Histidine Promotes the Glucose Synthesis through Activation of the Gluconeogenic Pathway in Bovine Hepatocytes

Histidine (His) is considered to be the first-limiting amino acid (AA) on grass silage-based diets in lactation cows, which correlate positively with lactose yield. The higher glucose requirements of lactating cows can be met through a combination of increased capacity for gluconeogenesis and increased supply of gluconeogenic precursors. However, the effect of His on the expression of gluconeogenic genes in the bovine hepatocytes is less known. Therefore, this study aimed to investigate the regulatory effect of His on the key gluconeogenic genes and glucose output in bovine hepatocytes. The addition of 0.15, 0.6, and 1.2 mM His in a medium significantly enhanced (p < 0.05) the viability of bovine hepatocytes. Remarkably, 1.2 mM His induced profound changes (p < 0.05) in the mRNA level of key genes involved in gluconeogenesis, including PCK1, PCK2, FBP1, and G6PC in vitro. Furthermore, the mRNA expression of PCK1 was significantly elevated (p < 0.05) by the addition of 1.2 mM His at 3, 6, 12, and 24 h of incubation. The hepatic glucose output increased (p < 0.05) linearly with increasing His concentration. These findings indicate that the addition of His may be efficiently converted into glucose via the upregulation of genes related to the gluconeogenic pathway.

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Autoregulation of hepatic glucose production

Acta Endocrinologica ◽

10.1530/eje.0.1380240 ◽

1998 ◽

pp. 240-248 ◽

Cited By ~ 77

Author(s):

MC Moore ◽

CC Connolly ◽

AD Cherrington

Keyword(s):

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Glycogen ◽

Neural Pathways ◽

Hepatic Glucose Output ◽

Counterregulatory Hormones ◽

Hepatic Glucose ◽

Glucose Output

In vitro evidence indicates that the liver responds directly to changes in circulating glucose concentrations with reciprocal changes in glucose production and that this autoregulation plays a role in maintenance of normoglycemia. Under in vivo conditions it is difficult to separate the effects of glucose on neural regulation mediated by the central nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause significant changes in net hepatic glucose balance. In response to hyperglycemia, net hepatic glucose output can be decreased by as much as 60-90% by nonhormonal mechanisms. Under conditions in which hepatic glycogen stores are high (i.e. the overnight-fasted state), a decrease in the glycogenolytic rate and an increase in the rate of glucose cycling within the liver appear to be the explanation for the decrease in hepatic glucose output seen in response to hyperglycemia. During more prolonged fasting, when glycogen levels are reduced, a decrease in gluconeogenesis may occur as a part of the nonhormonal response to hyperglycemia. A substantial role for hepatic autoregulation in the response to insulin-induced hypoglycemia is most clearly evident in severe hypoglycemia (< or = 2.8 mmol/l). The nonhormonal response to hypoglycemia apparently involves enhancement of both gluconeogenesis and glycogenolysis and is capable of supplying enough glucose to meet at least half of the requirement of the brain. The nonhormonal response can include neural signaling, as well as autoregulation. However, even in the absence of the ability to secrete counterregulatory hormones (glucocorticoids, catecholamines, and glucagon), dogs with denervated livers (to interrupt neural pathways between the liver and brain) were able to respond to hypoglycemia with increases in net hepatic glucose output. Thus, even though the endocrine system provides the primary response to changes in glycemia, autoregulation plays an important adjunctive role.

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Possible role of free radicals generated by pseudohypoxia in the regulation of hepatic glucose output. An in vitro model using rat liver microsomal glucose 6-phosphatase

Diabetologia ◽

10.1007/s001250050817 ◽

1997 ◽

Vol 40 (11) ◽

pp. 1251-1254 ◽

Cited By ~ 3

Author(s):

I. Wittmann ◽

I. Mazák ◽

L. Wagner ◽

J. Nagy

Keyword(s):

Free Radicals ◽

Rat Liver ◽

In Vitro Model ◽

Hepatic Glucose Output ◽

Hepatic Glucose ◽

Vitro Model ◽

Glucose Output

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Blood flow and nutrient exchange across the liver and gut of the dairy cow

