Prolactin regulatory element-binding (PREB) protein regulates hepatic glucose homeostasis

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1864; no. 6; pp. 2097 - 2107
• Main Authors: Park, Joo-Man, Kim, Mi-Young, Kim, Tae-Hyun, Min, Dong-Kook, Yang, Ga Eul, Ahn, Yong-Ho
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2018
• Subjects: Animals; Blood Glucose; Diet, High-Fat - adverse effects; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation; Fasting; Gluconeogenesis; Glucose - metabolism; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; HEK293 Cells; Hepatocytes - metabolism; Humans; Insulin - metabolism; Liver - cytology; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity - blood; Obesity - etiology; Obesity - metabolism; Primary Cell Culture; Prolactin - metabolism; Prolactin core-binding element; Prolactin element-binding protein; Promoter Regions, Genetic; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA, Small Interfering - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Type-2 diabetes mellitus; Up-Regulation; Prolactin core-binding element; Type-2 diabetes mellitus; Prolactin element-binding protein; Gluconeogenesis
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2018.03.024

Prolactin regulatory element-binding (PREB) protein is a transcription factor that regulates prolactin (PRL) gene expression. PRL, also known as luteotropic hormone or luteotropin, is well known for its role in producing milk. However, the role of PREB, in terms of hepatic glucose metabolism, is not well elucidated. Here, we observed expression of Preb in the mouse liver, in connection with glucose homeostasis. Morevoer, Preb was downregulated in db/db, ob/ob and high-fat diet-induced obese (DIO) mice, concurrent with upregulation of the liver genes glucose-6-phosphatase (G6pc) and phosphoenolpyruvate carboxykinase-1 (Pck). Administration of adenovirus-Preb (Ad-Preb) to db/db, ob/ob, and DIO mice diminished glucose, insulin, and pyruvate tolerance, which analogously, were impaired in normal (C57BL/6) mice knocked down for Preb, via infection with Ad-shPreb (anti-Preb RNA), indicating Preb to be a negative regulator of liver gluconeogenic genes. We further demonstrate that Preb negatively influences gluconeogenic gene expression, by directly binding to their promoters at a prolactin core-binding element (PCBE). A better understanding of Preb gene expression, during the pathogenesis of hepatic insulin resistance, could ultimately provide new avenues for therapies for metabolic syndrome, obesity, and type-2 diabetes mellitus, disorders whose worldwide incidences are increasing drastically. •PREB expression is decreased in fasting states and insulin-resistant diabetic model mice.•Glucose homeostasis is improved by Ad-Preb administration in diabetic model mice.•PREB directly binds to PCBE on promoter of gluconeogenic genes.•The protein levels of PREB is regulated by hormones (cAMP and insulin).