatory mechanisms may help identify control points for inhibition of olanzapine-mediated dyslipidemia.
Identifiants
pubmed: 35029705
doi: 10.1007/s00213-021-06042-z
pii: 10.1007/s00213-021-06042-z
doi:
Substances chimiques
PCSK9 protein, human
EC 3.4.21.-
Pcsk9 protein, mouse
EC 3.4.21.-
Proprotein Convertase 9
EC 3.4.21.-
Olanzapine
N7U69T4SZR
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
83-91Subventions
Organisme : the National Nature Science Foundation of China
ID : 81622018
Organisme : Innovative Research Group Project of the National Natural Science Foundation of China
ID : 81901401
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Abifadel M, Rabès JP, Devillers M, Munnich A, Erlich D, Junien C, Varret M, Boileau C (2009) Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum Mutat 30:520–529
doi: 10.1002/humu.20882
Abifadel M, Varret M, Rabès J-P, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34:154–156
doi: 10.1038/ng1161
Aringhieri S, Carli M, Kolachalam S, Verdesca V, Cini E, Rossi M, McCormick PJ, Corsini GU, Maggio R, Scarselli M (2018) Molecular targets of atypical antipsychotics: from mechanism of action to clinical differences. Pharmacol Ther 192:20–41
doi: 10.1016/j.pharmthera.2018.06.012
Aringhieri S, Kolachalam S, Gerace C, Carli M, Verdesca V, Brunacci MG, Rossi C, Ippolito C, Solini A, Corsini GU, Scarselli M (2017) Clozapine as the most efficacious antipsychotic for activating ERK 1/2 kinases: role of 5-HT receptor agonism. Eur Neuropsychopharmacol 27:383–398
doi: 10.1016/j.euroneuro.2017.02.005
Bushe CJ, Taylor M, Haukka J (2010) Mortality in schizophrenia: a measurable clinical endpoint. J Psychopharmacol 24:17–25
doi: 10.1177/1359786810382468
Cariou B, Langhi C, Le Bras M, Bortolotti M, Lê K-A, Theytaz F, Le May C, Guyomarc’h-Delasalle B, Zaïr Y, Kreis R (2013) Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets. Nutr Metab 10:4
doi: 10.1186/1743-7075-10-4
Carli M, Kolachalam S, Longoni B, Pintaudi A, Baldini M, Aringhieri S, Fasciani I, Annibale P, Maggio R, Scarselli M (2021) Atypical antipsychotics and metabolic syndrome: from molecular mechanisms to clinical differences. Pharmaceuticals (Basel) 14:3
Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 37:161–165
doi: 10.1038/ng1509
Costet P, Cariou B, Lambert G, Lalanne F, Lardeux B, Jarnoux A-L, Grefhorst A, Staels B, Krempf M (2006) Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c. J Biol Chem 281:6211–6218
doi: 10.1074/jbc.M508582200
Council NR (2010) Guide for the care and use of laboratory animals, 8th edn. The National Academies Press, Washington
Dasgupta A, Singh OP, Rout JK, Saha T, Mandal S (2010) Insulin resistance and metabolic profile in antipsychotic naive schizophrenia patients. Prog Neuro-Psychopharmacol Biol Psychiatry 34:1202–1207
doi: 10.1016/j.pnpbp.2010.06.011
Haas JT, Miao J, Chanda D, Wang Y, Zhao E, Haas ME, Hirschey M, Vaitheesvaran B, Farese RV Jr, Kurland IJ (2012) Hepatic insulin signaling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expression. Cell Metab 15:873–884
doi: 10.1016/j.cmet.2012.05.002
Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, Goldstein JL (2003) Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci 100:12027–12032
doi: 10.1073/pnas.1534923100
Hu D-Y (2017) New guidelines and evidence for prevention and treatment of dyslipidemia and atherosclerotic cardiovascular disease in China. Chronic Dis Transl Med 3:73
pubmed: 29063058
Huang J, Hei G-R, Yang Y, Liu C-C, Xiao J-M, Long Y-J, Peng X-J, Yang Y, Zhao J-P, Wu R-R (2020) Increased appetite plays a key role in olanzapine-induced weight gain in. Front Pharmacol 11:739
doi: 10.3389/fphar.2020.00739
Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, Arndt T, Bäckers L, Rothe P, Cipriani A (2019) Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia:a systematic review and network meta-analysis. Lancet 394:939–951
doi: 10.1016/S0140-6736(19)31135-3
Humphries S, Whittall R, Hubbart C, Maplebeck S, Cooper J, Soutar A, Naoumova R, Thompson G, Seed M, Durrington P (2006) Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J Med Genet 43:943–949
doi: 10.1136/jmg.2006.038356
Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL, Cohen JC, Hobbs HH (2006) A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet 78:410–422
doi: 10.1086/500615
Lagace TA (2014) PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Curr Opin Lipidol 25:387
doi: 10.1097/MOL.0000000000000114
Laursen TM, Nordentoft M, Mortensen PB (2014) Excess early mortality in schizophrenia. Annu Rev Clin Psychol 10:425–48
doi: 10.1146/annurev-clinpsy-032813-153657
Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lassig B, Salanti G, Davis JM (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382:951–62
doi: 10.1016/S0140-6736(13)60733-3
Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM (2009) Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373:31–41
doi: 10.1016/S0140-6736(08)61764-X
Li R, Zhang Y, Zhu W, Ding C, Dai W, Su X, Dai W, Xiao J, Xing Z, Huang X (2020) Effects of olanzapine treatment on lipid profiles in patients with schizophrenia: a systematic review and meta-analysis. Sci Rep 10:17028
doi: 10.1038/s41598-020-73983-4
Liu X, Deng C, Cao S, Gong J, Wang BC, Hu CH (2015) Acute effects of oral olanzapine treatment on the expression of fatty acid and cholesterol metabolism-related gene in rats. Life Sci 128:72–8
doi: 10.1016/j.lfs.2015.01.033
Maxwell KN, Breslow JL (2004) Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci 101:7100–7105
doi: 10.1073/pnas.0402133101
Nahmias A, Stahel P, Dash S (2020) Assessment of lipid response to acute olanzapine administration in healthy adults. Endocrinol Diabetes Metab 3:e00119
pubmed: 32318637
pmcid: 7170459
Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho Y, Hammer RE, Moon Y-A, Horton JD (2005) Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci 102:5374–5379
doi: 10.1073/pnas.0501652102
Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R, Wu R, Pordy R (2012) Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 380:29–36
doi: 10.1016/S0140-6736(12)60771-5
Tomasik J, Lago SG, Vázquez-Bourgon J, Papiol S, Suárez-Pinilla P, Crespo-Facorro B, Bahn S (2019) Association of insulin resistance with schizophrenia polygenic risk score and response to antipsychotic treatment. JAMA Psychiatry 76:864–867
doi: 10.1001/jamapsychiatry.2019.0304
Wu R, Zhang F, Gao K, Ou J, Shao P, Jin H, Guo W, Chan P, Zhao J (2016) Metformin treatment of antipsychotic-induced dyslipidemia: an analysis of two randomized, placebo-controlled trials. Mol Psychiatry 21:1537
doi: 10.1038/mp.2015.221