Loss of glucagon control of gluconeogenesis in liver cells from rats with bile duct obstruction.

Bile acids induce membrane alterations including reduced response to peptide hormones in vitro. Isolated liver cells from rats with bile duct obstruction were studied regarding gluconeogenesis and its hormonal control. While cells from shamoperated animals showed an 63% increase of glucose release in the presence of glucagon (1 microM), cells from cholestatic livers did not response regardless of the duration of obstruction. Cholestatic cells also showed other signs of membrane alterations, such as an increased enzyme leakage while redoxstatus and other metabolic responses were unchanged. These results suggest that a loss of hormonal control in the liver could contribute to disturbations of glucose homeostasis in cholestatic conditions.

Zinc and vitamin A deficiency in patients with Crohn's disease is correlated with activity but not with localization or extent of the disease.

A study of serum zinc and plasma vitamin A concentrations in 54 patients with Crohn's disease was performed. Compared with controls the patients had significantly lowered zinc and vitamin A concentrations. There was a marked correlation between zinc and vitamin A and the activity of the disease, as measured by the Crohn's disease activity index, and a weaker correlation with serum proteins considered to be indicators of disease activity. No correlation was found to vitamin B12 absorption, to the localization of the disease, or to previous ileal resection. The results suggest that zinc and vitamin A deficiency occurs in patients with active Crohn's disease and is not primarily caused by absorption abnormalities. Substitution might be helpful or even necessary in patients with highly active disease.

Influence of hydroxylation and conjugation of bile salts on their membrane-damaging properties--studies on isolated hepatocytes and lipid membrane vesicles.

To characterize the relative toxicity of different bile salts, isolated hepatocytes were incubated with different concentrations of one bile salt or with identical concentrations of different bile salts and their conjugates. Incubation lasted for 1 hr; samples were taken at intervals and studied for enzyme release, urea synthesis and stimulation by glucagon, and by electron microscopy. While the trihydroxylated bile salt, taurocholate, did not produce alterations at concentrations up to 1,500 microM, the dihydroxylated salts, chenodeoxy- and deoxycholate, caused enzyme release and membrane lysis, and inhibited urea synthesis at concentrations above 500 microM. In contrast, ursodeoxycholate was ineffective at concentrations up to 1,500 microM. Conjugation of these bile salts did not result in significant differences with the exception of deoxycholate conjugates which induced enzyme leakage more rapidly. Studies of lipid membrane vesicles revealed corresponding alterations. The monohydroxylated salt, taurolithocholate, caused cellular damage as indicated by enzyme loss and impairment of hormonal sensitivity of cells at low concentrations (30 to 100 microM). Dihydroxylated salts produced a different time course of membrane leakage, ultrastructural changes and release of volume marker and lipid in liposomes, suggesting a possible different mechanism of damage induced by this bile salt. Both systems can readily be used to study bile salt membrane interactions.

The influence of portosystemic shunting on zinc and vitamin A metabolism in liver cirrhosis.

To elucidate the possible role of portosystemic shunting on zinc and vitamin A deficiency which has been described in patients with cirrhosis of the liver, a study on 37 hospitalized patients with liver cirrhosis was performed. Patients with surgical portosystemic shunt were found to have a significantly lower levels of zinc, vitamin A and retinol-binding protein (RBP) than controls and patients with cirrhosis without shunt. Patients with portal hypertension--considered to have spontaneous shunting--also has lower levels than those without this symptom. A significant correlation between zinc and vitamin A and RBP levels, respectively, was found. Also an increased renal zinc output was demonstrated. An influence of portosystemic shunting on zinc deficiency and subsequent vitamin A deficiency by decreased RBP release is concluded. The importance of these metabolic disorders for clinical symptoms is discussed.

[Different effect of taurolithocholate and chenodeoxycholate on structure and function of isolated hepatocytes (author's transl)]. / Differente Wirkung von Taurolithocholsäure und Chenodesoxycholsäure auf Membranstruktur und Funktion isolierter Hepatozyten.

Alterations of cellular membranes under the influence of bile acids seem to be of pathophysiological importance in cholestasis. The effect of taurolithocholic acid (TLCA) and chenodeoxycholic acid (CDCA) on membrane structure and release of cellular enzymes was studied on isolated rat hepatocytes. The response of urea synthesis to glucagon was used as a parameter of membrane function. The threshold dose of TLCA, marked by rapidly increasing enzyme release, was about 100 micrometers, whereas that of CDCA was between 500 and 1,000 micrometers. Addition of albumin (1 g-%) increased the threshold dose of CDCA; this occurred for TLCA only 8 g-%. Electron-microscopical alterations of the endoplasmic reticulum and submembranous areas were found with concentrations below these threshold doses even in the presence of albumin. These alterations are interpreted as disturbance of cellular transport and energy metabolism. TLCA inhibited glucagon response of cells in concentrations below 100 micrometers. These results demonstrate an influence of the bile acids studied on structure and function of liver cell membranes, which may be of importance in the pathogenesis of cholestasis. The rough endoplasmic reticulum could be another cellular structure which is affected by these bile acids.