Intestinal ABCA1 directly contributes to HDL biogenesis in vivo

Abstract

Plasma HDL cholesterol levels are inversely related to risk for atherosclerosis. The ATP-binding cassette, subfamily A, member 1 (ABCA1) mediates the rate-controlling step in HDL particle formation, the assembly of free cholesterol and phospholipids with apoA-I. ABCA1 is expressed in many tissues; however, the physiological functions of ABCA1 in specific tissues and organs are still elusive. The liver is known to be the major source of plasma HDL, but it is likely that there are other important sites of HDL biogenesis. To assess the contribution of intestinal ABCA1 to plasma HDL levels in vivo, we generated mice that specifically lack ABCA1 in the intestine. Our results indicate that approximately 30% of the steady-state plasma HDL pool is contributed by intestinal ABCA1 in mice. In addition, our data suggest that HDL derived from intestinal ABCA1 is secreted directly into the circulation and that HDL in lymph is predominantly derived from the plasma compartment. These data establish a critical role for intestinal ABCA1 in plasma HDL biogenesis in vivo.Introduction HDL particles mediate the transport of cholesterol from peripheral tissues to the liver in a process termed reverse cholesterol transport (1, 2), which is postulated to explain, at least in part, their ability to protect against foam cell formation and atherosclerosis. Despite the widespread interest in HDL as a potential therapeutic target (3), the origins of plasma HDL are still elusive. The ATP-binding cassette, subfamily A, member 1 (ABCA1) mediates the rate-controlling step in HDL particle formation by promoting the efflux of cholesterol and phospholipids to apoA-I (4, 5). Mutations in ABCA1 cause Tangier disease (6-8), characterized by near absence of HDL cholesterol and increased risk for atherosclerosis (9-11). ABCA1 is widely expressed throughout the body (12, 13); however, the contributions of ABCA1 in specific tissues to HDL levels and reverse cholesterol transport are still being unraveled, and only recently the role of hepatic ABCA1 in homeostasis of HDL levels was elucidated.Overexpression of hepatic ABCA1 raises HDL cholesterol levels (14, 15), and liver-specific deletion of ABCA1 results in a substantial (∼80%) decrease in plasma HDL cholesterol in chow-fed mice (16). Similarly, a 50% knockdown of hepatic ABCA1 expression by adenovirus-mediated RNA interference in mice is associated with a 40% decrease in HDL cholesterol (17). These results indicate that the liver is the single most important source of plasma HDL in vivo but also suggest the existence of additional, extrahepatic sites of HDL biogenesis.The intestine, along with the liver, is an important site for the synthesis and secretion of apoA-I, the principal apoprotein of HDL,

Intestinal lipid absorption

“…1) (91, 93). The importance of ABCA1 in the biogenesis of HDL in the intestine was demonstrated by deleting intestinal Abca1, which resulted in a 30% decrease in plasma HDL cholesterol levels (24). Enterocytes deficient in ABCA1 absorb smaller amounts of cholesterol (24).…”

“…The measurement of cholesterol in lymph led to the hypothesis that HDL is not important in cholesterol transport. However, Brunham et al (24) recently demonstrated that the HDL in lymph is dependent on the activity of hepatic ABCA1 and enters the lymph from plasma. Thus, quantification of HDL in lymph may not provide an accurate assessment of the extent of cholesterol absorption via this pathway.…”

Molecular bases of copper and iron deficiency-associated dyslipidemia: a microarray analysis of the rat intestinal transcriptome

“…Widely reported models for lipid metabolism investigations are hepatocytes and adipocytes, even though the digestion and absorption of dietary lipids, as well as their re-synthesis and packaging for transport, take place in the intestine. The same tissue, together with the liver, controls the cholesterol homeostasis and plasma cholesterol levels, and contributes to the HDL-CL levels [7,8]. The interest for a better characterization of the metabolic switches that regulate the onset and the evolution of lipid dismetabolisms in metal deficiencies prompted us to analyze the intestinal transcriptome in order to identify reliable genetic markers for the early diagnosis and, hopefully, for more effective early treatments.…”

High-density lipoprotein metabolism in human apolipoprotein B100transgenic/brown adipose tissue deficient mice: a model of obesity-induced hyperinsulinemia

“…Absence of functional ABCA1 reduced plasma HDL-C concentrations by ∼95% in humans and mice (Oram 2000;Brunham et al 2006), suggesting ABCA1 is quantitatively the most important factor in maintaining plasma HDL-C levels. In particular, as ABCA1 in the liver accounts for ∼80% of plasma HDL-C levels , hepatic expression of ABCA1 was evaluated to gain an insight into a potential contribution of hepatic ABCA1 to the HDL metabolism in obesity.…”

“…As mentioned, ABCA1 plays a pivotal role in nascent HDL formation. Importantly, deletion of Abca1 in the liver and intestine reduced plasma HDL-C concentrations by ∼80% and ∼30% in mice, respectively, indicating that ABCA1 in these tissues is quantitatively most important for maintaining plasma HDL-C levels Brunham et al 2006). In addition to its role in nascent HDL formation, hepatic ABCA1 has been implicated in HDL catabolism.…”