The Neglected Cousin of the Hepatocyte: How Gallbladder Epithelial Cells Might Contribute to Cholesterol Gallstone Formation

Abstract

The regulation of biliary cholesterol secretion by hepatocytes has received much interest [1], since it has a major impact on two highly relevant disease complexes, namely, the generation of cholesterol gallstones which have an overall prevalence of 10–20 % in developed countries [2] and reverse cholesterol transport [3], an important protective pathway against atherosclerotic cardiovascular disease as well as the main cause for morbidity and mortality in industrialized societies [4]. Less attention has thus far been given to the potential participation of the gallbladder itself in metabolism, which is somewhat surprising, since the gallbladder has the capacity to actively absorb cholesterol from bile and thereby modulate bile cholesterol content [5]. Changes in transporters mediating this metabolic activity of gallbladder epithelial cells could conceivably contribute to cholesterol gallstone formation in disease. However, only a very limited number of studies exist that have functionally explored the relative contributions of known cholesterol transport proteins to cholesterol transport in and out of the gallbladder (Fig. 1). The study by Yoon et al. [6] in this issue of Digestive Diseases and Sciences reports that the ATP-binding cassette transporters G5/G8 (ABCG5/G8) are expressed on the apical side, while ABCA1 is found on the basolateral side of gallbladder epithelial cells. Both transporters are upregulated in gallbladders from patients with cholesterol gallstone disease [6]. Thus far, on the apical side the expression of ACBG5/G8 [7], scavenger receptor class B type I (SR-BI) [8], cubilin and megalin [9] was reported in gallbladder epithelial cells. The obligate heterodimer ABCG5/G8 is a cholesterol transporter expressed in enterocytes and hepatocytes, where it mediates the excretion of cholesterol and plant sterols out of the cell [1]. About 70 % of total biliary cholesterol secretion is ABCG5/G8 dependent. Total genetic deletion of ABCG5/ G8 produces sitosterolemia, a disease associated with hyperabsorption of cholesterol and plant sterols that is linked to accelerated atherosclerosis [1]. Interestingly, the ABCG5/G8 locus has also long been implicated in the formation of cholesterol gallstones [10]. Recently, specific coding variants have been identified in genome-wide association studies that likely result in a gain-of-function of ABCG5/G8, supposedly translating into increased biliary cholesterol secretion [11]. Neither in animal experiments nor in human material has the functionality of ABCG5/G8, specifically in the gallbladder, been explored; although, derived from their function in liver and intestine increasing cholesterol secretion into bile would be expected. In this context the higher expression of these transporters noted by Yoon et al. [6] in patients with gallstone disease points towards a causative contribution of ABCG5/G8 to gallstone formation. However, results from studies using the perfused gallbladder model indicated reduced cholesterol absorption from bile in gallbladders from gallstone disease patients [12], although the methods used did not formally distinguish between decreased uptake versus uptake followed by accelerated resecretion, e.g. via increased ABCG5/G8 expression [12]. Moreover, decreased expression of uptake receptors on the apical side such as cubilin or megalin might also explain these results. Interestingly, cholesterol uptake and secretion can occur on the apical side [13] providing further indirect evidence for a potential functional role of ABCG5/G8 in the gallbladder. A. Dikkers U. J. F. Tietge (&) Department of Pediatrics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands e-mail: u_tietge@yahoo.com