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Association between gadoxetic acid-enhanced MR imaging, organic anion transporters, and farnesoid X receptor in benign focal liver lesions


van Rosmalen, Belle V; Visentin, Michele; Furumaya, Alicia; van Delden, Otto M; Kazemier, Geert; van Gulik, Thomas M; Verheij, Joanne; Stieger, Bruno (2024). Association between gadoxetic acid-enhanced MR imaging, organic anion transporters, and farnesoid X receptor in benign focal liver lesions. Drug Metabolism and Disposition, 52(2):118-125.

Abstract

The organic anion uptake and efflux transporters (OATP1B1, OATP1B3, MRP2 and MRP3) that mediate the transport of the hepatobiliary-specific contrast agent gadoxetate (Gd-EOB-DTPA), are direct or indirect targets of the farnesoid X receptor (FXR), a key regulator of bile acid and lipid homeostasis. In benign liver tumours, FXR expression and activation is not yet characterized. We investigated the expression and activation of FXR and its targets in hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH) and their correlation with Gd-EOB-DTPA-enhanced MRI. Gd-EOB-DTPA MRI pattern were assessed by an expert radiologist. The intensity of the lesions on the hepatobiliary phase was correlated to mRNA expression levels of OATP1B1, OATP1B3, MRP2, MRP3, FXR and small heterodimer partner (SHP) in fresh surgical specimens of patients with FNH or HCA subtypes. Normal and tumour sample pairs of 43 HCA and 14 FNH were included. All FNH (14/14) were hyperintense. Of the 34 HCA with available Gd-EOB-DTPA-enhanced MRI, six were hyperintense and 28 HCA were hypointense. OATP1B3 was downregulated in the hypointense tumours compared to normal surrounding liver tissue (2.77{plus minus}3.59 vs 12.9{plus minus}15.6, p<0.001). A significant positive correlation between FXR expression and activation and OATP1B3 expression level was found in the HCA cohort. SHP showed a trend towards downregulation in hypointense HCA. In conclusion, this study suggests that the MRI relative signal in HCA may reflect expression level and/or activity of SHP and FXR. Moreover, our data confirms the pivotal role of OATP1B3 in Gd-EOB-DTPA uptake in HCA. Significance Statement Farnesoid X receptor (FXR) represents a valuable target for the treatment of liver disease and metabolic syndrome. Currently, two molecules, ursodeoxycholate and obeticholate, are approved for the treatment of primary biliary cirrhosis and cholestasis, with several compounds in clinical trials for the treatment of metabolic dysfunction-associated fatty liver disease (MAFLD). Because FXR expression and activation is associated with gadoxetate accumulation in HCA, atypical gadoxetate-enhanced MRI pattern might arise in patients under FXR-targeted therapy, thereby complicating the differential diagnosis.

Abstract

The organic anion uptake and efflux transporters (OATP1B1, OATP1B3, MRP2 and MRP3) that mediate the transport of the hepatobiliary-specific contrast agent gadoxetate (Gd-EOB-DTPA), are direct or indirect targets of the farnesoid X receptor (FXR), a key regulator of bile acid and lipid homeostasis. In benign liver tumours, FXR expression and activation is not yet characterized. We investigated the expression and activation of FXR and its targets in hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH) and their correlation with Gd-EOB-DTPA-enhanced MRI. Gd-EOB-DTPA MRI pattern were assessed by an expert radiologist. The intensity of the lesions on the hepatobiliary phase was correlated to mRNA expression levels of OATP1B1, OATP1B3, MRP2, MRP3, FXR and small heterodimer partner (SHP) in fresh surgical specimens of patients with FNH or HCA subtypes. Normal and tumour sample pairs of 43 HCA and 14 FNH were included. All FNH (14/14) were hyperintense. Of the 34 HCA with available Gd-EOB-DTPA-enhanced MRI, six were hyperintense and 28 HCA were hypointense. OATP1B3 was downregulated in the hypointense tumours compared to normal surrounding liver tissue (2.77{plus minus}3.59 vs 12.9{plus minus}15.6, p<0.001). A significant positive correlation between FXR expression and activation and OATP1B3 expression level was found in the HCA cohort. SHP showed a trend towards downregulation in hypointense HCA. In conclusion, this study suggests that the MRI relative signal in HCA may reflect expression level and/or activity of SHP and FXR. Moreover, our data confirms the pivotal role of OATP1B3 in Gd-EOB-DTPA uptake in HCA. Significance Statement Farnesoid X receptor (FXR) represents a valuable target for the treatment of liver disease and metabolic syndrome. Currently, two molecules, ursodeoxycholate and obeticholate, are approved for the treatment of primary biliary cirrhosis and cholestasis, with several compounds in clinical trials for the treatment of metabolic dysfunction-associated fatty liver disease (MAFLD). Because FXR expression and activation is associated with gadoxetate accumulation in HCA, atypical gadoxetate-enhanced MRI pattern might arise in patients under FXR-targeted therapy, thereby complicating the differential diagnosis.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Pharmaceutical Science, Pharmacology
Language:English
Date:1 February 2024
Deposited On:08 Dec 2023 13:55
Last Modified:29 Jun 2024 01:41
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0090-9556
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1124/dmd.123.001492
PubMed ID:38050024