Prevention of hepatocellular adenoma and correction of metabolic abnormalities in murine glycogen storage disease type Ia by gene therapy
| Autor: | Janice Y. Chou, Chi-Jiunn Pan, Hyun Sik Jun, Young Mok Lee, Lane H. Wilson, Su-Ru Lin, Brian C. Mansfield |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Adenoma
Blood Glucose Male G6PC medicine.medical_specialty Monosaccharide Transport Proteins medicine.medical_treatment Genetic Vectors Biology Glycogen Storage Disease Type I Antiporters Body Mass Index Mice Internal medicine medicine Glucose homeostasis Animals Homeostasis Insulin RNA Messenger Promoter Regions Genetic Mice Knockout Glycogen storage disease type I Glucose tolerance test Hepatology medicine.diagnostic_test Body Weight Liver Neoplasms Genetic Therapy Hepatocellular adenoma Dependovirus Glucose Tolerance Test medicine.disease Disease Models Animal Endocrinology Liver biology.protein Glucose-6-Phosphatase Female Steatosis Glucose 6-phosphatase |
| Zdroj: | Hepatology (Baltimore, Md.). 56(5) |
| ISSN: | 1527-3350 |
| Popis: | Glycogen storage disease type Ia (GSD-Ia), which is characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA), is caused by deficiencies in the endoplasmic reticulum (ER)-associated glucose-6-phosphatase-α (G6Pase-α or G6PC) that hydrolyzes glucose-6-phosphate (G6P) to glucose. G6Pase-α activity depends on the G6P transporter (G6PT) that translocates G6P from the cytoplasm into the ER lumen. The functional coupling of G6Pase-α and G6PT maintains interprandial glucose homeostasis. We have shown previously that gene therapy mediated by AAV-GPE, an adeno-associated virus (AAV) vector expressing G6Pase-α directed by the human G6PC promoter/enhancer (GPE), completely normalizes hepatic G6Pase-α deficiency in GSD-Ia (G6pc−/−) mice for at least 24 weeks. However, a recent study showed that within 78 weeks of gene deletion, all mice lacking G6Pase-α in the liver develop HCA. We now show that gene therapy mediated by AAV-GPE maintains efficacy for at least 70-90 weeks for mice expressing more than 3% of wild-type hepatic G6Pase-α activity. The treated mice displayed normal hepatic fat storage, had normal blood metabolite and glucose tolerance profiles, had reduced fasting blood insulin levels, maintained normoglycemia over a 24-hour fast, and had no evidence of hepatic abnormalities. After a 24-hour fast, hepatic G6PT messenger RNA levels in G6pc−/− mice receiving gene therapy were markedly increased. Because G6PT transport is the rate-limiting step in microsomal G6P metabolism, this may explain why the treated G6pc−/− mice could sustain prolonged fasts. The low fasting blood insulin levels and lack of hepatic steatosis may explain the absence of HCA. Conclusion: These results confirm that AAV-GPE–mediated gene transfer corrects hepatic G6Pase-α deficiency in murine GSD-Ia and prevents chronic HCA formation. (HEPATOLOGY 2012;56:1719–1729) |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text