This Review Is Part of a Thematic Series on Abc Transporters in the Cardiovascular System, Which Includes the following Articles: Atp-binding Cassette Cholesterol Transporters and Cardiovascular Disease Structure and Function of Abc Transporters Atp-binding Cassette Cholesterol Transporters and Card

—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. Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and inhibit transcription of all 4 transporters. Thus, impaired ABC cholesterol transporters might contribute to the enhanced atherogenesis associated with common inflammatory and metabolic disorders. Their beneficial effects on cholesterol homeostasis have made these transporters important new therapeutic targets for preventing and reversing CVD. C holesterol is an abundant metabolite in mammalian tissues that is essential for several biological systems. Membrane fluidity of all cells is tightly modulated by the ordered packing of cholesterol between phospholipid molecules. Cholesterol also concentrates in sphingolipid-rich domains of the plasma membrane called rafts that contain a variety of important signaling molecules. 1 Cholesterol co-valently links to sonic hedgehog, 2 a cell morphogen required for normal embryonic development and cell differentiation. In addition to its structural functions, cholesterol is a substrate for steroid production. Thus, an inadequate supply of cholesterol would have devastating effects on cell function, tissue development, and whole-body physiology. Too much cholesterol, however, can also have pathological consequences. Cholesterol is a waxy substance that is poorly soluble in water. An uncontrolled buildup of cholesterol in cells can disrupt membranes and promote apoptosis. Accumulation of excess cholesterol causes atherosclerotic cardio-vascular disease (CVD) 3 and might contribute to the early …