Hepatic bile acid transport increases in the postprandial state: A functional 11C-CSar PET/CT study in healthy humans

Abstract

Background & aims: It is not known how hepatic bile acids transport kinetics changes postprandially in the intact liver. We used positron emission tomography (PET)/computed tomography (CT) with the tracer [N-methyl-¹¹C]cholylsarcosine (¹¹C-CSar), a synthetic sarcosine conjugate of cholic acid, to quantify fasting and postprandial hepatic bile acid transport kinetics in healthy human participants.

Methods: Six healthy human participants underwent dynamic liver ¹¹C-CSar PET/CT (60 min) during fasting and from 15 min after ingestion of a standard liquid meal. Hepatobiliary secretion kinetics of ¹¹C-CSar was calculated from PET data, blood samples (arterial and hepatic venous) and hepatic blood flow measured using indocyanine green infusion.

Results: In the postprandial state, hepatic blood perfusion increased on average by 30% (p <0.01), and the flow-independent hepatic intrinsic clearance of ¹¹C-CSar from blood into bile increased by 17% from 1.82 (range, 1.59-2.05) to 2.13 (range, 1.75-2.50) ml blood/min/ml liver tissue (p = 0.042). The increased intrinsic clearance of ¹¹C-CSar was not caused by changes in the basolateral clearance efficacy of ¹¹C-CSar but rather by an upregulated apical transport, as shown by an increase in the rate constant for apical secretion of ¹¹C-CSar from hepatocyte to bile from 0.40 (0.25-0.54) min^-1 to 0.67 (0.36-0.98) min^-1 (p = 0.03). This resulted in a 33% increase in the intrahepatic bile flow (p = 0.03).

Conclusions: The rate constant for the transport of bile acids from hepatocytes into biliary canaliculi and the bile flow increased significantly in the postprandial state. This reduced the mean ¹¹C-CSar residence time in the hepatocytes.

Lay summary: Bile acids are important for digestion of dietary lipids including vitamins. We examined how the secretion of bile acids by the liver into the intestines changes after a standard liquid meal. The transport of bile acids from liver cells into bile and bile flow was increased after the meal.

Keywords: 11C-CSar, [N-methyl-11C]cholylsarcosine; BSEP, bile salt export pump; CT, computed tomography; FGF-19, fibroblast growth factor 19; FXR, farnesoid X receptor; Hepatobiliary kinetics; ICG, indocyanine green; Liver physiology; NTCP, Na+ taurocholate co-transporting polypeptide; PET, positron emission tomography; Positron emission tomography; liver-VOI, liver volume of interest.

Graphical abstract

Fig. 1

Kinetic compartmental model of the hepatic transport of ¹¹C-CSar. The model describes compartments of blood, liver tissue, and intrahepatic bile within the liver-VOI. The exchange of ¹¹C-CSar between the compartments is described by rate constants: K₁, unidirectional clearance of ¹¹C-CSar from blood to hepatocytes (ml blood/min/ml liver tissue); k₂, rate constant for the backflux from hepatocytes to blood (min⁻¹); k₃, rate constant for secretion from hepatocytes to intrahepatic bile (min⁻¹); and k_5, rate constant for flow of ¹¹C-CSar to extrahepatic bile (min⁻¹). ¹¹C-CSar, [N-methyl-¹¹C]cholylsarcosine; liver-VOI, liver volume of interest.

Fig. 2

Time courses of the ¹¹C-CSar concentration in arterial blood (red), hepatic venous blood (purple), and liver tissue (black) in the fasting and postprandial states. ¹¹C-CSar concentration are shown as standardized uptake values, where the concentrations are corrected for the individual dose of ¹¹C-CSar and body weight. ¹¹C-CSar, [N-methyl-¹¹C]cholylsarcosine.

Fig. 3

Individual pairs of fasting and postprandial values of k₃, the rate constant for secretion of ¹¹C-CSar from hepatocyte to intrahepatic bile (min⁻¹). p <0.05 (paired t test). ¹¹C-CSar, [N-methyl-¹¹C]cholylsarcosine.

Fig. 4

Individual pairs of fasting and postprandial values of intrahepatic bile flow (ml bile/min). p <0.05 (paired t test).

Fig. 5

Individual time courses of arterial (red) and hepatic venous (purple) plasma concentrations of FGF-19 (pg/ml plasma) and endogenous bile acids (pg/ml plasma). The meal was ingested 15 min before the start of the postprandial examination. FGF-19, fibroblast growth factor 19.