title: Targeted deletion of hepatocyte ABCA1 leads to very low density lipoprotein triglyceride overproduction and low density lipoprotein hypercatabolism.
abstract: Loss of ABCA1 activity in Tangier disease (TD) is associated with abnormal apoB lipoprotein (Lp) metabolism in addition to the complete absence of high density lipoprotein (HDL). We used hepatocyte-specific ABCA1 knock-out (HSKO) mice to test the hypothesis that hepatic ABCA1 plays dual roles in regulating Lp metabolism and nascent HDL formation. HSKO mice recapitulated the TD lipid phenotype with postprandial hypertriglyceridemia, markedly decreased LDL, and near absence of HDL. Triglyceride (TG) secretion was 2-fold higher in HSKO compared with wild type mice, primarily due to secretion of larger TG-enriched VLDL secondary to reduced hepatic phosphatidylinositol 3-kinase signaling. HSKO mice also displayed delayed clearance of postprandial TG and reduced post-heparin plasma lipolytic activity. In addition, hepatic LDLr expression and plasma LDL catabolism were increased 2-fold in HSKO compared with wild type mice. Last, adenoviral repletion of hepatic ABCA1 in HSKO mice normalized plasma VLDL TG and hepatic phosphatidylinositol 3-kinase signaling, with a partial recovery of HDL cholesterol levels, providing evidence that hepatic ABCA1 is involved in the reciprocal regulation of apoB Lp production and HDL formation. These findings suggest that altered apoB Lp metabolism in TD subjects may result from hepatic VLDL TG overproduction and increased hepatic LDLr expression and highlight hepatic ABCA1 as an important regulatory factor for apoB-containing Lp metabolism.
authors.affiliation: Department of Pathology/Section on Lipid Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, USA.
authors.forename: Soonkyu
authors.initials: S
authors.lastname: Chung
authors.forename: Jenelle M
authors.initials: JM
authors.lastname: Timmins
authors.forename: Myngan
authors.initials: M
authors.lastname: Duong
authors.forename: Chiara
authors.initials: C
authors.lastname: Degirolamo
authors.forename: Shunxing
authors.initials: S
authors.lastname: Rong
authors.forename: Janet K
authors.initials: JK
authors.lastname: Sawyer
authors.forename: Roshni R
authors.initials: RR
authors.lastname: Singaraja
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Rudel
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Shelness
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D018390:Gene Targeting; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000096:biosynthesis; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013631:Tangier Disease / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000096:biosynthesis*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001055:Apolipoproteins B; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011994:Recombinant Proteins; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D019869:Phosphatidylinositol 3-Kinases