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Diabetologia

Erschienen in:

01.01.2012 | Article

Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions

verfasst von: K. Y. Chu, H. Li, K. Wada, J. D. Johnson

Erschienen in: Diabetologia | Ausgabe 1/2012

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Abstract

Aims/hypothesis

Ubiquitin C-terminal hydrolase L1 (UCHL1) is associated with neurodegenerative diseases and has been suggested to have roles in pancreatic beta cells. Our proteomic analysis revealed that UCHL1 was the most increased protein in MIN6 cells exposed to palmitate. The present study used a genetic loss-of-function model to test the hypothesis that UCHL1 is required for normal beta cell function and fate under lipotoxic conditions.

Methods

Human islets, mouse islets and MIN6 cells were used to analyse UCHL1 protein levels and regulation of UCHL1 by palmitate. The levels of free mono-ubiquitin and poly-ubiquitinated proteins were assessed. Gracile axonal dystrophy (GAD) mutant mice lacking UCHL1 were fed a normal or lipotoxic high-fat diet. Glucose tolerance, insulin tolerance and insulin secretion were assessed in vivo. Beta cell death and proliferation were assessed by TUNEL and proliferating cell nuclear antigen (PCNA) staining. Insulin secretion, calcium signalling, endoplasmic reticulum (ER) stress, apoptosis and SNARE protein levels were assessed in vitro.

Results

UCHL1 protein, which was highly specific to beta cells, was increased by palmitate at basal glucose, but not in the context of hyperglycaemia associated with frank diabetes. Although islet development and function were initially normal in Uchl1 ^−/− mice, a 4-week high-fat diet caused glucose intolerance and impaired insulin secretion. Uchl1 ^−/− mice had increased ER stress and beta cell apoptosis. The levels of SNARE proteins were dysregulated in Uchl1 ^−/− islets. Palmitate-stimulated vesicle-associated membrane protein 2 (VAMP2) ubiquitination was modulated by a chemical UCHL1 inhibitor.

Conclusions/interpretation

Together, these data suggest that UCHL1 has essential functional and anti-apoptotic roles in beta cells under stress conditions associated with lipotoxicity.

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Titel: Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions
verfasst von: K. Y. Chu
H. Li
K. Wada
J. D. Johnson
Publikationsdatum: 01.01.2012
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 1/2012
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-011-2323-1

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Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions

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Conclusions/interpretation

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