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Results for “LIVER GLYCOGEN”

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PubMed2005

CCAAT/enhancer binding protein alpha knock-in mice exhibit early liver glycogen storage and reduced susceptibility to hepatocellular carcinoma.

The CCAAT/enhancer binding protein alpha (C/EBPalpha) is vital for establishing normal hepatic energy homeostasis and moderating hepatocellular growth. CEBPA loss-of-function mutations identified in acute myeloid leukemia patients support a tumor suppressor role for C/EBPalpha. Recent work showed reductions of C/EBPalpha levels in human hepatocellular carcinoma with the reductions correlating to tumor size and progression. We investigated the potential of reactivating c/ebpalpha expression during hepatic carcinogenesis to prevent tumor cell growth. We have developed a c/ebpalpha knock-in mouse in which a single-copy c/ebpalpha is regulated by one allele of the alpha-fetoprotein (AFP) gene promoter. The knock-in mice are physically indistinguishable from wild-type (WT) controls. However, knock-in animals were found to deposit fetal hepatic glycogen earlier than WT animals. Quantitative real-time PCR confirmed early c/ebpalpha expression and early glycogen synthase gene activation in knock-in fetuses. We then used diethylnitrosamine to induce hepatocellular carcinoma in our animals. Diethylnitrosamine produced half the number of hepatocellular nodules in knock-in mice as in WT mice. Immunohistochemistry showed reduced C/EBPalpha content in WT nodules whereas knock-in nodules stained strongly for C/EBPalpha. The p21 protein was examined because it mediates a C/EBPalpha growth arrest pathway. Nuclear p21 was absent in WT nodules whereas cytoplasmic p21 was abundant; knock-in nodules were positive for nuclear p21. Interestingly, only C/EBPalpha-positive nodules were positive for nuclear p21, suggesting that C/EBPalpha may be required to direct p21 to the cell nucleus to inhibit growth. Our data establish that controlled C/EBPalpha production can inhibit liver tumor growth in vivo.

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PubMed1997

Insulin regulates liver glycogen synthase and glycogen phosphorylase activity reciprocally in rhesus monkeys.

In skeletal muscle of both humans and monkeys, the effects of in vivo insulin during a euglycemic hyperinsulinemic clamp on the enzymes and substrates of glycogen metabolism have been well established. In liver, such effects of insulin during a clamp have not been previously studied in primates. To examine insulin action at the liver, euglycemic hyperinsulinemic clamps were performed in 10 lean young adult male rhesus monkeys. Liver biopsies were obtained at three time points: basal (fasting), that is, immediately before the onset of the clamp, and during insulin infusion at 130 and 195 min. Glycogen synthase (GS), glycogen phosphorylase (GP), glucose 6-phosphate (G-6-P), and glycogen were determined at each time point, with the greatest effects observed most frequently at 195 min. Whole body insulin-mediated glucose disposal rate was related to the change in the independent activity of GS (r = 0.63, P < 0.05). Insulin increased the GS fractional activity (P < 0.005) and decreased the activity ratio of GP (P < 0.001) compared with basal. The changes in fractional activity of GS and in activity ratio of GP were inversely related (r = - 0.68, P < 0.05), G-6-P concentration was decreased during insulin stimulation compared with basal (P = 0.01). Glycogen concentration was not significantly different between the basal and insulin-stimulated time points. We conclude that insulin during a euglycemic clamp activates liver GS while inhibiting liver GP and that insulin action on liver GS is positively related to whole body insulin-mediated glucose disposal rates in lean young adult rhesus monkeys.

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PubMed1976

Evidence for the coordinate control of activity of liver glycogen synthase and phosphorylase by a single protein phosphatase.

Homogeneous rabbit liver phosphorylase phosphatase (Brandt, H., Capulong, Z. L., and Lee, E. Y. C. (1975) J. Biol. Chem. 250, 8038-8044) also dephosphorylates glycogen synthase b. During purification, phosphorylase phosphatase and glycogen synthase phosphatase co-purified with a constant ratio of activities. The two activities co-migrated on disc gel electrophoresis. Both substrates competed with each other for the phosphatase, and both phosphatase activities were inhibited by lysine ethyl ester. It is concluded that liver phosphorylase phosphatase and glycogen synthase phosphatase have a common identity and that coordinate regulation of the phosphatase-catalyzed activation of glycogen synthase and inactivation of phosphorylase occurs in vivo. This provides a parallel and opposing mechanism to that mediated by adenosine 3':5'-monophosphate-dependent protein kinase, which coordinately inactivates glycogen synthase and, via phosphorylase kinase, activates phosphorylase. Maximal glycogen synthase phosphatase activity was observed near neutrality. Mg2+ and glucose-6-P activated the glycogen synthase phosphatase reaction and this activation was pH-dependent. The Km for glycogen synthase b was 0.12 muM.

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