Human Cholestatic Liver Diseases Research Articles

Regulation of organic anion and drug transporters of the sinusoidal membrane

T” LIVER plays a key role in the clearance and metabolism of endogenous and xenobiotic lipophilic organic substances. Following uptake into the liver cell, these compounds undergo biotransformation and are subsequently eliminated from the hepatocyte via secretion into the bile canaliculus. Bile formation is driven primarily by the vectorial secretion of bile acids from sinusoidal blood into bile. Numerous transport systems have been identified on the functional and the molecular level which are involved in the basolateral uptake and the canalicular secretion of amphipathic organic substrates across the hepatocyte membrane (Fig. 1). The regulative pathways which modulate the expression and function of the multiple transport systems have been partially elucidated, in particular with respect to alterations of transport protein expression in cholestatic liver disease (l-3). Several studies have focussed on the effects of cholestasis on hepatic membrane transport processes, both in experimental rat models and in human cholestatic liver disease. The aim of this review is to summarize the most recent developments concerning the function and regulation of basolateral (sinusoidal) transport proteins involved in the uptake of organic anions and cations into the hepatocyte (Table 1).

Cholestasis confers resistance to the rat liver mitochondrial permeability transition

Background & Aims: Bile salts can cause hepatocyte death by inducing the mitochondrial permeability transition (MPT). However, the slow progression of human cholestatic liver diseases suggests that hepatocytes adapt to resist the MPT. Bcl-x, a protein, and increased mitochondrial cardiolipin, a membrane lipid, elevate the threshold for the MPT. Our aims were to determine if liver mitochondria become resistant to the MPT during cholestasis and, if so, if the resistance is mediated by Bcl-x and/or increased cardiolipin. Methods: Hepatocytes and liver mitochondria were obtained from bile duct–ligated (BDL) rats and sham-operated rats (control). Results: After addition of glycochenodeoxycholate (GCDC), the magnitude of the MPT was reduced in mitochondria from BDL rats vs. controls. Although Bcl-x L was not increased, mitochondrial cardiolipin content was significantly greater in BDL rats vs. controls. Cell viability was also increased in hepatocytes from BDL rats vs. controls after treatment with GCDC. Feeding BDL rats a fatty acid–deficient diet prevented the increase in mitochondrial cardiolipin content; mitochondria and hepatocytes from these rats were susceptible to the MPT and hepatocellular death by GCDC. Conclusions: These data suggest that an increase in mitochondria cardiolipin content occurs during cholestasis as an adaptive phenomenon to resist cell death by the MPT. GASTROENTEROLOGY 1998;115:693-701

Semiquantitation of intrahepatic MDR3 mRNA levels by reverse transcription/competitive polymerase chain reaction

Background/Aims: Knockout mice lacking mdr2, the murine analogue of human MDR3 P-glycoprotein, develop chronic non-suppurative cholangitis. Recently, a deficiency in MDR3 messenger RNA (mRNA) has been reported in a subtype of progressive familial intrahepatic cholestasis. Thus, reduced MDR3 gene expression could be involved in human cholestatic liver diseases. Methods: We developed a sensitive and specific reverse transcription/competitive polymerase chain reaction for the semiquantitation of intrahepatic MDR3 mRNA levels. Using this method we determined the MDR3 mRNA levels in 52 liver specimens from primary biliary cirrhosis ( n=11), chronic hepatitis B ( n-5), chronic hepatitis C ( n=14), non-cholestatic cirrhosis ( n=9) and controls ( n=13). Results: MDR3 mRNA was detected in all specimens with some variation in mRNA levels. No significant differences in the mean MDR3 mRNA levels were present between the groups studied, including normal controls. Conclusions: We found no evidence for deficient or severely reduced intrahepatic MDR3 mRNA in primary biliary cirrhosis, nor were mRNA levels altered significantly by virus-induced inflammation or by cirrhosis. The reverse transcription/competitive polymerase chain reaction assay described here should be a useful tool in the semiquantitative study of MDR3 mRNA levels in small tissue specimens.

Integral membrane and matrix heparansulfate proteoglycan expression in human chronic cholestatic liver disease

Integral membrane and matrix heparansulfate proteoglycan expression in human chronic cholestatic liver disease

Lipid deposition in kidneys in experimental liver disease: a study in dogs with choledochocaval anastomosis.

Abstract. To study the ultrastructural changes in kidneys in an experimental model with an increase in the plasma concentration of lipoproteins rich in free cholesterol and phospholipids, cholecystectomy and choledochocaval anastomosis were performed in four dogs. In three dogs the glomeruli were markedly abnormal with deposition of osmiophilic material mainly in the subendothelial regions. The isolated glomeruli contained increased amounts of free cholesterol and phospholipids. In these dogs the plasma concentrations of free cholesterol and phospholipids rose markedly and cholesteryl esters fell. Abnormal plasma lipoprotein particles ultrastructurally similar to those seen in human cholestatic liver disease and in familial deficiency of the enzyme lecithin:cholesterol acyltransferase (LCAT) were found. Large myelin structures in the low density lipoprotein (LDL) range were especially prominent. Serum creatinine and urea concentrations were normal.In the fourth dog there was complete obstruction of the bile duct at the suture line, and changes in plasma lipids and lipoproteins were less pronounced. Large myelin structures were not present in LDL. The glomerular ultrastructure and lipid content were normal.This study demonstrates that lipid is deposited in the glomeruli in dogs when plasma lipoproteins rich in free cholesterol and phospholipids are present in increased concentration. The results suggest that the large myelin structures found in the subendothelial regions of the glomeruli originate from similar particles present in plasma LDL by filtration.