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Biomedical subjects

A G Morell

Publications and source records attributed to A G Morell.

45 records · Page 3Linked to original sources
PubMedDate not supplied

Modulation of the transport of bilirubin and asialoorosomucoid during liver regeneration.

The normal rat hepatocyte divides approximately once per year but, following two thirds hepatectomy, rapid cellular replication occurs throughout the remaining liver remnant. Using a multiple indicator dilution technique, single-pass transport of 3H-bilirubin and 125I-asialoorosomucoid was studied in isolated perfused liver from 6 hr to 6 d after two thirds hepatectomy or sham surgery. Influx (k1), efflux (k2), and sequestration (k3) rates were quantitated by computer analysis. k1 for 3H-bilirubin fell by over 50% within 6 hr after two thirds hepatectomy and returned to normal 4 d later. k2 progressively decreased with a nadir at 2 d, and returned to normal by 4 d. k3 was transiently depressed, and became normal within 2 d. Although hepatic uptake of asialoglycoproteins has been thought to be irreversible, the experimental data required k2 and k3 parameters for best fit. Similar to results for 3H-bilirubin, the k1 of 125I-asialoorosomucoid was 20% of normal at 1 d after two thirds hepatectomy, and returned to normal by 6 d. Unlike results for 3H-bilirubin, there was a prolonged 50% reduction of k2 and k3 with return to normal by 6 d. The transport changes during regeneration are independent of reduced liver mass or changes in hepatic spaces of distribution. The fact that influx of both compounds reaches a nadir at the time of greatest cellular proliferation with subsequent return to normal suggests a "maturation" of liver cell function for restoration of these specific hepatocyte functions. Modulation of the hepatocyte receptor for desialylated glycoproteins may also be required for cellular recognition as a prerequisite for proliferative responses.

Animals↗
PubMedDate not supplied

Hepatic lysosomal copper protein in dogs with an inherited copper toxicosis.

Hepatic copper overload inherited as an autosomal recessive trait in Bedlington Terriers is characterized by the presence of hepatocellular lysosomal granules of unusually high specific gravity and electron density which contain at least two thirds of the total hepatic copper. Fractionation of homogenates of liver from such affected Bedlington Terriers yielded a low-speed pellet which contained the lysosomal granules. This fraction was used for isolation of a copper-binding protein by alkaline-reduction, solubilization, fractional acetone precipitation, and gel filtration. The purified protein yielded a single band on polyacrylamide gel electrophoresis and resembled other metallothioneins in containing 15 cysteine residues and 7 to 8 atoms of copper (but no zinc) per 54 amino acid residues. No methionine, histidine, or any aromatic amino acid was present. The accumulation of this lysosomal copper protein appears to be related to the primary genetic defect which underlies the hepatic copper toxicosis of the Bedlington Terrier.

Animals↗
PubMedDate not supplied

Asialoglycoprotein receptor expression in murine pregnancy and development.

Hepatic asialoglycoprotein receptor activity of pregnant mice increased from the tenth day of gestation, reaching 3-fold the normal adult level just prior to parturition and returning to normal within 1 week postpartum. Increases in activity involved both intracellular and cell-surface associated receptors and were associated with enhanced endocytosis of asialoorosomucoid by isolated hepatocytes. Modulation of hepatic binding protein expression during murine pregnancy represents the first situation in which this receptor's concentration has been shown to exceed normal levels in response to a physiologic change. In the fetus, receptor activity was barely detectable throughout gestation, steadily increased in the neonatal period, and reached adult levels by the fifth postpartum day.

Animals↗
PubMedDate not supplied

Origins of biliary copper.