British Journal Of Nutrition ◽

10.1079/bjn19830057 ◽

1983 ◽

Vol 49 (3) ◽

pp. 481-496 ◽

Cited By ~ 122

Author(s):

M. A. Lomax ◽

G. D. Baird

Keyword(s):

Fatty Acids ◽

Blood Flow ◽

Flow Rate ◽

Ketone Bodies ◽

Blood Flow Rate ◽

Hepatic Uptake ◽

Hepatic Glucose Output ◽

Lactating Cows ◽

Hepatic Glucose ◽

Glucose Output

1. The rate of blood flow in the portal and hepatic veins, and the net exchange across the gut and liver of volatile fatty acids (VFA), glucose, lactate, pyruvate, amino acids, ketone bodies, glycerol, non-esterified fatty acids (NEFA) and oxygen, were measured in lactating and non-lactating cows (a) in the normal, fed state and (b) before, during and after 6 d of fasting.2. Blood flow rate through the liver was 52% higher in normal, fed, lactating cows as compared with non-lactating cows, and was decreased by fasting in both groups of cows. Portal blood flow rate increased with an increase in metabolizable energy (ME) intake.3. Lactating, as compared with non-lactating, cows exhibited lower arterial concentrations of glucose and lactate, higher net portal outputs of VFA and ketone bodies, a higher net hepatic output of glucose, and higher net hepatic uptakes of propionate and lactate. The splanchnic outputs of acetate, glucose and hydroxybutyrate were all apparently greater in the lactating cows.4. Fasting caused a rapid decrease in the blood concentrations of the VFA and an increase in those of glycerol and NEFA. The portal, i.e. gut, outputs of VFA, lactate, ketone bodies, alanine and (serine+threonine), and the portal uptake of O2, were all decreased by fasting. Fasting for 6 h also decreased the hepatic output of glucose and acetate by 77 and 95% respectively, increased the hepatic uptake of pyruvate, glycerol and NEFA, and doubled hepatic ketone-body output. The splanchnic output of acetate and glucose and the splanchnic uptake of O2 were also decreased by fasting.5. The net portal outputs of VFA, lactate and hydroxybutyrate, and the net hepatic output of glucose, were all correlated with ME intake in fed and fasted cows. Hepatic glucose output was also correlated with milk yield.6. The net hepatic uptake of gluconeogenic precursors measured in this study could account for net hepatic glucose output in the fasted cows, but not in the fed cows. The net hepatic uptake of the ketogenic precursors butyrate and NEFA was sufficient to account for the hepatic output of ketone bodies in both fed and fasted cows, but it is unlikely that the hepatic uptake of ketogenic precursors could also account for the observed hepatic output of acetate.

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THE EFFECT OF L-LEUCINE ON HEPATIC GLUCOSE FORMATION

PEDIATRICS ◽

10.1542/peds.37.6.934 ◽

1966 ◽

Vol 37 (6) ◽

pp. 934-941 ◽

Cited By ~ 2

Author(s):

Robert Greenberg ◽

Gerald Reaven

Keyword(s):

Mechanism Of Action ◽

Inhibitory Effect ◽

Current Understanding ◽

Hepatic Glucose Output ◽

Hepatic Glucose ◽

Intracellular Regulation ◽

Direct Inhibitory Effect ◽

Glucose Output ◽

Glucose Formation

A direct inhibitory effect of leucine on hepatic glucose output has been suggested by previous observations in our laboratory. However, it has not been possible to separate the action of leucine from that of insulin. The current studies were undertaken in order to determine the effect of leucine on hepatic glucose formation in vitro, in the absence of insulin. In liver slices from fasted mice, leucine was shown to inhibit the incorporation of C14 from various C14-labeled precursors into glucose. These results are consistent with the postulate that leucine inhibits the rate of gluconeogenesis, and thus hepatic glucose output, independent of insulin. Accordingly, the effect of leucine on production of hypoglycemia cannot be regarded as a specific cause of hypoglycemia in certain infants. Assuming that the action of leucine is similar in all individuals, the induction of hypoglycemia by leucine in some individuals must reflect underlying defects in the intracellular regulation of the complex, multi-enzyme pathway of gluconeogenesis. Clarification of the mechanism of action of leucine on gluconeogenesis should contribute to current understanding of the means by which hepatic glucose output is regulated.

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