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Abstract
Kruppel-like factor 2 (KLF2) belongs to Kruppel-like factor (KLFs) family. It plays important roles in many biochemical processes, such as lung development, embryonic erythropoiesis, epithelial integrity, T-cell viability, and adipogenesis. KLF2 negatively regulates adipogenesis in adipose tissues by inhibition of PPARγ at the transcriptional level. But, the roles of KLF2 in metabolism in the liver are seldom studied and largely unknown. Until now, only one report is about hepatic KLF2 suggesting that KLF2 promotes steatosis in nonalcoholic fatty liver disease (NAFLD); while there is no report on the relation between KLF2 and glucose metabolism. Since NAFLD is close related to insulin resistance and type II diabetes mellitus, suggesting hepatic KLF2 may play a role in glucose metabolism in diabetes.
Indeed, KLF2 regulated lipid metabolism in the liver. Upregulation of Klf2 in primary hepatocytes increased lipid content as detected by BODIPY staining. Oil red O staining showed liver-specific overexpression of Klf2, induced by adenovirus, by minicircle DNA, or in transgenic mice, also raised the lipid level in liver.
Liver-specific upregulation of Klf2 not only promoted steatosis, but also regulated glucose metabolism. A greater impairment of glucose response was observed in oral glucose tolerance test in Ad-ALB-Klf2-treated HFD fed C57BL/6J mice compared to non-treated mice. The relative low increase of pAkt (T308) and pAkt (S473) in the liver of Ad-ALB-Klf2-treated db/db mice after insulin infusion, indicating the occurrence of insulin resistance in the Klf2 overexpression mice. Long-term overexpression of Klf2 showed dynamic changes in glucose response in high fat high sucrose diet fed C57BL/6J mice. Overexpression of Klf2 slightly improved glucose response in the early stage when the body weight was similar to control mice. However, as the body weight increased, there was more impaired glucose response in Klf2 overexpression mice as reflected in oral glucose tolerance test (OGTT), insulin tolerance test (ITT) and pyruvate tolerance test (PTT). While downregulation of Klf2 in the liver improved glucose response in HFD fed C57BL/6J mice as shown in OGTT. In addition, glycogen in the liver sections from ALB-Klf2-His tag transgenic mice was found to increase as compared to wild type mice, while knockdown of Klf2 by adenovirus decreased the glycogen level in the liver of db/db mice.
KLF2 was significantly upregulated by statin both in vitro and in vivo. Statins were reported to increase the risk of diabetes in patients. My study also found that simvastatin treatment increased the fasting glucose level in HFD fed mice and elevated liver Klf2 expression. Klf2 might be an important factor to mediate this side effect of statin therapy.
In conclusion, KLF2, a novel metabolic regulator in glucose metabolism and it may play an important role in statins-related risk of diabetes.
