Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice.
Granuphilin is a crucial component of the docking machinery of insulin-containing vesicles to the plasma membrane. Here, we show that the granuphilin promoter is a target of SREBP-1c, a transcription factor that controls fatty acid synthesis, and MafA, a beta cell differentiation factor. Potassium-stimulated insulin secretion (KSIS) was suppressed in islets with adenoviral-mediated overexpression of granuphilin and enhanced in islets with knockdown of granuphilin (in which granuphilin had been knocked down). SREBP-1c and granuphilin were activated in islets from beta cell-specific SREBP-1c transgenic mice, as well as in several diabetic mouse models and normal islets treated with palmitate, accompanied by a corresponding reduction in insulin secretion. Knockdown- or knockout-mediated ablation of granuphilin or SREBP-1c restored KSIS in these islets. Collectively, our data provide evidence that activation of the SREBP-1c/granuphilin pathway is a potential mechanism for impaired insulin secretion in diabetes, contributing to beta cell lipotoxicity.
Kato
Toyonori
T
Department of Internal Medicine, Endocrinology and Metabolism, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba Ibaraki 305-8575, Japan.
Shimano
Hitoshi
H
Yamamoto
Takashi
T
Yokoo
Tomotaka
T
Endo
Yuko
Y
Ishikawa
Mayumi
M
Matsuzaka
Takashi
T
Nakagawa
Yoshimi
Y
Kumadaki
Shin
S
Yahagi
Naoya
N
Takahashi
Akimitsu
A
Sone
Hirohito
H
Suzuki
Hiroaki
H
Toyoshima
Hideo
H
Hasty
Alyssa H
AH
Takahashi
Satoru
S
Gomi
Hiroshi
H
Izumi
Tetsuro
T
Yamada
Nobuhiro
N
D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D051473:Maf Transcription Factors, Large / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010168:Palmitates / Q000494:pharmacology / Q000633:toxicity; D011188:Potassium / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism / Q000494:pharmacology*; D033921:Vesicular Transport Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*
D007328:Insulin; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D010168:Palmitates; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C122015:Sytl4 protein, mouse; D033921:Vesicular Transport Proteins; D011188:Potassium