Aquaporin gene transfer for hepatocellular cholestasis

Vilgrain

2021

Cells

Fat accumulation (steatosis) in ballooned hepatocytes alters the expression of membrane transporters in Zucker fatty (fa/fa) rats. The aim of the study was to quantify the functions of these transporters and their impact on hepatocyte concentrations using a clinical hepatobiliary contrast agent (Gadobenate dimeglumine, BOPTA) for liver imaging. In isolated and perfused rat livers, we quantified BOPTA accumulation and decay profiles in fa/+ (normal) and fa/fa hepatocytes by placing a gamma counter over livers. Profiles of BOPTA accumulation and decay in hepatocytes were analysed with nonlinear regressions to characterise BOPTA influx and efflux across hepatocyte transporters. At the end of the accumulation period, BOPTA hepatocyte concentrations and influx clearances were not significantly different in fa/+ and fa/fa livers. In contrast, bile clearance was significantly lower in fatty hepatocytes while efflux clearance back to sinusoids compensated the low efflux into canaliculi. The time when BOPTA cellular efflux impacts the accumulation profile of hepatocyte concentrations was slightly delayed (2 min) by steatosis, anticipating a delayed emptying of hepatocytes. The experimental model is useful for quantifying the functions of hepatocyte transporters in liver diseases.

Section: Discussionmentioning

confidence: 99%

Steatosis Alters the Activity of Hepatocyte Membrane Transporters in Obese Rats

Vilgrain

2021

Cells

“…BOPTA biliary clearance (CL bile ) and BOPTA bile concentrations were much lower in MCT livers, and the choleretic effect of BOPTA was nearly abolished. Mrp2 function is linked to that of aquaporin 8 on cholesterol-enriched domains in the canalicular membrane [ 21 ]. However, the mechanism of this link was never investigated.…”

Section: Discussionmentioning

confidence: 99%

Monocrotaline Toxicity Alters the Function of Hepatocyte Membrane Transporters in Rats

Vilgrain

2022

IJMS

Pyrrolizidine alkaloid monocrotaline (MCT) induces sinusoidal obstruction syndrome (SOS) in rats characterised by a sinusoidal congestive obstruction. Additionally, MCT administration decreases the biliary excretion of gadobenate dimeglumine (BOPTA), a hepatobiliary substrate used in clinical imaging. BOPTA crosses hepatocyte membranes through organic anion transporting polypeptides, multidrug-resistance-associated protein 2, and Mrp3/4 transporters, and a modified function of these transporters is likely to explain the decreased biliary excretion. This study compared BOPTA transport across hepatocytes in livers isolated from normal (Nl) rats and rats with intragastric administration of MCT. BOPTA hepatocyte influx clearance was similar in both groups, while biliary clearance and bile concentrations were much lower in MCT than in Nl livers. BOPTA efflux clearance back to the sinusoids compensated for the low biliary excretion, and hepatocyte concentrations remained similar in both groups. This SOS-associated changes of transporter functions might impact the pharmacokinetics of numerous drugs that use similar transporters to cross hepatocytes.

“…In cholestatic rat livers, the down-regulation of BSEP and MRP2 is associated with a reduced expression of AQP8. [2] Delivery of an adenovector encoding for human AQP1 redistributes BSEP and MRP2 in the canalicular cholesterol-rich microdomains and improves bile secretion.…”

Section: Excretionmentioning

confidence: 99%

Letter to the editor: “On the mechanisms of biliary flux”

2022

Hepatology

To the editor, I read with interest the review published by Vartak et al. [1] that questions the site of water transport associated with the bile excretion of choleretic bile acids and organic anions. The authors deny a water efflux associated with bile salt export pump (BSEP)-and multidrug resistance-associated protein 2 (MRP2)-dependent transport at the canaliculi membrane because no bile flow was observed with intravital microscopy. In contrast, bile flow is well evidenced in ductules and ducts where water efflux into ductular lumen might originate from cholangiocytes in association with HCO − 3