title: Hypoxia-mediated impaired erythrocyte Lands' Cycle is pathogenic for sickle cell disease.
abstract: Although Lands' cycle was discovered in 1958, its function and cellular regulation in membrane homeostasis under physiological and pathological conditions remain largely unknown. Nonbiased high throughput metabolomic profiling revealed that Lands' cycle was impaired leading to significantly elevated erythrocyte membrane lysophosphatidylcholine (LysoPC) content and circulating and erythrocyte arachidonic acid (AA) in mice with sickle cell disease (SCD), a prevalent hemolytic genetic disorder. Correcting imbalanced Lands' cycle by knockdown of phospholipase 2 (cPLA2) or overexpression of lysophosphatidycholine acyltransferase 1 (LPCAT1), two key enzymes of Lands' cycle in hematopoietic stem cells, reduced elevated erythrocyte membrane LysoPC content and circulating AA levels and attenuated sickling, inflammation and tissue damage in SCD chimeras. Human translational studies validated SCD mouse findings and further demonstrated that imbalanced Lands' cycle induced LysoPC production directly promotes sickling in cultured mouse and human SCD erythrocytes. Mechanistically, we revealed that hypoxia-mediated ERK activation underlies imbalanced Lands' cycle by preferentially inducing the activity of PLA2 but not LPCAT in human and mouse SCD erythrocytes. Overall, our studies have identified a pathological role of imbalanced Lands' cycle in SCD erythrocytes, novel molecular basis regulating Lands' cycle and therapeutic opportunities for the disease.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Bogdanov
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.|Graduate School of Biomedical Science, University of Texas, Houston, TX, USA.
authors.forename: Kaiqi
authors.initials: K
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.
authors.forename: Shushan
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.
authors.forename: Anren
authors.initials: A
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.
authors.forename: Renna
authors.initials: R
authors.lastname: Luo
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.|Graduate School of Biomedical Science, University of Texas, Houston, TX, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Parchim
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.|Graduate School of Biomedical Science, University of Texas, Houston, TX, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.
authors.forename: Aji
authors.initials: A
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.|Graduate School of Biomedical Science, University of Texas, Houston, TX, USA.
authors.forename: Morayo G
authors.initials: MG
authors.lastname: Adebiyi
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Jin
authors.affiliation: Metabolon, Inc., Durham, NC, USA.
authors.forename: Danny C
authors.initials: DC
authors.lastname: Alexander
authors.affiliation: Metabolon, Inc., Durham, NC, USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Milburn
authors.affiliation: Department of Internal Medicine, University of Texas-Medical School, Houston, TX, USA.
authors.forename: Modupe
authors.initials: M
authors.lastname: Idowu
authors.affiliation: Department of Internal Medicine, University of Texas-Medical School, Houston, TX, USA.
authors.forename: Harinder S
authors.initials: HS
authors.lastname: Juneja
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.|Graduate School of Biomedical Science, University of Texas, Houston, TX, USA.
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.
authors.forename: William
authors.initials: W
authors.lastname: Dowhan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Medical School, Houston, TX, USA.|Graduate School of Biomedical Science, University of Texas, Houston, TX, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000235:genetics; D000755:Anemia, Sickle Cell / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid / Q000097:blood*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D054513:Group IV Phospholipases A2 / Q000235:genetics; D006801:Humans; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D008297:Male; D055432:Metabolomics / Q000379:methods*; D051379:Mice
chemical_list: D008244:Lysophosphatidylcholines; D016718:Arachidonic Acid; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C526202:Lpcat1 protein, human; D054513:Group IV Phospholipases A2