Preadipocyte factor 1 induces pancreatic ductal cell differentiation into insulin-producing cells

Marie Rhee; Seung-Hwan Lee; Ji-Won Kim; Dong-Sik Ham; Heon-Seok Park; Hae Kyung Yang; Ju-Young Shin; Jae-Hyoung Cho; Young-Bum Kim; Byung-Soo Youn; Hei Sook Sul; Kun-Ho Yoon

doi:10.1038/srep23960

Preadipocyte factor 1 induces pancreatic ductal cell differentiation into insulin-producing cells

Sci Rep. 2016 Apr 5:6:23960. doi: 10.1038/srep23960.

Authors

Marie Rhee^{1

2}, Seung-Hwan Lee^{1

2}, Ji-Won Kim^{1

2}, Dong-Sik Ham^{1

2}, Heon-Seok Park^{1

2}, Hae Kyung Yang^{1

2}, Ju-Young Shin¹, Jae-Hyoung Cho¹, Young-Bum Kim³, Byung-Soo Youn⁴, Hei Sook Sul⁵, Kun-Ho Yoon^{1

2}

Affiliations

¹ Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
² Convergent Research Consortium for Immunologic Disease, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
³ Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁴ Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
⁵ Department of Nutritional Science and Toxicology, University of California, Berkeley, CA, USA.

Abstract

The preadipocyte factor 1 (Pref-1) is involved in the proliferation and differentiation of various precursor cells. However, the intracellular signaling pathways that control these processes and the role of Pref-1 in the pancreas remain poorly understood. Here, we showed that Pref-1 induces insulin synthesis and secretion via two independent pathways. The overexpression of Pref-1 activated MAPK signaling, which induced nucleocytoplasmic translocation of FOXO1 and PDX1 and led to the differentiation of human pancreatic ductal cells into β-like cells and an increase in insulin synthesis. Concurrently, Pref-1 activated Akt signaling and facilitated insulin secretion. A proteomics analysis identified the Rab43 GTPase-activating protein as a downstream target of Akt. A serial activation of both proteins induced various granular protein syntheses which led to enhanced glucose-stimulated insulin secretion. In a pancreatectomised diabetic animal model, exogenous Pref-1 improved glucose homeostasis by accelerating pancreatic ductal and β-cell regeneration after injury. These data establish a novel role for Pref-1, opening the possibility of applying this molecule to the treatment of diabetes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium-Binding Proteins
Cell Differentiation*
Cell Line, Tumor
Enzyme Inhibitors / chemistry
Extracellular Signal-Regulated MAP Kinases / metabolism
Forkhead Box Protein O1 / metabolism
GTP Phosphohydrolases / metabolism
Glucose / metabolism
Homeodomain Proteins / metabolism
Humans
Insulin / metabolism
Insulin-Secreting Cells / metabolism*
Intercellular Signaling Peptides and Proteins / metabolism*
MAP Kinase Signaling System
Membrane Proteins / metabolism*
Pancreatic Ducts / cytology*
Pancreatic Neoplasms / metabolism
Phosphorylation
Proteomics
Proto-Oncogene Proteins c-akt / metabolism
RNA, Small Interfering / metabolism
Rats
Rats, Sprague-Dawley
Signal Transduction
Trans-Activators / metabolism
rab GTP-Binding Proteins / metabolism

Substances

Calcium-Binding Proteins
DLK1 protein, human
Enzyme Inhibitors
FOXO1 protein, human
Forkhead Box Protein O1
Homeodomain Proteins
Insulin
Intercellular Signaling Peptides and Proteins
Membrane Proteins
RNA, Small Interfering
Trans-Activators
pancreatic and duodenal homeobox 1 protein
AKT1 protein, human
Proto-Oncogene Proteins c-akt
Extracellular Signal-Regulated MAP Kinases
GTP Phosphohydrolases
rab11 protein
rab GTP-Binding Proteins
Glucose