Adipose Triglyceride Lipase Is a Key Lipase for the Mobilization of Lipid Droplets in Human β-Cells and Critical for the Maintenance of Syntaxin 1a Levels in β-Cells.

Autor:	Liu S; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA.; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA., Promes JA; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA.; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA., Harata M; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA.; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA., Mishra A; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA.; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA., Stephens SB; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA.; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA., Taylor EB; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA.; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA., Burand AJ Jr; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA.; Roy J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, IA., Sivitz WI; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA.; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA., Fink BD; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA.; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA., Ankrum JA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA.; Roy J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, IA., Imai Y; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA yumi-imai@uiowa.edu.; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2020 Jun; Vol. 69 (6), pp. 1178-1192. Date of Electronic Publication: 2020 Apr 20.
DOI:	10.2337/db19-0951
Abstrakt:	Lipid droplets (LDs) are frequently increased when excessive lipid accumulation leads to cellular dysfunction. Distinct from mouse β-cells, LDs are prominent in human β-cells. However, the regulation of LD mobilization (lipolysis) in human β-cells remains unclear. We found that glucose increases lipolysis in nondiabetic human islets but not in islets in patients with type 2 diabetes (T2D), indicating dysregulation of lipolysis in T2D islets. Silencing adipose triglyceride lipase (ATGL) in human pseudoislets with shRNA targeting ATGL (shATGL) increased triglycerides (TGs) and the number and size of LDs, indicating that ATGL is the principal lipase in human β-cells. In shATGL pseudoislets, biphasic glucose-stimulated insulin secretion (GSIS), and insulin secretion to 3-isobutyl-1-methylxanthine and KCl were all reduced without altering oxygen consumption rate compared with scramble control. Like human islets, INS1 cells showed visible LDs, glucose-responsive lipolysis, and impairment of GSIS after ATGL silencing. ATGL-deficient INS1 cells and human pseudoislets showed reduced SNARE protein syntaxin 1a (STX1A), a key SNARE component. Proteasomal degradation of Stx1a was accelerated likely through reduced palmitoylation in ATGL-deficient INS1 cells. Therefore, ATGL is responsible for LD mobilization in human β-cells and supports insulin secretion by stabilizing STX1A. The dysregulated lipolysis may contribute to LD accumulation and β-cell dysfunction in T2D islets. (© 2020 by the American Diabetes Association.)
Databáze:	MEDLINE
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