SIRT1 Participates In Bile Acid Metabolism By Regulating Foxa2 Transcriptional Activity & KLF11 Regulates Liver Glycometabolism By Inhibiting PEPCK-C Transcription

Bile acids are the end product of cholesterol metabolism and play important roles in glucose homeostasis,lipid metabolism and energy expenditure.Sirtuin 1(SIRT1)is a NAD+-dependent deacetylase activated in response to fasting and caloric restriction and has been implicated in multiple metabolic processes.However,whether and how SIRT1 regulates hepatic bile acid metabolism is largely unclear.We show here that deletion of hepatic SIRT1 increases hepatic and serum bile acids levels and cause an abnormal gallbladder.We find that SIRT1 directly interacts with and deacetylates forkhead box protein A2(Foxa2)to inhibit its transcriptional activity on expression of genes involved in bile acids synthesis and transport such as Cytochrome P450 7al(Cyp7al)and Na+/taurocholate cotransporting Polypeptide(Ntcp).In contrast,in SIRT1-deficient mouse livers,Foxa2 acetylation levels are elevated,which promotes Foxa2 binding to and activating these downstream target genes,impairing hepatic and systemic bile acid homeostasis.Moreover,overexpression of wild-type Foxa2,but not acetylation-deficient Foxa2 mutant(5R),in livers of SIRT1-deficient mice further increases bile acid pool size and hepatic and serum bile acids levels,which further confirms that acetylation regulates Foxa2 activity in vivo and indicates that Foxa2,at least in part,mediates SIRT1 effects on bile acid metabolism.Our study links SIRT1 to bile acid metabolism and indicates that modulation of SIRT1 activity in liver may be an attractive approach for treatment of bile acid-related diseases such as cholestasis.Abnormal hepatic gluconeogenesis is related to hyperglycemia in mammals with insulin resistance.Despite the strong evidences linking Kriipple-like factor 11(KLF11)gene mutations to development of Type ? diabetes,the precise physiological functions of KLF11 in vivo remain unknown.In current investigation,we showed that KLF11 is involved in modulating hepatic glucose metabolism in mice.Overexpression of KLF11 in primary mouse hepatocytes could inhibit the expression of gluconeogenic genes,including phosphoenolpyruvate carboxykinase(PEPCK)and peroxisome proliferator-activated receptor y coactivator-la(PGC-la),subsequently decreasing the cellular glucose output.Dual-luciferase report assay showed that KLF11 could inhibit PEPCK-C promoter activity and deletion or mutation of the candidated cis-acting elements abolished the regulation of KLF11.Diabetic mice with overexpression of KLF11 gene in livers significantly ameliorated hyperglycemia and glucose intolerance;in contrast,the knockdown of KLF11 expression in db/m and C57BL/6J mice livers impaired glucose tolerance.Our data strongly indicated the involvement of KLF11 in hepatic glucose homeostasis via modulating the expression of PEPEK.