The transcription factor Prep1 controls hepatic insulin sensitivity and gluconeogenesis by targeting nuclear localization of FOXO1.
Liver plays a key role in controlling body carbohydrate homeostasis by switching between accumulation and production of glucose and this way maintaining constant level of glucose in blood. Increased blood glucose level triggers release of insulin from pancreatic β-cells. Insulin represses hepatic glucose production and increases glucose accumulation. Insulin resistance is the main cause of type 2 diabetes and hyperglycemia. Currently thiazolidinediones (TZDs) targeting transcriptional factor PPARγ are used as insulin sensitizers for treating patients with type 2 diabetes. However, TZDs are reported to be associated with cardiovascular and liver problems and stimulate obesity. Thus, it is necessary to search new approaches to improve insulin sensitivity. A promising candidate is transcriptional factor Prep1, as it was shown earlier it could affect insulin sensitivity in variety of insulin-sensitive tissues. The aim of the present study was to evaluate a possible involvement of transcriptional factor Prep1 in control of hepatic glucose accumulation and production. We created mice with liver-specific Prep1 knockout and discovered that hepatocytes derived from these mice are much more sensitive to insulin, comparing to their WT littermates. Incubation of these cells with 100 nM insulin results in almost complete inhibition of gluconeogenesis, while in WT cells this repression is only partial. However, Prep1 doesn't affect gluconeogenesis in the absence of insulin. Also, we observed that nuclear content of gluconeogenic transcription factor FOXO1 was greatly reduced in Prep1 knockout hepatocytes. These findings suggest that Prep1 may control hepatic insulin sensitivity by targeting FOXO1 nuclear stability.
Lomonosov Moscow State University, Faculty of Fundamental Medicine, Department of Biochemistry and Molecular Medicine, Lomonosovsky Prospekt 31-5, Moscow, 117192, Russia. Electronic address: konstantin-kuleb@mail.ru.
Konstantin
K
Kulebyakin
Lomonosov Moscow State University, Faculty of Fundamental Medicine, Department of Biochemistry and Molecular Medicine, Lomonosovsky Prospekt 31-5, Moscow, 117192, Russia; IFOM - the FIRC Institute of Molecular Oncology, Via Adamello 16, Milan, 20139, Italy.
Dmitry
D
Penkov
IFOM - the FIRC Institute of Molecular Oncology, Via Adamello 16, Milan, 20139, Italy.
Francesco
F
Blasi
Lomonosov Moscow State University, Faculty of Fundamental Medicine, Department of Biochemistry and Molecular Medicine, Lomonosovsky Prospekt 31-5, Moscow, 117192, Russia.
Zhanna
Z
Akopyan
Lomonosov Moscow State University, Faculty of Fundamental Medicine, Department of Biochemistry and Molecular Medicine, Lomonosovsky Prospekt 31-5, Moscow, 117192, Russia.
Vsevolod
V
Tkachuk
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000096:biosynthesis; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D014157:Transcription Factors / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000502:physiology
D007328:Insulin; D014157:Transcription Factors; D005947:Glucose
Gluconeogenesis; Hepatocytes; Insulin sensitivity; Prep1