title: Spontaneous and diet-aggravated hemolysis and its correction by probucol in SR-BI knockout mice with LDL-R deficiency.
abstract: BACKGROUND
  High density lipoprotein receptor SR-BI plays a vital role in cholesterol homeostasis. Depletion of SR-BI causes plasma free cholesterol (FC) accumulation, which disrupts erythrocytes membrane and might induce hemolytic anemia. Here we explored the effects of hypercholesteremia, induced by depletion of low density lipoprotein receptor (LDL-R) and high fat diet (HFD) feeding, on plasma FC and possible hemolysis in SR-BI knockout (KO) mice, and the therapeutic effects of a lipid-lowering drug probucol.
  
  
  RESULTS
  To determine the effects of LDL-R depletion, SR-BI KO mice were cross-bred with LDL-R KO mice to generate SR-BI/LDL-R double KO (dKO) mice. Compared to control wild type (WT), SR-BI KO and LDL-R KO mice fed normal chow diet (NCD), dKO mice fed NCD had increased plasma FC and developed macrocytic anemia, splenomegaly, jaundice and renal tubular hemosiderin deposition, indicating spontaneous hemolysis. To determine the effects of HFD feeding and probucol therapy, dKO and LDL-R KO mice were fed HFD containing 0.5% cholesterol and 20% fat with or without 1% probucol. HFD further increased plasma FC and aggravated hemolysis while probucol almost normalized plasma FC and corrected hemolysis in dKO mice.
  
  
  CONCLUSIONS
  We demonstrated that in SR-BI KO mice, hypercholesteremia due to LDL-R deficiency significantly increased plasma FC and induced spontaneous hemolysis, which could be further exacerbated by HFD feeding. Probucol almost normalized plasma FC and corrected diet-aggravated hemolysis in SR-BI KO mice with LDL-R deficiency.
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Liao
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Gao
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Mengyu
authors.initials: M
authors.lastname: Wang
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China. Electronic address: huangwei@bjmu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China; Center for Molecular and Translational Medicine, Peking University Health Science Center, Beijing 100191, China. Electronic address: georgeliu@bjmu.edu.cn.
authors.forename: George
authors.initials: G
authors.lastname: Liu
mesh_terms: D000748:Anemia, Macrocytic / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D006461:Hemolysis / Q000187:drug effects* / Q000502:physiology*; D006485:Hemosiderin / Q000378:metabolism; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011341:Probucol / Q000494:pharmacology*; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D051122:Scavenger Receptors, Class B / Q000172:deficiency* / Q000235:genetics
chemical_list: D000924:Anticholesteremic Agents; D011973:Receptors, LDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D006485:Hemosiderin; D002784:Cholesterol; D011341:Probucol
keywords: Free cholesterol; Hemolysis; Probucol; SR-BI