Study On The Molecular Mechanism Of Metformin Damaging The Body's Bile Acid Homeostasis & Transcription Factor KLF10 Regulates Liver Glucose Metabolism In Mice

Metformin is widely used to treat hyperglycemia.However,metformin treatment may induce intrahepatic cholestasis and liver injury in a few patients with type ? diabetes through an unknown mechanism.Here we show that metformin decreases SIRT1 protein levels in primary hepatocytes and liver.Both metformin-treated wild-type C57BL/6J mice and hepatic SIRT1-mutant mice had increased hepatic and serum bile acid levels.However,metformin failed to change systemic bile acid levels in hepatic SIRT1-mutant mice.Molecular mechanism study indicates that SIRT1 directly interacts with and deacetylates Foxa2 to inhibit its transcriptional activity on expression of genes involved in bile acids synthesis and transport.Hepatic SIRT1 mutation elevates Foxa2 acetylation levels,which promotes Foxa2 binding to and activating genes involved in bile acids metabolism,impairing hepatic and systemic bile acid homeostasis.Our data clearly suggest that hepatic SIRT1 mediates metformin effects on systemic bile acid metabolism and modulation of SIRT1 activity in liver may be an attractive approach for treatment of bile acid-related diseases such as cholestasis.Abnormal activation of hepatic gluconeogenesis leads to hyperglycemia.However,the molecular mechanisms underlying the abnormal hepatic gluconeogenesis remain to be fully delineated.KLF10 is highly expressed in the liver,however,the function of KLF10 in hepatic glucose metabolism remains unknown.Here we explore the physiological role of KLF10 in regulating hepatic glucose metabolism in mice.We found that hepatic KLF10 expression is regulated by nutritional status in wild-type mice and up-regulated in diabetic,obese and DIO mice.Overexpression of KLF10 in primary hepatocytes increased the expression of gluconeogenic genes and cellular glucose output.C57BL/6J mice with KLF10 overexpression in liver displayed increased blood glucose levels and impaired glucose tolerance.Conversely,hepatic KLF10 knockdown in db/db and DIO mice decreased blood glucose levels and improved glucose tolerance.Further luciferase reporter gene assay and chromatin immunoprecipitation analysis indicate that KLF10 activates PGC-la gene transcription via directly binding to its promoter region.These results indicate that KLF10 is an important regulator of hepatic glucose metabolism,and modulation of KLF10 expression in liver may be an attractive approach for treatment of type 2 diabetes.