We tested the hypothesis that the copper present in bile--the major route of elimination of the metal from the body--is derived exclusively from hepatocytes by administering radiocopper (64Cu or 67Cu)-labeled ionic Cu, desialylated (AsCPN) or intact human ceruloplasmin (CPN), intravenously, to rats with cannulated bile ducts. The rates of appearance and the total amounts of radiolabeled isotope recovered in bile were measured. The three vehicles chosen for the delivery of radiocopper interact differently with hepatocytes: ionic Cu is taken up by a passive process (Schmitt, R. C. et al., Am. J. Physiol. 1983; 244:G183-G191); AsCPN is promptly cleared from the circulation by specific receptor-mediated endocytosis, and CPN largely remains in the circulation for the duration of the experiment. Similar amounts of radiocopper were recovered following injections of ionic Cu (3.1%) or CPN (2%), but substantially larger amounts (8.1%) were excreted after administration of AsCPN. Using an antibody to CPN which reacts also with AsCPN, we found about 70% of the bile radioactivity to be immunoprecipitable following injections of either glycoprotein, indicating that a fraction of these copper proteins had entered the bile essentially unmodified. Our observations indicate that in addition to the lysosomal compartment which catabolizes a portion of the AsCPN in hepatocytes, there appears to be a direct route for AsCPN from hepatocellular sinusoids to the bile canaliculi. Since CPN does not interact significantly with hepatocytes, its presence in bile suggests transcytosis via the biliary epithelium.

Animals↗
PubMedDate not supplied

Transport and intracellular distribution of copper in a human hepatoblastoma cell line, HepG2.

The uptake of radiocopper by HepG2 cells is a saturable, temperature-dependent and cellular energy-independent process with a Vmax of 7.1 +/- 0.2 pmoles min-1 mg protein-1 and an estimated Km of 3.3 +/- 0.5 microM. The rate of copper uptake is reduced at an equimolar concentration of albumin and is unaffected by zinc at a 10-fold molar excess. Approximately 70% of the newly incorporated radiocopper binds to membranes and organelles, while 30% is recovered in the cytosol. The soluble fraction can be resolved into two copper-binding protein peaks. Incubation of HepG2 with nonisotopic copper results in displacement of radiocopper associated with the proteins contained in the lower molecular weight peak. Exposure of the cells to cycloheximide inhibits the incorporation of the isotope into this fraction.

Biological Transport↗
PubMedDate not supplied

Selective regulation of intrinsic membrane proteins in HepG2.

Expression of three hepatocellular membrane proteins--the asialoglycoprotein receptor (hepatic binding protein) the insulin receptor and organic anion binding protein--have been studied in the HepG2 cell line. HepG2 grown in minimal essential medium supplemented with 10% fetal bovine serum maximally expressed hepatic binding protein and insulin receptor only at confluence while organic anion binding protein appeared independent of the state of cellular proliferation. When cells were grown in medium supplemented with dialyzed fetal bovine serum, adult bovine serum or in chemically defined medium, expression of hepatic binding protein and insulin receptor but not organic anion binding protein was reduced by 60 to 80%. Immunoblotting techniques revealed that cells grown in dialyzed fetal bovine serum contained virtually no mature, glycosylated 45 kD hepatic binding protein, but a small amount of 36 kD protein. Metabolic labeling of cells grown in dialyzed fetal bovine serum with [35S] methionine indicated reduced synthesis of the 45 kD hepatic binding protein and the absence of the 36 kD protein. Restoration of normal expression of hepatic binding protein and insulin receptor was achieved by addition to dialyzed fetal bovine serum of: fetal bovine serum; 2,000 dalton ultrafiltrate of fetal bovine serum, or 300 to 350 dalton fraction of the ultrafiltrate. The normal concentration of organic anion binding protein demonstrable in cells grown in dialyzed fetal bovine serum indicates that the low molecular weight factor(s) is not a generalized modulator of plasma membrane biogenesis. However, its effect on the steady-state level of the hepatic binding protein and insulin receptor, characteristic of mature hepatocytes, suggests a role for this fetal serum factor in hepatocellular differentiation.

Anion Transport Proteins↗