Stimulation of murine biliary cholesterol secretion by thyroid hormone is dependent on a functional ABCG5/G8 complex

Ylva Bonde,Mats Rudling,Torsten Plösch,Bo Angelin,Folkert Kuipers

doi:10.1002/hep.25861

Ylva Bonde, Mats Rudling + Show 3 more

Open Access

https://doi.org/10.1002/hep.25861

Copy DOI

Abstract

Secretion of cholesterol into bile is important for the elimination of cholesterol from the body. Thyroid hormone (TH) increases biliary cholesterol secretion and hepatic gene expression of adenosine triphosphate (ATP)-binding cassette, subfamily G (WHITE), member 5 (ABCG5) and ATP-binding cassette, subfamily G (WHITE), member 8 (ABCG8), two half-transporters that act as a heterodimeric complex promoting sterol secretion. In addition, nuclear liver x receptor-alpha (LXRa), also regulated by TH, induces gene expression of ABCG5/G8. We here investigated if the TH-induced stimulation of biliary cholesterol secretion is mediated by the ABCG5/G8 complex in vivo, and if so, whether LXRa is involved. Mice homozygous for disruption of Abcg5 (Abcg5−/−) or Lxra (Lxra−/−) and their wild-type counterparts were treated with triiodothyronine (T3) for 14 days and compared to untreated mice of corresponding genetic backgrounds. Bile was collected by gallbladder cannulation, and liver samples were analyzed for gene expression levels. Basal biliary cholesterol secretion in Abcg5−/− mice was 72% lower than in Abcg5+/+ mice. T3 treatment increased cholesterol secretion 3.1-fold in Abcg5+/+ mice, whereas this response was severely blunted in Abcg5−/− mice. In contrast, biliary cholesterol secretion in T3-treated Lxra+/+ and Lxra−/− mice was increased 3.5- and 2.6-fold, respectively, and did not differ significantly. Conclusions: TH-induced secretion of cholesterol into bile is largely dependent on an intact ABCG5/G8 transporter complex, whereas LXRa is not critical for this effect. (HEPATOLOGY 2012;56:1828–1837)

Highlights

An important and presumably rate-limiting step in the process of biliary secretion of cholesterol is mediated by the half-transporters ATP-binding cassette, subfamily G (WHITE), member 5 (ABCG5) and Abbreviations:: ABCG5, ATP-binding cassette, subfamily G (WHITE), member 5; ABCG8, ATP-binding cassette, subfamily G (WHITE), member 8; Alpha-muricholic acid (aMCA), alpha-muricholic acid; ATP, adenosine triphosphate; bile acids (BAs), bile acid; b-muricholic acid (b-MCA), beta-muricholic acid; CA, cholic acid; Chenodeoxycholic acid (CDCA), chenodeoxycholic acid; CYP, cytochrome P450; DCA, deoxycholic acid; Gapdh, glyceraldehyde-3-phosphate dehydrogenase; GC, gas chromatography; HDL, high-density lipoprotein; HMG CoA red, hydroxymethylglutaryl coenzyme A reductase; Hprt, hypoxanthine guanine phosphoribosyl transferase; LCA, litocholic acid; LDL, low-density lipoprotein; LDLr, LDL receptor; liver x receptor-alpha (LXRa), liver x receptor alpha; MS, mass spectrometry; T3, triiodothyronine; Thyroid hormone (TH), thyroid hormone; TH receptor-beta (TRb), thyroid hormone receptor beta; UDCA, ursodeoxycholic acid; WT, wild type
We present three novel findings: (1) Biliary cholesterol secretion induced by TH is predominantly excerted by ABCG5/G8; (2) this TH-induced biliary cholesterol secretion is independent of LXRa; and (3) a minor part of the TH-induced stimulation of biliary cholesterol secretion occurs independently of the ABCG5/G8 complex
Compared to untreated Abcg5þ/þ mice, CYP7A1, hydroxymethylglutaryl coenzyme A reductase (HMG CoA red), and LDLr gene expressions were increased 4.6, 3.7, and 1.6-fold, respectively, in T3-treated Abcg5þ/þ mice, whereas they were unaltered in untreated Abcg5À/À mice

Summary

Introduction

An important and presumably rate-limiting step in the process of biliary secretion of cholesterol is mediated by the half-transporters ATP-binding cassette, subfamily G (WHITE), member 5 (ABCG5) and Abbreviations:: ABCG5, ATP-binding cassette, subfamily G (WHITE), member 5; ABCG8, ATP-binding cassette, subfamily G (WHITE), member 8; aMCA, alpha-muricholic acid; ATP, adenosine triphosphate; BA, bile acid; b-MCA, beta-muricholic acid; CA, cholic acid; CDCA, chenodeoxycholic acid; CYP, cytochrome P450; DCA, deoxycholic acid; Gapdh, glyceraldehyde-3-phosphate dehydrogenase; GC, gas chromatography; HDL, high-density lipoprotein; HMG CoA red, hydroxymethylglutaryl coenzyme A reductase; Hprt, hypoxanthine guanine phosphoribosyl transferase; LCA, litocholic acid; LDL, low-density lipoprotein; LDLr, LDL receptor; LXRa, liver x receptor alpha; MS, mass spectrometry; T3, triiodothyronine; TH, thyroid hormone; TRb, thyroid hormone receptor beta; UDCA, ursodeoxycholic acid; WT, wild type. Hepatic gene expression of ABCG5/G8 is not always concurrent with biliary cholesterol secretion,[16,19,20,21] and there are indications that other pathways, independent of ABCG5/G8, promote cholesterol transfer into bile.[11,22,23] it is unclear whether the stimulation of biliary cholesterol secretion is a direct effect of TH It may well be mediated by nuclear liver x receptor-alpha (LXRa), the expression of which has recently been reported to be positively regulated by TH receptor-beta (TRb) in the mouse.[24] LXRa regulates the transcription of several genes involved in cholesterol metabolism[25] and the administration of the LXR agonist T0901317 to mice increases hepatic ABCG5/G8 gene expression and biliary cholesterol concentration and secretion.[15,17,26]. The question of if LXRa is important for the effect of TH on biliary cholesterol secretion was explored

Methods

Results

Conclusion