Prevention of diabetic alterations in transgenic mice overexpressing Myc in the liver.

Abstract

Recent studies have demonstrated that the overexpression of the c-myc gene in the liver of transgenic mice leads to an increase in both utilization and accumulation of glucose in the liver, suggesting that c-Myc transcription factor is involved in the control of liver carbohydrate metabolism in vivo. To determine whether the increase in c-Myc might control glucose homeostasis, an intraperitoneal glucose tolerance test was performed. Transgenic mice showed lower levels of blood glucose than control animals, indicating that the overexpression of c-Myc led to an increase of blood glucose disposal by the liver. Thus, the increase in c-Myc might counteract diabetic hyperglycemia. In contrast to control mice, transgenic mice treated with streptozotocin showed normalization of concentrations of blood glucose, ketone bodies, triacylglycerols and free fatty acids in the absence of insulin. These findings resulted from the normalization of liver metabolism in these animals. While low glucokinase activity was detected in the liver of diabetic control mice, high levels of both glucokinase mRNA and enzyme activity were noted in the liver of streptozotocin-treated transgenic mice, which led to an increase in intracellular levels of glucose 6-phosphate and glycogen. The liver of these mice also showed an increase in pyruvate kinase activity and lactate production. Furthermore, normalization of both the expression of genes involved in the control ofgluconeogenesis and ketogenesis and the production of glucose and ketone bodies was observed in streptozotocin-treated transgenic mice. Thus, these results suggested that c-Myc counteracted diabetic alterations through its ability to induce hepatic glucose uptake and utilization and to block the activation of gluconeogenesis and ketogenesis.c-myc is part of a gene family encoding nuclear phosphoproteins that can bind to DNA in a sequence-specific manner and act as transcription factors. The c-Myc protein is invoived in the control of cell proliferation, differentiation, neoplasia, apoptosis, and energy metabolism (1-3). This transcription factor recognizes an "E-box" motif with the central consensus sequence CACGTG (1-3), which is also contained in the glucose/carbohydrate regulatory elements located in the promoter of genes coding for some of the enzymes of glycolysis and lipogenesis (4, 5). A glucose-responsive element (GlcRE) was identified in the promoter of the L-pyruvate kinase gene (6-8), which consists of two imperfect E boxes, CACGGG, which differ from the c-Myc family E box by a single nucleotide. This GlcRE is closely related functionally to the carbohydrate response element (ChoRE) described in the S14 and the fatty acid synthase genes, which also contains a c-Myc family E-box motif, CACGTG (9, 10). We have recently shown that an increase in c-Myc protein in liver nuclei of transgenic animals that overexpress c-myc under control of the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter (11) leads to an induction of hepatic glycolysis by increasing bothThe ...

Inhibition of Ubiquitin Ligase F-box and WD Repeat Domain-containing 7α (Fbw7α) Causes Hepatosteatosis through Krüppel-like Factor 5 (KLF5)/Peroxisome Proliferator-activated Receptor γ2 (PPARγ2) Pathway but Not SREBP-1c Protein in Mice

“…Careful interpretation of this molecular process is required as KLF5 may have various biological effects on cell growth (51,52) and secondary metabolic disturbances. Based on previous reports that Myc overexpression in transgenic mice contributed to glucose metabolism (53,54), it is possible that c-Myc, potentially induced by Fbw7i, could be involved in steatosis in Fbw7-knockdown livers.…”

Counteraction of Type 1 Diabetic Alterations by Engineering Skeletal Muscle to Produce Insulin

“…This agrees with the increased glucose disposal observed after a glucose tolerance test in Tg1 transgenic mice. Similarly, transgenic mice with increased glucose uptake because their liver or skeletal muscle has been engineered to overexpress key genes in the regulation of glucose transport, such as GLUT4 (47)(48)(49)(50) or GLUT1 (51), or glucose phosphorylation, such as glucokinase (52,53) or c-myc (33,54), show reduced blood glucose levels and improved glucose tolerance. Forty-five days after STZ-treatment, fed control mice were highly hyperglycemic, while constitutive expression of insulin in skeletal muscle of Tg1 transgenic mice led to increased insulinemia and to marked reduction of hyperglycemia.…”

“…However, 45 days after STZ-treatment, the increased insulinemia of Tg1 transgenic mice resulted in increased GK activity that led to an increase in hepatic glucose metabolism, which may have contributed to the decrease in blood glucose levels and normalization of serum ketone body, triglycerides, and FFAs. Similarly, after STZ treatment, increased hepatic glucose utilization by overexpressing glucokinase (58) or c-myc (54) in the liver leads to normalization of hepatic glucose metabolism, reduction of diabetic hyperglycemia, and normalization of serum parameters.…”

c-Myc Is Required for the Glucose-mediated Induction of Metabolic Enzyme Genes

“…The expression of glucose transporter 2 (GLUT2), L-PK, and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2) all increase, as well as liver glycogen content, indicating that hepatic glucose metabolism is enhanced. Furthermore, in c-Myc overexpressing animals treated with streptozotocin, and therefore lacking insulin, glucose and ketone production decrease (8). These changes are accompanied by a decrease in mRNA levels for PEPCK and carnitine palmitoyltransferase I and II.…”

“…One transcription factor that is a candidate for establishing hepatic glucose-dependent gene expression patterns is the basic, helix-loop-helix leucine-zipper (bHLH-LZ) transcription factor c-Myc (8,9). The Myc family of proteins (e.g.…”