Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I.
Patients with Tangier disease exhibit extremely low plasma HDL concentrations resulting from mutations in the ATP-binding cassette, sub-family A, member 1 (ABCA1) protein. ABCA1 controls the rate-limiting step in HDL particle assembly by mediating efflux of cholesterol and phospholipid from cells to lipid-free apoA-I, which forms nascent HDL particles. ABCA1 is widely expressed; however, the specific tissues involved in HDL biogenesis are unknown. To determine the role of the liver in HDL biogenesis, we generated mice with targeted deletion of the second nucleotide-binding domain of Abca1 in liver only (Abca1(-L/-L)). Abca1(-L/-L) mice had total plasma and HDL cholesterol concentrations that were 19% and 17% those of wild-type littermates, respectively. In vivo catabolism of HDL apoA-I from wild-type mice or human lipid-free apoA-I was 2-fold higher in Abca1(-L/-L) mice compared with controls due to a 2-fold increase in the catabolism of apoA-I by the kidney, with no change in liver catabolism. We conclude that in chow-fed mice, the liver is the single most important source of plasma HDL. Furthermore, hepatic, but not extrahepatic, Abca1 is critical in maintaining the circulation of mature HDL particles by direct lipidation of hepatic lipid-poor apoA-I, slowing its catabolism by the kidney and prolonging its plasma residence time.
Timmins
Jenelle M
JM
Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Lee
Ji-Young
JY
Boudyguina
Elena
E
Kluckman
Kimberly D
KD
Brunham
Liam R
LR
Mulya
Anny
A
Gebre
Abraham K
AK
Coutinho
Jonathan M
JM
Colvin
Perry L
PL
Smith
Thomas L
TL
Hayden
Michael R
MR
Maeda
Nobuyo
N
Parks
John S
JS
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism*; D018390:Gene Targeting; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000097:blood*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D013631:Tangier Disease / Q000235:genetics* / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL