ATP-Binding Cassette Cholesterol Transporters and Cardiovascular Disease

Abstract

Abstract-A hallmark of atherosclerotic cardiovascular disease (CVD) is the accumulation of cholesterol in arterial macrophages. Factors that modulate circulating and tissue cholesterol levels have major impacts on initiation, progression, and regression of CVD. Four members of the ATP-binding cassette (ABC) transporter family play important roles in this modulation. ABCA1 and ABCG1 export excess cellular cholesterol into the HDL pathway and reduce cholesterol accumulation in macrophages. ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion. All 4 transporters are induced by the same sterol-sensing nuclear receptor system. ABCA1 expression and activity are also highly regulated posttranscriptionally by diverse processes. ABCA1 mutations can cause a severe HDL-deficiency syndrome characterized by cholesterol deposition in tissue macrophages and prevalent atherosclerosis. ABCG5 or ABCG8 mutations can cause sitosterolemia, in which patients accumulate cholesterol and plant sterols in the circulation and develop premature CVD. Disrupting Abca1 or Abcg1 in mice promotes accumulation of excess cholesterol in macrophages, and manipulating mouse macrophage ABCA1 expression affects atherogenesis. Overexpressing ABCG5 and ABCG8 in mice attenuates diet-induced atherosclerosis in association with reduced circulating and liver cholesterol.

The g.−762T>C polymorphism of the NPC1L1 gene is common in Chinese and contributes to a higher promoter activity and higher serum cholesterol levels

“…Several genetic variations in ABCG5/8 have been identified to cause sitosterolemia, a rare disorder characterized by increased serum sitosterol levels. [12][13][14][15] However, there are a limited number of studies that focus on the effects of NPC1L1 genetic variation. Therefore, the aim of this study was to identify genetic variations of NPC1L1 and to investigate whether these variations are associated with variations in serum cholesterol levels.…”

Significant association of ABCG8:D19H gene polymorphism with hypercholesterolemia and insulin resistance

“…In healthy individuals, the average Western diet contains 250-500 mg of cholesterol and 200-400 mg of non-cholesterol sterols (e.g., plant sterol) per day. Typically more than 50% of the cholesterol is absorbed and retained in the body, in contrast to only 1-5% of plant sterols (Lammert and Wang 2005;Wang 2007;Oram and Vaughan 2006). Plant sterol (phytosterol) acts at the enterocytes to reduce cholesterol absorption by 40-60% by binding with cholesterol esterase, cocrystallizing with cholesterol and competing with cholesterol for adenosine triphophate-binding cassette proteins (Kassis et al 2008).…”

“…In humans, intestinal cholesterol absorption efficiency varies over a broad interindividual range (20-80%). This wide range implies that dietary and genetic factors may play a crucial role in the cholesterol absorption process (Lammert and Wang 2005;Oram and Vaughan 2006;Sehayek 2003).…”

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

“…Cholesterol uptake involves plasma lipoproteins (mainly low density lipoprotein [LDL] and very low density lipoprotein [VLDL]) after interactions with their specific receptors, LDLR and VLDLR, respectively. Cholesterol efflux is mainly mediated by specific transporters, ABCA1 and ABCG1, in association with extracellular cholesterol acceptors, including apolipoproteins (APO) APOA1 and APOE, or lipoprotein particles (e.g., nascent high density lipoprotein [HDL] or HDL2) ( Figure 3) 93 . ABCG1 is rather localized within the cell and seems to move sterols between intracellular compartments 88 .…”