Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol

Abstract

IntroductionMultiple physiological mechanisms limit the entry of dietary sterols into the bloodstream. Excess cholesterol is removed from the body either by direct secretion into the bile or after conversion to bile acids. Although the mechanisms by which dietary sterols are absorbed by the intestine and secreted into the bile have been well characterized physiologically, the machinery responsible for these two processes has not been molecularly defined. The most abundant sterols in the human diet are cholesterol, the principal animal-derived sterol, and sitosterol, the major plant sterol. These two sterols, although structurally very similar, are handled quite differently by the intestine and liver of normal mammals. The absorption of sitosterol is significantly more limited than that of cholesterol. Humans absorb less than 5% of dietary sitosterol (1), and the small amount of sitosterol that reaches the liver is preferentially secreted into the bile (2). Consequently, plasma levels of sitosterol are very low (<1 mg/dl) in normal individuals. A much higher proportion (45-55%) of dietary cholesterol is absorbed by the proximal small intestine in humans, and the fractional excretion of sterols into the bile is lower for cholesterol than for sitosterol (3).Recently, a critical component of the transport machinery for dietary sterols was revealed by the finding that mutations in the genes encoding the ATPbinding cassette (ABC) half-transporters ABCG5 and ABCG8 cause sitosterolemia, a rare autosomal recessive disorder of sterol metabolism (4, 5). Patients with sitosterolemia have increased fractional absorption and decreased biliary secretion of all dietary neutral sterols (3, 6-8), which invariably leads to dramatically elevated plasma levels of sitosterol and other plant sterols. Most sitosterolemic individuals are also hypercholesterolemic (9). The disease phenotypically resembles homozygous familial hypercholesterolemia in that both diseases are characterized by the development of xanthomas in childhood accompanied by premature coronary atherosclerosis (6, 9, 10). ABCG5 and ABCG8 are expressed predominantly in hepatocytes and enterocytes in the proximal small intestine of Two ATP-binding cassette (ABC) transporters, ABCG5 and ABCG8, have been proposed to limit sterol absorption and to promote biliary sterol excretion in humans. To test this hypothesis, a P1 clone containing the human ABCG5 and ABCG8 genes was used to generate transgenic mice. The transgenes were expressed primarily in the liver and small intestine, mirroring the expression pattern of the endogenous genes. Transgene expression only modestly affected plasma and liver cholesterol levels but profoundly altered cholesterol transport. The fractional absorption of dietary cholesterol was reduced by about 50%, and biliary cholesterol levels were increased more than fivefold. Fecal neutral sterol excretion was increased three-to sixfold and hepatic cholesterol synthesis increased twoto fourfold in the transgenic mice. No significant changes in the pool s...

Role of naturally-occurring plant sterols on intestinal cholesterol absorption and plasmatic levels

“…Nevertheless, unesterified cholesterol can also be transported back into the intestinal tract through ATP-binding cassette (ABC) transporters, such as ABCG5 and ABCG8 (10,76). Furthermore, growing evidence supports the role of other transporters, such as ATP-binding cassette transporter A1 (ABCA1), the scavenger receptors CD36 and class B type I (SR-BI), the membrane-bound ectoenzyme aminopeptidase N (APN), the human P-glycoprotein (Pgp) or ABCB1 and the microsomal triacylglycerol transfer protein (MTP) (34), but their significance is not clearly defined yet (6).…”

Liver X receptors as therapeutic targets in metabolism and atherosclerosis

“…This effect appears to depend on the ability of LXRs to induce transcription of the ABCG5 and ABCG8 transporter in the liver and intestines, resulting in increased cholesterol excretion into the bile and decreased cholesterol absorption, respectively [15,32]. Consistent with these studies, deficiency of ABCG5 and ABCG8 in a rare genetic disorder known as sitosterolemia results in increased absorption of cholesterol from the intestine, diminished secretion of sterols into bile, hypercholesterolemia, and subsequent premature cardiovascular disease [33].…”

ATP-Binding Cassette Sterol Transporters Are Differentially Expressed in Normal and Diseased Human Gallbladder

“…GBEC probably contribute to cholesterol efflux into bile via ABCG5 and ABCG8, in a manner analogous to the function of this twinned sterol transporter at the canalicular pole of hepatocytes. In previous studies, ABCG5 and ABCG8 were found to move from the cytoplasm to the apical membrane upon LXRa/RXR ligand treatment [1,12]. The mixed bile salt micelles found in the gallbladder lumen are likely to result from ABCG5/ABCG8-mediated cholesterol efflux [19].…”

“…These cholesterol efflux pathways include unmediated diffusion [8] and proteinmediated transport by scavenger receptor BI (SR-BI) or ATP-binding cassette transporter A1 (ABCA1) [9,10]. ABCG5 and ABCG8 form heterodimers that are expressed on the canalicular membranes of hepatocytes, where they excrete cholesterol into bile [11,12]. It has been suggested that ABCG5/ABCG8 play a role in sterol flux at the apical pole of polarized epithelial cells in the liver.…”