Journal article
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
Diabetes (New York, N.Y.), Vol.69(6), pp.1178-1192
06/2020
DOI: 10.2337/db19-0951
PMCID: PMC7243295
PMID: 32312867
Abstract
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.
Details
- Title: Subtitle
- 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
- Creators
- Siming Liu - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IAJoseph A Promes - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IAMikako Harata - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IAAkansha Mishra - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IASamuel B Stephens - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IAEric B Taylor - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IAAnthony J Burand Jr - Roy J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, IAWilliam I Sivitz - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IABrian D Fink - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IAJames A Ankrum - Roy J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, IAYumi Imai - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.69(6), pp.1178-1192
- DOI
- 10.2337/db19-0951
- PMID
- 32312867
- PMCID
- PMC7243295
- NLM abbreviation
- Diabetes
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Publisher
- United States
- Grant note
- S10 RR018998 / NCRR NIH HHS R01 DK090490 / NIDDK NIH HHS R01 DK104998 / NIDDK NIH HHS T32 NS045549 / NINDS NIH HHS S10 RR025439 / NCRR NIH HHS UC4 DK098085 / NIDDK NIH HHS
- Language
- English
- Date published
- 06/2020
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Internal Medicine
- Record Identifier
- 9984001083602771
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