Edward J. Sarcione

STUDIES OF GLYCOGEN METABOLISM IN LIVER GLYCOGEN DISEASE (VON GIERKE'S DISEASE): SIX CASES WITH SIMILAR METABOLIC ABNORMALITIES AND RESPONSES TO GLUCAGON

Glycogen disease of the liver (von Gierkes disease) is a rare and incompletely understood disorder of childhood. It is characterized by defective breakdown of liver glycogen to glucose. In most cases, excessive liver glycogen deposition occurs, reaching levels as high as 14 to 17 per cent of the wet liver weight (1, 2). Major clinical manifestations include hepatomegaly; fasting hypoglycemia, acidosis and ketosis; delayed growth and development, and increased morbidity with even minor infections. The most severely affected children have usually died during infancy. Histologic studies of autopsy or biopsy specimens of liver reveal essentially normal architecture, but hepatic cells contain excessive amounts of glycogen and often, fat. The glycogen is usually normal in structure (3) and can be broken down to glucose by homogenates of normal animal or human liver (2, 4, 5). Spontaneous breakdown of glycogen during in vitro incubation of liver tissue from affected children is deficient (2, 4, 6). The currently accepted pathways of liver glycogen metabolism are summarized in Figure 1. It was formerly believed that glycogen was synthesized through the action of phosphorylase, the same enzyme that catalyzes its breakdown. However, it is now agreed that this reaction, which occurs readily in vitro, is not an important one in vivo (7), and that glycogen synthesis probably proceeds through the uridine-diphosphoglucose pathway described by Leloir and Cardini (8). Glycogen breakdown is mediated by phosphorylase

Conservation of IL-6 trans-signaling mechanisms controlling L-selectin adhesion by fever-range thermal stress.

Fever is associated with improved survival during infection in endothermic and ectothermic species although the protective mechanisms are largely undefined. Previous studies indicate that fever‐range thermal stress increases the binding activity of the L‐selectin homing receptor in human or mouse leukocytes, thereby promoting trafficking to lymphoid tissues across high endothelial venules (HEV). Here, we examined the evolutionary conservation of thermal regulation of L‐selectin‐like adhesion. Leukocytes from animals representing four taxa of vertebrates (mammals, avians, amphibians, teleosts) were shown to mediate L‐selectin‐like adhesion under shear to MECA‐79‐reactive ligands on mouse HEV in cross‐species in vitro adherence assays. L‐selectin‐like binding activity was markedly increased by fever‐range thermal stress in leukocytes of all species examined. Comparable increases in L‐selectin‐like adhesion were induced by thermal stress, IL‐6, or the IL‐6/soluble IL‐6 receptor fusion protein, hyper‐IL‐6. Analysis of the molecular basis of thermal regulation of L‐selectin‐like adhesion identified a common IL‐6 trans‐signaling mechanism in endotherms and ectotherms that resulted in activation of JAK/STAT signaling and was inhibited by IL‐6 neutralizing antibodies or recombinant soluble gp130. Conservation of IL‐6‐dependent mechanisms controlling L‐selectin adhesion over hundreds of millions of years of vertebrate evolution strongly suggests that this is a beneficial focal point regulating immune surveillance during febrile inflammatory responses.

Synthesis of alpha fetoprotein by immature rat uterus

Abstract Reported free and bound molecular forms of alpha fetoprotein detected in immature uterine cytosol could be due to either selective uptake from the serum and/or intracellular synthesis by this tissue. In this study immature rat uterus synthesized initially immunounreactive bound alpha fetoprotein, which becomes immunoreactive after treatment with 0.4M KCl, but failed to synthesize free alpha fetoprotein. This indicates that bound alpha fetoprotein is not a conversion product of the free form, and suggests a relationship between alpha fetoprotein synthesis and uterine growth and development.

Failure of blood glucose levels to reflect hepatic glycogenolysis; experiences with glucagon.

