Sepsis-induced depression of rat glucose-6-phosphatase gene expression and activity

Abstract

Sepsis in rats decreases the hepatic expression of the gluconeogenic enzyme glucose-6-phosphatase (G6Pase). The aim of this study was to investigate the relationship among G6Pase transcription, mRNA, enzymatic activity, and serum glucose levels at different intervals during mild or fulminant sepsis. Both fulminant and mild sepsis immediately decreased hepatic G6Pase mRNA levels. In mild sepsis, levels began to recover late in the time course. Serum glucose levels were maintained in mild sepsis but decreased markedly in fulminant sepsis. G6Pase transcription after fulminant sepsis decreased and never recovered. A similar transcriptional decrease was noted in mild sepsis, but some recovery occurred in this state. Histochemistry after mild sepsis revealed a decrease in G6Pase protein and enzymatic activity that paralleled transcription. These studies suggest that changes in G6Pase transcription and activity are early markers for sepsis-induced alterations in hepatic function. Mechanisms other than gene expression and enzymatic activity serve to maintain glucose levels in mild sepsis, but in the fulminant disorder, compensatory mechanisms fail and hypoglycemia develops.

Major Reduction in Plasma Lp(a) Levels During Sepsis and Burns

“…In addition, blood glucose levels were Ͻ3.0 mmol/L (2.3Ϯ0.2 mmol/L) in LPS-pretreated mice at the initiation of clearance studies compared with Ͼ6.8 mmol/L in vehicle-pretreated mice (8.3Ϯ0.6 mmol/L, PϽ0.001), a finding consistent with severe sepsis. 32 Blood was collected 90 seconds and 1, 2, 3, 4, and 5 hours after injection, and serum levels of Lp(a) were quantified. In vehicle-pretreated mice, serum levels of Lp(a) decreased progressively from 1.09Ϯ0.07 mg/dL at baseline (90 seconds) to 0.41Ϯ0.02 mg/dL after 5 hours, with a half-life of 3.7Ϯ0.2 hours (Figure 2A).…”

Il-6 Modulates Sepsis-Induced Decreases in Transcription of Hepatic Organic Anion and Bile Acid Transporters

“…Because hepatic dysfunction is an important but poorly understood component of these disorders, we have investigated changes in hepatic gene expression, structure, and function after cecal ligation and puncture (CLP), a clinically relevant murine model of sepsis (2)(3)(4)(5)(6). Early on, CLP provokes a hyper-inflammatory state.…”

“…The expression of each is reduced shortly after CLP (11). Because sepsis is associated with cholestasis and steatosis (5,8,11), we have postulated that the development of these clinically relevant abnormalities might result from altered expression of these genes (11). Studies by others have implicated several cytokines in the development of cholestasis and steatosis and in the expression of Ntcp, MRP-2, and OATP in response to toxic and anatomical insults (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

Phosphatidylinositol 3-kinase and protein kinase C contribute to the inhibition by interleukin 6 of phosphoenolpyruvate carboxykinase gene expression in cultured rat hepatocytes

“…47 This has been attributed to the lowered capacity of the liver to supply glucose because of the inhibition of gluconeogenesis as a consequence of the inhibition of the expression of control enzymes of gluconeogenesis and because of the exhaustion of hepatic glycogen pools by proinflammatory cytokines. [10][11][12][13][14][15][16][17][18][19][20][21][22] From the presented results it is concluded that IL-6 and insulin share in part common signal transduction components. This may impair insulin signaling ultimately leading to insulin resistance.…”

“…Also, in the septic rat, 17,18 in 12-hour TNF-␣-treated mice, 19 and in IL-6-secreting tumor transplanted mice 20 the expression of the gluconeogenic enzyme, glucose-6-phosphatase, was inhibited, which together with the inhibition of PCK gene expression indicates a general impairment of gluconeogenesis by proinflammatory cytokines. In cultured rat hepatocytes 24-hour chronic treatment of hepatocytes with a mixture of IL-1␤, TNF-␣, interferon ␥, and bacterial endotoxin inhibited gluconeogenesis.…”