Hepatocyte nuclear factor 1a controls the proliferation of pancreatic beta-cells by regulating the expression of a Golgi-associated protein

ABSTRACT: HNF1A gene encodes a transcription factor hepatocyte nuclear factor 1α (HNF1α), and mutations in this gene cause maturity-onset diabetes of the young type 3 (MODY3), which is characterized by impaired insulin secretion. Previous studies have shown that HNF1α controls the proliferation and number of pancreatic β-cells. However, the molecular mechanism by which HNF1α regulates β-cell growth remains unclear. Here, we demonstrate that TMED6 (transmembrane p24 trafficking protein 6), a transmembrane protein involved in transport processes at the ER-Golgi interface, is a novel HNF1α target in pancreatic β-cells. TMED6 expression was decreased in the β-cells of Hnf1a knockout (KO) mice. Suppressing TMED6 in mouse MIN6 β-cells reduced cell growth. Conversely, overexpression of TMED6 rescued the proliferation of Hnf1a knockdown (KD) MIN6 cells. Furthermore, TMED6 KO mice fed a high-fat diet exhibited reduced β-cell mass and impaired insulin secretion. Biochemical studies revealed that TMED6 controls β-cell proliferation by regulating the proteasomal degradation of GOLGA2, a Golgi-associated protein that regulates cell proliferation. Overexpression of GOLGA2 restored proliferation in both Hnf1a KD and Tmed6 KD MIN6 cells. Taken together, our results indicate that HNF1α controls pancreatic β-cell proliferation via the TMED6-GOLGA2 axis. We performed proteome analyses of control and Tmed6 KD MIN6 cells in triplicate.

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Yoshifumi Sato 

PROVIDER: PXD065932 | JPOST Repository | Thu Jul 09 00:00:00 GMT+01:00 2026

REPOSITORIES: jPOST