Molecular regulation of the hepatic bile acid uptake transporter and HBV entry receptor NTCP

Background: A fascinating aspect of bile acid homeostasis is the coordination between bile acid uptake in intestine and hepatic bile acid synthesis. In response to bile acid uptake in enterocytes, farnesoid X receptor is activated and induces transcription of fibroblast growth factor (FGF)15 in mice, or FGF19 in humans. FGF15/19 is secreted into the enterohepatic circulation, and through activation of hepatic receptors, leads to repression of Cyp7a1, a rate-limiting enzyme for bile acid synthesis. Using a genetic approach, we identified a novel protein, Diet1, as a control point for FGF15/19 production. Key Messages: Mice with a Diet1-null mutation have reduced FGF15 secretion, causing impaired feedback repression of hepatic bile acid synthesis, and increased fecal bile acid excretion. As a result, Diet1-deficient mice constitutively convert cholesterol to bile acids and are resistant to diet-induced hypercholesterolemia and atherosclerosis. Diet1 affects FGF15/19 production at the posttranscriptional level, and the proteins appear to have overlapping subcellular localization in enterocytes. Diet1 appears to be a control point for the production of FGF15/19 in enterocytes, and thus a regulator of bile acid and lipid homeostasis. Studies to evaluate the role of common and rare DIET1 genetic variants in human health and disease are warranted. Conclusions: Further elucidation of the Diet1-FGF15/19 interaction will provide new insights into the intricate regulatory mechanisms underlying bile acid metabolism.

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cAMP stimulates fluorescent bile acid uptake into hepatocytes by membrane hyperpolarization

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1996.270.2.g339 ◽

1996 ◽

Vol 270 (2) ◽

pp. G339-G346 ◽

Cited By ~ 2

Author(s):

S. Grune ◽

X. J. Meng ◽

S. A. Weinman

Keyword(s):

Bile Acid ◽

Voltage Clamp ◽

Uptake Rate ◽

Direct Consequence ◽

Acid Uptake ◽

Net Charge ◽

Membrane Hyperpolarization ◽

Whole Cell ◽

Bile Acid Uptake ◽

Stimulation Of

Elevation of intracellular adenosine 3',5'-cyclic monophosphate (cAMP) hyperpolarizes hepatocytes and increases the uptake rate of bile acids. The purpose of this study was to determine to what extent these two phenomena are linked. Fluorescent bile acid analogues (FBA) were used to probe bile acid transport into whole cell patch-clamped hepatocytes. Na(+)-dependent uptake of cholyl-nitrobenz-2-oxa-1,3-diazol-4-yl-lysine (C-NBD-L), an FBA with a net charge of -1, was shown to be electrogenic, whereas uptake of cholylglycylamidofluorescein (CGamF), an FBA with a net charge of -2, was neutral. Incubation of hepatocytes with 8-bromo-cAMP (8-BrcAMP; 100 microM) increased the uptake rate of the electrogenically transported FBA by 25% (P = 0.002), but had no effect on the uptake rate of the electroneutrally transported FBA. Microelectrode impalements revealed that 8-BrcAMP or forskolin hyperpolarized hepatocytes by 6-8 mV. To determine if hyperpolarization is responsible for the cAMP-induced increase in uptake rate, cAMP was directly introduced into hepatocytes during whole cell patch clamp under voltage-clamp conditions. As long as voltage clamp was maintained at -30 mV there was no stimulation of C-NBD-L uptake. However, when voltage clamp was terminated by either pipette removal or current clamp, cAMP increased the uptake rate by 25-34% (P < 0.002). In both of these protocols, cAMP had no effect on uptake of the electroneutrally transported FBA, CGamF. Finally, in voltage-clamped hepatocytes in the absence of cAMP, a 10-mV hyperpolarization increased the uptake rate of C-NBD-L by 23%. We therefore conclude that short-term cAMP-induced stimulation of fluorescent bile acid uptake in hepatocytes is a direct consequence of membrane hyperpolarization.

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