Generation of floxed Sirtuin 6 for the construction of conditional knockout mice.

The Sirtuins (Sirt1-7), a family of seven proteins related to yeast Sir2, are histone deacetylases that regulate many critical biological processes including genomic stability, adaptation to calorie restriction and aging. Mice with a targeted disruption of Sirt6 had very low levels of blood glucose (and paradoxically, low insulin levels) and died shortly after weaning. Hypoglycemia, attributed to increased sensitivity to insulin, was the major cause for lethality.

Because of the post-weaning mortality of Sirt6 null mice, liver-specific Sirt6 conditional knockout mice were constructed using Cre-Lox technology to study the effects on glucose and lipid metabolism. Hepatic-specific Sirt6 deficient mice exhibited increased glycolysis and triglyceride synthesis, resulting in the development of fatty liver. Sirt6 is a potential therapeutic target for treating fatty liver disease, the most common cause of liver dysfunction.