Browsing by Subject "Liver Glycogen"
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Item Regulation of Hepatic Glycogen Metabolism by Glycogen Targeting Subunits of Protein Phosphatase 1(2007-05-01) Clark, Catherine Renee; Newgard, Christopher B., M.D.Glycogen targeting subunits of protein phosphatase 1 play a critical role in fuel homeostasis through the regulation of glycogen metabolism. Adenovirus-mediated overexpression of the liver subunit GL, the muscle subunit GM, or a truncated version of GM, GMdeltaC increased hepatic glycogen content in high fat fed rats, a model of insulin resistance. Rats expressing GMdeltaC and GL had similar amounts of hepatic glycogen following an oral glucose tolerance test, but only GMdeltaC expression improved glucose tolerance. The explanation for this difference is that animals with overexpressed GMdeltaC experience a larger increment in hepatic glycogen storage during OGTT than animals with overexpressed GL, probably related to the much higher fasting liver glycogen levels in the latter group. Since it is possible to improve glucose tolerance via expression of glycogen targeting subunits, the remaining research focused on designing and testing a dominant-negative glycogen targeting subunit, PTG-VF. Overexpression of PTG-VF caused an 83% reduction in glycogen content in hepatocytes indicating that the activity of glycogen targeting subunits is necessary for glycogen accumulation. Further studies found that PTG-VF was more potent in blocking glycogen synthesis in hepatocytes with overexpressed GL than PTG. PTG-VF expression increases phosphoryalse a levels, which preferentially inhibits GL through its C-terminal phosphorylase a binding site that is lacking in PTG. Removal of the phosphorylase a binding site from GL renders the subunit less susceptible to inhibition by PTG-VF. PTG-VF was overexpressed in rats fed on standard chow (SC) or high fat (HF) diet to determine if suppression of glycogen targeting subunit activity could cause glucose intolerance or diabetes. Hepatic glycogen stores were decreased by PTG-VF, but this did not lead to alterations in glucose homeostasis.Item Regulation of Liver Metabolism by Fibroblast Growth Factor 19(2012-07-20) Kir, Serkan; Mangelsdorf, David J.Fibroblast Growth Factor (FGF) 19 is a postprandial enterokine up-regulated by bile acid receptor FXR upon bile acid uptake into the ileum. FGF19 inhibits hepatic bile acid synthesis through transcriptional repression of cholesterol 7 alpha-hydroxylase (CYP7A1) via a mechanism involving nuclear receptor Small Heterodimer Partner (SHP). Here, I show that two other nuclear receptors, Hepatocyte Nuclear Factor 4 alpha (HNF4 alpha) and Liver Receptor Homolog-1 (LRH-1), enable SHP binding to the Cyp7a1 promoter and therefore are important for negative feedback regulation of Cyp7a1. HNF4 alpha and LRH-1 are also crucial activators of Cyp7a1 transcription. They maintain active transcription histone marks on the Cyp7a1 promoter, whereas FGF19 down-regulates these marks in a SHP-dependent way. Secondly, I show that the MEK/ERK signaling pathway is an integral regulator of bile acid metabolism. ERK activity is necessary to maintain hepatic Shp and Cyp7a1 transcription at their physiologic levels. Inhibition of this pathway causes loss of Shp transcription by disrupting HNF4 alpha and LRH-1 binding to the Shp promoter. Independent from the effects on Shp, MEK/ERK inhibition induces Cyp7a1 transcription. Unexpectedly, the MEK/ERK pathway is not required for repression of Cyp7a1 by FGF19. Although this pathway is activated by FGF19 in livers of Fgf receptor 4 (Fgfr4)-deficient mice probably via other FGFRs, Cyp7a1 repression is largely impaired. Thus, I propose that a signaling mechanism uniquely regulated by FGFR4 must be responsible for FGF19-dependent repression of bile acid synthesis. In addition to its roles in bile acid metabolism, I also show that FGF19 stimulates hepatic protein and glycogen synthesis, but does not induce lipogenesis. The effects of FGF19 are independent of the activity of either insulin or the protein kinase Akt, and instead are mediated through a mitogen-activated protein kinase signaling pathway that activates components of the protein translation machinery and stimulates glycogen synthase activity. Mice lacking FGF15 (the mouse FGF19 ortholog) fail to properly regulate blood glucose and fail to maintain normal postprandial amounts of liver glycogen. FGF19 treatment restored the loss of glycogen in diabetic animals lacking insulin. Thus, FGF19 activates a physiologically important, insulin-independent endocrine pathway that regulates hepatic protein and glycogen metabolism. [Keywords: bile acids, FGF19, CYP7A1, HNF4 alpha, LRH-1, SHP, protein synthesis, glycogen synthesis, ERK, GSK3]