Background Huntington's disease (HD) is dominantly inherited neurodegenerative disorder caused by a CAG expansion in the huntingtin gene (The Huntington's Disease Collaborative Research Group, 1993). However, several examples of peripheral dysfunction have been reported (Sassone et al, 2009). In a previous study, we showed hepatic lactate-based gluconeogenesis to be compromised in the HD mouse model R6/2 along with a decrease in mRNA level and activity of the key gluconeogenic enzyme PEPCK (Josefsen et al, 2010).
Results To explore the development of this issue, a longitudinal lactate challenge study assessing systemic gluconeogeneic capacity was conducted. Already at 4 weeks of age, R6/2 mice showed signs of changes in lactate metabolism in the form of significantly higher post-injection lactate levels, which rose steadily with increasing age. Conversely, a gradual decrease was seen in post-injection glucose levels, indicating a decreased ability for conversion of lactate into glucose by the liver. This defect was also found in primary R6/2 hepatocytes, which also displayed a reduced ATP content compared to control cells. No difference was seen in lactate release or overall redox capacity. Functionally, a decrease in gluconeogeneic capacity could lead to problems with blood sugar regulation during fasting. During fasting, R6/2 mice displayed significantly lower blood glucose levels compared to littermates. Furthermore, QPCR analysis using liver tissue showed a general pattern of dysregulation of transcription factors involved in regulation of gluconeogenesis.
Conclusions The results confirm our previous findings, and indicate that liver function deteriorates with disease progression. Further studies using primary R6/2 hepatocytes are currently being undertaken. The investigations may lead to new insights in the role of reduced liver metabolism in HD.
- peripheral tissue
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.