patient-oriented and epidemiological research Increased expression of LXRa, ABCG5, ABCG8, and SR-BI in the liver from normolipidemic, nonobese Chinese gallstone patients

Cholesterol supersaturation of bile is one prerequisite for gallstone formation. In the present study of Chinese patients with gallstones, we investigated whether this phenomenon was correlated with the hepatic expression of genes participating in the metabolism of cholesterol and bile acids. Twenty-two nonobese, normolipidemic patients (female-male, 11:11) with gallstones were investigated with 13 ageand body mass index-matched gallstone-free controls (female-male, 10:3). The bile from the gallstone patients had higher cholesterol saturation than that from the controls. The mRNA levels of ABCG5, ABCG8, and liver X receptor a (LXRa) in the gallstone patients were increased by 51, 59, and 102%, respectively, and significantly correlated with the molar percentage of biliary cholesterol and cholesterol saturation index (CSI). The mRNA and protein levels of the hepatic scavenger receptor class B type I (SR-BI) were increased, and a significant correlation was found between the protein levels and the CSI. No differences were recorded between the two groups concerning the hepatic synthesis of cholesterol, bile acids, and esterification of cholesterol. Our results suggest that the upregulation of ABCG5/ABCG8 in gallstone patients, possibly mediated by increased LXRa, may contribute to the cholesterol supersaturation of bile. Our data are consistent with the possibility that increased amounts of biliary cholesterol may originate from plasma HDL cholesterol by enhanced transfer via SR-BI.—Jiang, Z-Y., P. Parini, G. Eggertsen, M. A. Davis. H. Hu, G-J. Suo, S-D. Zhang, L. L. Rudel, T-Q. Han, and C. Einarsson. Increased expression of LXRa, ABCG5, ABCG8, and SR-BI in the liver from normolipidemic, nonobese Chinese gallstone patients. J. Lipid Res. 2008. 49: 464–472. Supplementary key words scavenger receptor class B type I & hepatocyte nuclear factor 4a & acyl-coenzyme A:cholesterol acyltransferase 2 & nuclear receptors & ATP binding cassette G5 & ATP binding cassette G8 & bile acids & cholesteryl esters & liver X receptor a Cholesterol gallstone disease is common in both industrialized and developing countries (1, 2). In 1995, the Chinese National Survey reported that gallstone disease accounted for nearly 10% of all diagnoses of patients hospitalized in surgical clinics, and the majority of their gallstones were composed of cholesterol (2). Gallstone disease can be viewed as the terminal outcome of different metabolic disorders caused by diverse genetic and environmental factors. It is a multifactorial disease, and the causes of gallstones are heterogeneous and mostly intrahepatic. The critical element for gallstone formation is supersaturation of bile with cholesterol (3). Early studies attempted to define enzymatic defects in the liver contributing to the cholesterol supersaturation of bile. The activity of 3-hydroxy-3-methylglutaryl coenzyme A Manuscript received 27 June 2007 and in revised form 15 October 2007. Published, JLR Papers in Press, November 15, 2007. DOI 10.1194/jlr.M700295-JLR200 Abbreviations: apoA-I, apolipoprotein A-I; CSI, cholesterol saturation index; CYP7A1, cholesterol 7a-hydroxylase; FXR, farnesoid X receptor; GS, gallstone patients; GSF, gallstone-free controls; HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; HNF4A, hepatocyte nuclear factor 4a; LXRa, liver X receptor a; MTTP, microsomal triglyceride transfer protein; PGC1a, peroxisome proliferator-activated receptor g coactivator 1a; SR-BI, scavenger receptor class B type I; SREBP, sterol-regulatory element binding protein. 1 Z-Y Jiang and P. Parini contributed equally to this study. 2 To whom correspondence should be addressed. e-mail: [email protected] (T-Q.H.); [email protected] (C.E.) Copyright D 2008 by the American Society for Biochemistry and Molecular Biology, Inc. This article is available online at http://www.jlr.org 464 Journal of Lipid Research Volume 49, 2008 at P E N N S T A T E U N IV E R S IT Y , on F ebuary 3, 2013 w w w .j.org D ow nladed fom reductase (HMGCR; the rate-limiting enzyme for de novo synthesis of cholesterol) was shown to be increased in gallstone patients (4). Conversely, the activities of cholesterol 7a-hydroxylase (CYP7A1; the rate-limiting enzymes for bile acid synthesis) and ACAT (the enzyme catalyzing cholesterol esterification) were both decreased in gallstone patients (4, 5). However, larger studies of different populations could not confirm these results (6, 7). Recently, in a study in Chilean Hispanics and Mapuche Indians, a surrogate marker of bile acid synthesis was measured in the plasma of gallstone patients that suggested increased CYP7A1 activity (8). The identification and characterization of the ATP binding cassette (ABC) transporters for cholesterol, bile acids, and phospholipids has brought new insights to our understanding of gallstone disease. ABCG5 and ABCG8 appear to function as a heterodimer for the secretion of cholesterol into the bile canaliculus (9). As shown previously in mice (10, 11), both the Abcg5 and Abcg8 genes are targets for the liver X receptor a (LXRa) and could be induced by LXRa agonists. ABCB11 (12) (also known as BSEP, for bile salt export pump) is a major bile acid transporter, and ABCB4 (also known as MDR3, for multiple drug-resistant transporter 3) is a phospholipid transporter. In animal models, either overexpression of Abcg5/ Abcg8 (9) or depletion of Abcb11 (13) or Abcb4 (14) modifies biliary lipid secretion and, in some cases, leads to the supersaturation of bile with cholesterol. As with most of the studies performed in mice, the role of ABC transporters in the pathogenesis of cholesterol gallstones is not well understood in humans. In this study, we attempted to identify some of the molecular defects in hepatic cholesterol and bile acid metabolism involved in the pathogenesis of cholesterol gallstone disease. We studied a group of normolipidemic, nonobese Chinese patients who had neither diabetes mellitus nor signs of insulin resistance. Our present results suggest that in these humans, supersaturation of bile is associated with an increased expression of ABCG5/ABCG8 and LXRa. We also observed an increased expression of scavenger receptor class B type I (SR-BI), which mediates the hepatic uptake of cholesterol from HDL (15) that is directed to biliary cholesterol secretion. MATERIALS AND METHODS