Hepatic Expression of ABC Transporters G5 and G8 Does Not Correlate With Biliary Cholesterol Secretion in Liver Transplant Patients *

Abstract

The adenosine triphosphate (ATP)-binding cassette (ABC)-transporters ABCG5 and ABCG8 have been shown to mediate hepatic and intestinal excretion of cholesterol. In various (genetically modified) murine models, a strong relationship was found between hepatic expression of ABCG5/ABCG8 and biliary cholesterol content. Our study aimed to relate levels of hepatic expression of ABCG5 and ABCG8 to biliary excretion of cholesterol in man. From 24 patients who had received a liver transplant, bile samples were collected daily after transplantation over a 2-week period to determine biliary composition. Expression of ABCG5, ABCG8, MDR3, and BSEP was assessed by real-time polymerase chain reaction (PCR) in liver biopsy specimens collected before and after transplantation. Levels of hepatic ABCG5, ABCG8, and MDR3 messenger RNA (mRNA) were strongly correlated. After transplantation, the biliary secretion rate of cholesterol continuously increased, coinciding with gradual increases in bile salt and phospholipid secretion. In contrast, hepatic levels of ABCG5 and ABCG8 mRNA remained unchanged. Surprisingly, no correlation was found between the hepatic expression of ABCG5 and ABCG8 and rates of biliary cholesterol secretion, normalized for biliary phospholipid secretion. As expected, the concentration of biliary phospholipids correlated well with MDR3 expression. In conclusion, the strong relationship between ABCG5 and ABCG8 gene expression is consistent with the coordinate regulation of both genes, and in line with heterodimerization of both proteins into a functional transporter. Hepatic ABCG5/ABCG8 expression, at least during the early phase after transplantation, is not directly related to biliary cholesterol secretion in humans. This finding suggests the existence of alternative pathways for the hepatobiliary transport of cholesterol that are not controlled by ABCG5/ABCG8. (HEPATOLOGY 2005;42:1166-1174

Scavenger Receptor Class B Type I Mediates Biliary Cholesterol Secretion Independent of ATP-Binding Cassette Transporter g5/g8 in Mice†

“…18,21,26 However, there is residual biliary cholesterol secretion in Abcg5 or Abcg8 knockout mice, 18,21,26 and previous studies involving our group have shown that Abcg5/Abcg8-independent biliary cholesterol secretion occurs. [21][22][23] Based on the results of this study, we would propose that SR-BI acts as a key candidate for mediating this Abcg5/Abcg8-independent fraction of biliary cholesterol secretion. As evidenced by the correction of the biliary cholesterol secretion deficit of Abcg5 knockout mice by hepatic SR-BI overexpression, SR-BI can drive biliary cholesterol secretion independent of Abcg5.…”

“…19 However, in the absence of Abcb4, even high-level overexpression of Abcg5/Abcg8 does not increase biliary cholesterol secretion, 20 delineating the crucial role for biliary phospholipids in mixed micelles with bile salts as acceptors for cholesterol solubilization. Importantly, an Abcg5/Abcg8-independent cholesterol secretion pathway has been described; [21][22][23] however, the mediator of this process remains unknown.…”

Evaluation of the Contribution of the ATP Binding Cassette Transporter, P-glycoprotein, to in Vivo Cholesterol Homeostasis

“…The dimer formed by the half transporters ABCG5 and ABCG8 is the primary efflux mechanism for unmodified cholesterol from cells of the small intestine and the liver. Deletion of ABCG5 and ABCG8 does not completely ablate cholesterol efflux suggesting that a secondary mechanism for the removal of cholesterol may exist in mice 3,4 , with confirmatory findings in humans 5 .…”

Sterolins ABCG5 and ABCG8: regulators of whole body dietary sterols

“…ABCG 5/ABCG8 may not be rate-limiting, because parents of sitosterolemic patients have no biochemical phenotype under physiological conditions, although they must have halfnormal functioning sterolins. In this context, a recent study of ABCG5/ABCG8 expression in liver transplant patients found no correlation between mRNA expression of these transporters and biliary cholesterol secretion (sitosterol secretion was not reported) [13].…”