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Abstract: The SLC37 family consists of four sugar-phosphate exchangers, A1, A2, A3, and A4, which are anchored in the endoplasmic reticulum (ER) membrane. The best characterized family member is SLC37A4, better known as the glucose-6-phosphate (G6P) transporter (G6PT). SLC37A1, SLC37A2, and G6PT function as phosphate (Pi)-linked G6P antiporters catalyzing G6P:Pi and Pi:Pi exchanges. The activity of SLC37A3 is unknown. G6PT translocates G6P from the cytoplasm into the lumen of the ER where it couples with either glucose-6-phosphatase-α (G6Pase-α) or G6Pase-β to hydrolyze intraluminal G6P to glucose and Pi. The functional coupling of G6PT with G6Pase-α maintains interprandial glucose homeostasis and the functional coupling of G6PT with G6Pase-β maintains neutrophil energy homeostasis and functionality. A deficiency in G6PT causes glycogen storage disease type Ib, an autosomal recessive disorder characterized by impaired glucose homeostasis, neutropenia, and neutrophil dysfunction. Neither SLC37A1 nor SLC37A2 can functionally couple with G6Pase-α or G6Pase-β, and there are no known disease associations for them or SLC37A3. Since only G6PT matches the characteristics of the physiological ER G6P transporter involved in blood glucose homeostasis and neutrophil energy metabolism, the biological roles for the other SLC37 proteins remain to be determined. [Copyright &y& Elsevier]

Background & Aims: Several studies have shown that bone marrow-derived committed myelomonocytic cells can repopulate diseased livers by fusing with host hepatocytes and can restore normal liver function. These data suggest that myelomonocyte transplantation could be a promising approach for targeted and well-tolerated cell therapy aimed at liver regeneration. We sought to determine whether bone marrow-derived myelomonocytic cells could be effective for liver reconstitution in newborn mice knock-out for glucose-6-phosphatase-α. Methods: Bone marrow-derived myelomonocytic cells obtained from adult wild type mice were transplanted in newborn knock-out mice. Tissues of control and treated mice were frozen for histochemical analysis, or paraffin-embedded and stained with hematoxylin and eosin for histological examination or analyzed by immunohistochemistry or fluorescent in situ hybridization. Results: Histological sections of livers of treated knock-out mice revealed areas of regenerating tissue consisting of hepatocytes of normal appearance and partial recovery of normal architecture as early as 1 week after myelomonocytic cells transplant. FISH analysis with X and Y chromosome paints indicated fusion between infused cells and host hepatocytes. Glucose-6-phosphatase activity was detected in treated mice with improved profiles of liver functional parameters. Conclusions: Our data indicate that bone marrow-derived myelomonocytic cell transplant may represent an effective way to achieve liver reconstitution of highly degenerated livers in newborn animals. [ABSTRACT FROM AUTHOR]

Glycogen storage disease type Ia (GSD-Ia) patients deficient in glucose-6-phosphatase-α (G6Pase-α or G6PC) manifest disturbed glucose homeostasis. We examined the efficacy of liver G6Pase-α delivery mediated by AAV-GPE, an adeno-associated virus (AAV) serotype 8 vector expressing human G6Pase-α directed by the human G6PC promoter/enhancer (GPE), and compared it to AAV-CBA, that directed murine G6Pase-α expression using a hybrid chicken β-actin (CBA) promoter/cytomegalovirus (CMV) enhancer. The AAV-GPE directed hepatic G6Pase-α expression in the infused G6pc−/− mice declined 12-fold from age 2 to 6 weeks but stabilized at wild-type levels from age 6 to 24 weeks. In contrast, the expression directed by AAV-CBA declined 95-fold over 24 weeks, demonstrating that the GPE is more effective in directing persistent in vivo hepatic transgene expression. We further show that the rapid decline in transgene expression directed by AAV-CBA results from an inflammatory immune response elicited by the AAV-CBA vector. The AAV-GPE-treated G6pc−/− mice exhibit normal levels of blood glucose, blood metabolites, hepatic glycogen, and hepatic fat. Moreover, the mice maintained normal blood glucose levels even after 6 hours of fasting. The complete normalization of hepatic G6Pase-α deficiency by the G6PC promoter/enhancer holds promise for the future of gene therapy in human GSD-Ia patients. [ABSTRACT FROM AUTHOR]

Background/Aims: Glycogen storage disease type Ib (GSD-Ib) patients deficient in a glucose-6-phosphate transporter (G6PT) manifest disturbed glucose homeostasis, myeloid dysfunctions, and hepatocellular adenoma (HCA). This study was conducted to evaluate whether maintaining normoglycemia in GSD-Ib could prevent HCA. Methods: We infused neonatal GSD-Ib mice with adeno-associated virus (AAV) carrying G6PT and examined their metabolic and myeloid phenotypes for the 72-week study. Results: The AAV vector delivered the G6PT transgene to the liver and bone marrow. Long-term metabolic correction was achieved alongside a transient myeloid correction. Hepatic G6PT activity was 50% of wild-type levels at 2 weeks post-infusion but declined rapidly thereafter to reach 3% of wild-type levels by age 6 to 72 weeks. Despite this, the infused mice maintained normoglycemia throughout the study, exhibited near normal growth and normalized serum metabolite profiles. However, all five AAV-treated GSD-Ib mice that lived over 50 weeks accumulated excessive hepatic glycogen and fat. Two mice developed steatohepatitis and multiple HCAs with one undergoing malignant transformation. Conclusions: Normoglycemia alone cannot prevent hepatic steatosis and glycogen accumulation or the development of HCAs in GSD-Ib, providing one explanation why GSD-Ib patients maintaining normoglycemia under intense dietary therapy continue at risk for this long-term complication. [Copyright &y& Elsevier]

Background/Aims: Glycogen storage disease type Ia (GSD-Ia) patients manifest the long-term complication of hepatocellular adenoma (HCA) of unknown etiology. We showed previously that GSD-Ia mice exhibit neutrophilia and elevated serum cytokine levels. This study was conducted to evaluate whether human GSD-Ia patients exhibit analogous increases and whether in GSD-Ia mice a correlation exists between immune abnormalities and, biochemical and histological alterations in the liver. Methods: Differential leukocyte counts and cytokine levels were investigated in GSD-Ia patients. Hepatic chemokine production, neutrophil infiltration, and histological abnormalities were investigated in GSD-Ia mice. Results: We show that GSD-Ia patients exhibit increased peripheral neutrophil counts and serum interleukin-8 (IL-8). Compared to normal subjects, HCA-bearing GSD-Ia patients have a 2.8-fold higher serum IL-8 concentration, while GSD-Ia patients without HCA have a 1.4-fold higher concentration. Hepatic injury in GSD-Ia mice is evidenced by necrotic foci, markedly elevated infiltrating neutrophils, and increased hepatic production of chemokines. Conclusions: Peripheral neutrophilia and elevated serum chemokines are characteristic of GSD-Ia with HCA-bearing GSD-Ia patients having the highest serum IL-8. In GSD-Ia mice these elevations correlate with elevated hepatic chemokine levels, neutrophil infiltration, and necrosis. Taken together, peripheral neutrophilia and increased serum chemokines may indicate hepatic injuries in GSD-Ia. [Copyright &y& Elsevier]