Search

BACKGROUND & AIMS: Pathophysiological conditions such as sepsis and hepatitis are mediated by inflammatory cytokines and frequently are associated with cholestasis. The aim of this study was to determine the effect of endotoxin (lipopolysaccharide [LPS]) and cytokine administration on hepatocellular transporters involved in bile salt transport. METHODS: LPS and cytokines were administered to Sprague- Dawley rats or C57BL/6 mice, and the expression and function of hepatocyte transporters involved in bile salt secretion were examined. RESULTS: LPS caused gene expression of the hepatocyte basolateral sodium-dependent taurocholate cotransporter (Ntcp) to decrease by more than 90%. Tumor necrosis factor alpha (TNF-alpha) or interleukin (IL) 1beta also produced a time-dependent decrease in Ntcp messenger RNA levels, whereas IL-6 had no effect. LPS administration resulted in a concordant 90% reduction of basolateral protein expression of the hepatocyte sodium taurocholate cotransporter and markedly diminished sodium-dependent taurocholate uptake. Activity of the hepatocyte basolateral Na+,K+-adenosine triphosphatase (ATPase) was also decreased by 50% in a posttranslational manner after endotoxin treatment. CONCLUSIONS: Endotoxin inhibits hepatocellular sodium-dependent bile salt uptake by decreasing both expression of Ntcp and activity of the Na+,K-ATPase. The effects on Ntcp are mediated via TNF-alpha and IL- 1beta. Alterations of these transporters may contribute to the cholestasis of sepsis and inflammation. (Gastroenterology 1996 Jul;111(1):193-8)

Background/Aims: Cluster of differentiation 1 (CD1) is a family of nonpolymorphic, major histocompatibility complex class I-like molecules with prominent expression in the liver and intestinal epithelium of humans and mice. Models of intestinal and hepatobiliary inflammation and experimental liver transplantation are conducted in the rat, yet nothing is known of CD1 expression in this species. Methods: Monoclonal antibodies against murine CD1 were used to identify a rat CD1 homologue. Tissue messenger RNA expression was confirmed by Northern blot analysis with a murine CD1 complementary DNA probe. Results: Immunoperoxidase staining detected CD1 in intestinal epithelial and liver cells but not in the thymus. Immunofluorescence of isolated hepatocytes and a rat fetal intestinal cell line, SLC-44, showed cell surface expression of CD1. Metabolic labeling and immunoprecipitation of the SLC-44 cell line and a mouse intestinal epithelial cell line, MODE-K, showed a protein of 55 kilodaltons. Immunoblotting of CD1 in isolated intestinal epithelial cells and hepatocytes showed a molecule of 55 kilodaltons. Northern blot analysis showed a single message of approximately 2.2 kilobases in hepatocytes. Conclusions: A CD1 homologue exists in the rat. Expression in the rat intestine and liver are similar to those in the human and mouse. The rat may be useful as a model for the study of CD1 function.

Background & Aims ABCB11 is a canalicular transport protein that controls the rate-limiting step in hepatic bile acid secretion. Its expression levels vary in humans, and it is not clear how these variations affect lipid metabolism. We investigated whether overexpression of Abcb11 in mice increases lipid absorption in the intestine and affects the development of obesity or hypercholesterolemia. Methods Transgenic mice that overexpress Abcb11 in liver (TTR- Abcb11 ) and FVB/NJ mice (controls) were fed a high-cholesterol or high-fat diet for 12 weeks. Intestinal lipid absorption was measured by the dual fecal isotope method. Energy expenditure was measured by indirect calorimetry. The bile acid pool was analyzed by high-performance liquid chromatography. Results TTR- Abcb11 mice had a nearly 2-fold increase in intestinal cholesterol absorption compared with controls. TTR- Abcb11 mice fed a high-cholesterol diet had greater increases in plasma and hepatic levels of cholesterol and became more obese than controls; they also had increased intestinal absorption of fatty acids and decreased energy expenditure. In the TTR- Abcb11 mice, the sizes of plasma and total bile acid pools were reduced; the bile acid pool contained more species of hydrophobic bile acids compared with controls. Conclusions Hepatic overexpression of Abcb11 in mice promotes diet-induced obesity and hypercholesterolemia; increased intestinal cholesterol absorption by hydrophobic bile acids might cause these features. Increased absorption of fatty acids in the intestine and reduced expenditure of energy could increase weight gain in TTR- Abcb11 mice. In humans, variations in expression of ABCB11 might confer genetic susceptibility to diet-induced hyperlipidemia and obesity.