Stimulation of Cholesterol Excretion by the Liver X Receptor Agonist Requires ATP-binding Cassette Transporters G5 and G8

Abstract

Liver X receptor (LXR) is a nuclear receptor that plays a crucial role in orchestrating the trafficking of sterols between tissues. Treatment of mice with a potent and specific LXR agonist, T0901317, is associated with increased biliary cholesterol secretion, decreased fractional cholesterol absorption, and increased fecal neutral sterol excretion. Here we show that expression of two target genes of LXR␣, the ATP-binding cassette (ABC) transporters Abcg5 and Abcg8, is required for both the increase in sterol excretion and the decrease in fractional cholesterol absorption associated with LXR agonist treatment. Mice expressing no ABCG5 and ABCG8 (G5G8 ؊/؊ mice) and their littermate controls were treated for 7 days with T0901317. In wild type animals, treatment with the LXR agonist resulted in a 3-fold increase in biliary cholesterol concentrations, a 25% reduction in fractional cholesterol absorption, and a 4-fold elevation in fecal neutral sterol excretion. In contrast, the LXR agonist did not significantly affect biliary cholesterol levels, fractional cholesterol absorption, or neutral fecal sterol excretion in the G5G8 ؊/؊ mice. Thus Abcg5 and Abcg8 are required for LXR agonist-associated changes in dietary and biliary sterol trafficking. These results establish a central role for ABCG5 and ABCG8 in promoting cholesterol excretion in vivo.Cholesterol is an important structural component of animal cell membranes. The cholesterol required to maintain membrane integrity can be synthesized de novo from acetyl-CoA or can be obtained from cholesterol-containing foods in the diet. The typical Western diet includes ϳ400 mg of cholesterol per day, of which 40 -50% is absorbed in the proximal small intestine. The major pathway by which cholesterol is eliminated from the body is by excretion into bile either as free cholesterol or after conversion to bile acids.A variety of noncholesterol sterols are also present in the diet. The most plentiful of these are the two plant sterols, sitosterol and campesterol. The levels of these sterols in tissues are very low, because plant sterols are poorly absorbed from the intestine and are preferentially secreted into the bile by hepatocytes (1-3).One mechanism by which excess cholesterol and other sterols are eliminated from the body involves the action of two ATP-binding cassette (ABC) 1 half-transporters, ABCG5 and ABCG8 (4, 5). Mutations in either of these genes cause sitosterolemia, a rare autosomal recessive disorder of sterol trafficking (4, 5). Subjects with sitosterolemia have increased fractional absorption of dietary noncholesterol sterols and decreased biliary secretion of plant-and animal-derived sterols (6, 7). Consequently, these patients accumulate sitosterol, as well as other plant-and shellfish-derived neutral sterols, in the blood and tissues (8, 9). Subjects with sitosterolemia also are frequently hypercholesterolemic and develop tendon xanthomas and premature coronary artery disease (8, 10).The pivotal role of ABCG5 and ABCG8 in enterohepatic sterol transport has ...

Sterolins ABCG5 and ABCG8: regulators of whole body dietary sterols

“…There are robust data to support the role of Lxrmediated increased mRNA expression of Abcg5 and Abcg8, both in vivo (Table 1) as well as in vitro [2,11,47,48,65,68]. LXR ligands have been shown to increase expression of the STSL locus in mouse liver and intestine and in rat hepatoma cells; cholesterol feeding upregulates Fig.…”

Angiopoietin-like Protein 3 Mediates Hypertriglyceridemia Induced by the Liver X Receptor

“…LXR-mediated induction of ABCA1 enhances cholesterol efflux from macrophages, accompanying the supply of cholesterol to ApoA1 and the increase of plasma high density lipoprotein (16). Furthermore, LXR-mediated induction of ABCG5/G8 in liver and small intestine increases excretion of cholesterol into bile and feces, resulting in reduction in cholesterol absorption (32). Based on these effects on macrophages and intestinal mucosa, LXR agonists were expected to act as antiatherogenic and antihypercholesterolemic agents (19,33).…”

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

“…NPC1L1 and ABCG5/8 are the two major factors mediating net cholesterol uptake. The former mediates cholesterol uptake, and the latter mediates excretion of excessive cholesterol into the intestinal lumen (22,23). CD36 also participates in cholesterol uptake at the brush border of enterocytes (24,25).…”