Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I

Abstract

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.

P2Y13 Receptor Is Critical for Reverse Cholesterol Transport

“…Hepatic expression of genes that are involved in cholesterol transport and metabolism was determined to assess potential changes due to P2Y 13 deletion (Table 2). Hepatic messenger RNA (mRNA) expression of ATP-binding cassette transporters abca1, which plays a pivotal role in the efflux of cholesterol to apoA-I, and abcg1, which has a similar role in the efflux to HDL, 12,13 were significantly lower in P2Y 13 (À/À) mice compared to (þ/þ) mice (Table 2; abca1 À56% 6 5% and abcg1 À67% 6 7%), suggesting that hepatic HDL biogenesis might be impaired in these mice. However, P2Y 13 deletion had no significant effect on the hepatic mRNA expression of biliary lipid transport proteins abcg5/abcg8, bile salt export pump (abcb11/bsep), sodium taurocholate cotransporting polypeptide (ntcp), and organic anion transport polypeptide (oatp).…”

“…Although not formally tested, these findings are consistent with the overall concept of the role of hepatic ABCA1/ABCG1 in HDL formation. 12,16 The phenotype observed in P2Y 13 -null mice suggests that plasma HDL cholesterol may not always be the most reliable marker for assessing the potential utility of new therapeutic agents targeting HDL. It is thus important to develop effective approaches to evaluate HDL functionality.…”

Lipid Absorption Defects in Intestine-specific Microsomal Triglyceride Transfer Protein and ATP-binding Cassette Transporter A1-deficient Mice

“…In rodent models, low plasma HDL concentrations in the absence of hepatic ABCA1 rise because of higher apoAI clearance via the kidney, because apoAI is not efficiently lipidated in these mice (10). Tissue-specific ablation studies show that hepatic and intestinal ABCA1 contribute ϳ70 and * This work was supported, in whole or in part, by National Institutes of Health 30% of plasma HDL, respectively (10,11). Higher plasma triglycerides in the absence of hepatic ABCA1 have been attributed to the attenuation of PI3K-mediated inhibition of the assembly of triglyceride-rich larger VLDL particles (9).…”

Conformational Adaptation of Apolipoprotein A-I to Discretely Sized Phospholipid Complexes

“…molecules of apoA-I (3,6,7). In this form, the conformation of apoA-I is an excellent coactivator for the plasma enzyme lecithin:cholesterol acyl transferase (LCAT) that rapidly converts apoA-I containing lipid particles to mature or spherical HDL with a core of cholesterol ester.…”

“…In this form, the conformation of apoA-I is an excellent coactivator for the plasma enzyme lecithin:cholesterol acyl transferase (LCAT) that rapidly converts apoA-I containing lipid particles to mature or spherical HDL with a core of cholesterol ester. If any part of this process is interrupted or impaired, the small apoA-I particles are rapidly removed from circulation by the kidney (6). Studies of human deficiencies have shown that if either ABCA1 or LCAT are inactive, plasma concentrations of HDL apoA-I are very low due to the rapid removal of lipid-poor HDL apoA-I from circulation (8,9).…”