Summary 1) Glucagon is as active a glycogenolytic agent when administered subcutaneously as it is by intraperitoneal or intravenous route. However increases in blood glucose may not be observed following subcutaneous administration of glucagon, even though liver glycogen is almost completely mobilized. In adrenodemedullated animals, this is the rule. 2) Total liver glycogen store of the rat is relatively small, compared to the capacity of glucose disposal mechanisms. Changes in rates of the major glucose disposal reactions can completely mask the anticipated effect of hepatic glycogenolysis on blood glucose concentration. Such changes may be induced by fluctuations of endogenous insulin secretion.

A comparison of iron induction of rat lymphocyte ferritin synthesis in vivo and in vitro

Abstract 1. 1. Administration of increasing amounts of iron to rats in vivo induced both liver and peripheral blood lymphocyte ferritin synthesis measured in vitro . 2. 2. Incubation of liver and lymphocytes with increasing concentrations of iron in vitro stimulated liver, but not lymphocyte ferritin synthesis. Exposure of lymphocytes to iron invitro produced only slight depression of ferritin and total protein synthesis and no appreciable change in cell viability compared to controls. 3. 3. Incubation of lymphocytes with 59 Fe-citrate in vitro resulted in continuous uptake and incorporation of labelled iron into both ferritin and total cell protein during 24 hr. 4. 4. These data suggest that induction of lymphocyte ferritin synthesis observed after iron administration in vivo resulted from secondary stimulatory mechanisms rather than due to iron per se .

Alphafetoprotein in testicular tumors

Abstract Fifty patients with testicular tumors of embryonal cell were evaluated for alpha one fetoprotein. The findings were compared with the clinical evolution and the significance of this determination is discussed.

6-Methylmercaptopurine:identification as metabolite of 6-mercaptopurine in vivo and its activity in vitro.

Conclusion 1. 6-methylmercaptopurine was identified as a urinary metabolite of 6-mercaptopurine in normal Sprague-Dawley rats. 2. In in vitro experiments, 6-MeMP exerted greater inhibition of both formate and glycine incorporation into the combined nucleic acid and protein fractions of Sarcoma 180 ascites tumor cells than did 6-MP.

Hepatic glycogenolysis induced by glucagon in a patient with type I liver glycogen disease

Abstract Direct evidence was obtained, by chemical and isotopic measurements, that glucagon induces active hepatic glycogenolysis in type I liver glycogen disease, at a rate comparable to that observed in normal rats and dogs and, presumably, normal man. This liver glycogen breakdown was associated with no increase in blood glucose, but in a rapid rise of blood lactate. Indirect evidence suggests that the response to endogenous secretion of glucagon is similar. The conclusion that both exogenous and endogenous glucagon exert their usual glycogenolytic effects in this disease but that the end product is lactic acid rather than glucose indicates that (1) the abnormal accumulation of liver glycogen observed in type I glycogen disease is not a consequence of the deficiency in glucose-6-phosphatase per se (2) increased glycogen synthesis must play a major role in accounting for this excessive liver glycogen content.

Origin and synthesis of α-macrofetoprotein in Zajdela ascites hepatoma-bearing rats☆

Abstract Both host liver and hepatoma cells synthesize α-macrofetoprotein and albumin in rats transplanted with Zajdela ascites hepatoma cells. Failure to detect α-fetoprotein in either the serum or ascitic fluid of these tumor-bearing animals suggests that these hepatoma cells have lost their capacity to produce this fetoprotein without affecting their malignant properties. Evidence that α-macrofetoprotein did not appear in the ascitic fluid before it became bloody, and was not secreted from Zajdela ascites hepatoma cells incubated in vitro suggests that (1) most of the α-macrofetoprotein found in the serum and ascitic fluid of rats with this hepatoma originates from the host liver rather than from the tumor cells and (2) secretory mechanisms for serum proteins are defective in Zajdela ascites hepatoma cells.