Hepatocyte ABCA1 deficiency is associated with reduced HDL sphingolipids

Area of Science:

• Lipid metabolism and transport
• Biochemistry of lipoproteins
• Genetic disorders of lipid metabolism

Background:

• ATP binding cassette transporter A1 (ABCA1) is crucial for high-density lipoprotein (HDL) formation.
• Genetic ABCA1 dysfunction leads to Tangier disease, characterized by severe HDL deficiency.
• The role of hepatic ABCA1 in regulating plasma sphingolipid levels remains largely uncharacterized.

Purpose of the Study:

• To investigate the impact of ABCA1 on plasma sphingolipid (SL) levels in humans and mice.
• To determine the contribution of hepatic ABCA1 to the total plasma sphingolipid pool.
• To explore the relationship between ABCA1, HDL, and specific sphingolipids like sphingosine-1-phosphate (S1P).

Main Methods:

• Analysis of plasma sphingolipid levels in a Tangier disease patient with ABCA1 mutations.
• Comparison of sphingolipid levels in heterozygous ABCA1 mutation carriers versus controls.
• Assessment of sphingolipids, apoM, and S1P in liver-specific Abca1 knockout (Abca1 HSKO) mice.
• In vitro studies using primary hepatocytes from Abca1 HSKO and wild-type (WT) mice.

Main Results:

• A Tangier patient with ABCA1 mutations exhibited drastically reduced plasma total sphingolipids.
• Abca1 HSKO mice showed significantly reduced total sphingolipids in plasma and liver.
• Plasma apoM and sphingosine-1-phosphate (S1P) levels were decreased in Abca1 HSKO mice.
• Abca1 HSKO hepatocytes displayed reduced total SL concentration despite increased SL synthesis and secretion.

Conclusions:

• Hepatic ABCA1 plays a significant role in maintaining the plasma pool of HDL-associated sphingolipids.
• ABCA1 deficiency profoundly affects sphingolipid metabolism, impacting levels of sphingomyelins and S1P.
• These findings highlight a critical link between ABCA1 function, HDL, and overall sphingolipid homeostasis.