ApoA-I Protects Pancreatic β-Cells From Cholesterol-Induced Mitochondrial Damage and Restores Their Ability to Secrete Insulin.

Manandhar, B; Pandzic, E; Deshpande, N; Chen, S-Y; Wasinger, VC; Kockx, M; Glaros, EN; Ong, KL; Thomas, SR; Wilkins, MR; Whan, RM; Cochran, BJ; Rye, K-A

ApoA-I Protects Pancreatic β-Cells From Cholesterol-Induced Mitochondrial Damage and Restores Their Ability to Secrete Insulin.

Pandzic, E Deshpande, N Chen, S-Y Wasinger, VC Kockx, M Glaros, EN Ong, KL Thomas, SR Wilkins, MR Whan, RM Cochran, BJ Rye, K-A

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Publisher:: LIPPINCOTT WILLIAMS & WILKINS
Publication Type:: Journal Article
Citation:: Arterioscler Thromb Vasc Biol, 2024, 44, (2), pp. e20-e38
Issue Date:: 2024-02

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Field	Value	Language
dc.contributor.author	Manandhar, B https://orcid.org/0000-0003-1276-6954
dc.contributor.author	Pandzic, E
dc.contributor.author	Deshpande, N
dc.contributor.author	Chen, S-Y
dc.contributor.author	Wasinger, VC
dc.contributor.author	Kockx, M
dc.contributor.author	Glaros, EN
dc.contributor.author	Ong, KL
dc.contributor.author	Thomas, SR
dc.contributor.author	Wilkins, MR
dc.contributor.author	Whan, RM
dc.contributor.author	Cochran, BJ
dc.contributor.author	Rye, K-A
dc.date.accessioned	2024-10-04T05:27:25Z
dc.date.available	2024-10-04T05:27:25Z
dc.date.issued	2024-02
dc.identifier.citation	Arterioscler Thromb Vasc Biol, 2024, 44, (2), pp. e20-e38
dc.identifier.issn	1079-5642
dc.identifier.issn	1524-4636
dc.identifier.uri	http://hdl.handle.net/10453/181192
dc.description.abstract	BACKGROUND: High cholesterol levels in pancreatic β-cells cause oxidative stress and decrease insulin secretion. β-cells can internalize apo (apolipoprotein) A-I, which increases insulin secretion. This study asks whether internalization of apoA-I improves β-cell insulin secretion by reducing oxidative stress. METHODS: Ins-1E cells were cholesterol-loaded by incubation with cholesterol-methyl-β-cyclodextrin. Insulin secretion in the presence of 2.8 or 25 mmol/L glucose was quantified by radioimmunoassay. Internalization of fluorescently labeled apoA-I by β-cells was monitored by flow cytometry. The effects of apoA-I internalization on β-cell gene expression were evaluated by RNA sequencing. ApoA-I-binding partners on the β-cell surface were identified by mass spectrometry. Mitochondrial oxidative stress was quantified in β-cells and isolated islets with MitoSOX and confocal microscopy. RESULTS: An F1-ATPase β-subunit on the β-cell surface was identified as the main apoA-I-binding partner. β-cell internalization of apoA-I was time-, concentration-, temperature-, cholesterol-, and F1-ATPase β-subunit-dependent. β-cells with internalized apoA-I (apoA-I+ cells) had higher cholesterol and cell surface F1-ATPase β-subunit levels than β-cells without internalized apoA-I (apoA-I- cells). The internalized apoA-I colocalized with mitochondria and was associated with reduced oxidative stress and increased insulin secretion. The IF1 (ATPase inhibitory factor 1) attenuated apoA-I internalization and increased oxidative stress in Ins-1E β-cells and isolated mouse islets. Differentially expressed genes in apoA-I+ and apoA-I- Ins-1E cells were related to protein synthesis, the unfolded protein response, insulin secretion, and mitochondrial function. CONCLUSIONS: These results establish that β-cells are functionally heterogeneous, and apoA-I restores insulin secretion in β-cells with elevated cholesterol levels by improving mitochondrial redox balance.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	LIPPINCOTT WILLIAMS & WILKINS
dc.relation.ispartof	Arterioscler Thromb Vasc Biol
dc.relation.isbasedon	10.1161/ATVBAHA.123.319378
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences
dc.subject.classification	Cardiovascular System & Hematology
dc.subject.classification	3201 Cardiovascular medicine and haematology
dc.subject.classification	3202 Clinical sciences
dc.subject.mesh	Mice
dc.subject.mesh	Animals
dc.subject.mesh	Insulin
dc.subject.mesh	Apolipoprotein A-I
dc.subject.mesh	Insulin-Secreting Cells
dc.subject.mesh	Cholesterol
dc.subject.mesh	Glucose
dc.subject.mesh	Adenosine Triphosphatases
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Cholesterol
dc.subject.mesh	Insulin
dc.subject.mesh	Glucose
dc.subject.mesh	Apolipoprotein A-I
dc.subject.mesh	Insulin-Secreting Cells
dc.subject.mesh	Adenosine Triphosphatases
dc.subject.mesh	Mice
dc.subject.mesh	Animals
dc.subject.mesh	Insulin
dc.subject.mesh	Apolipoprotein A-I
dc.subject.mesh	Insulin-Secreting Cells
dc.subject.mesh	Cholesterol
dc.subject.mesh	Glucose
dc.subject.mesh	Adenosine Triphosphatases
dc.title	ApoA-I Protects Pancreatic β-Cells From Cholesterol-Induced Mitochondrial Damage and Restores Their Ability to Secrete Insulin.
dc.type	Journal Article
utslib.citation.volume	44
utslib.location.activity	United States
utslib.for	1102 Cardiorespiratory Medicine and Haematology
utslib.for	1103 Clinical Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Health
pubs.organisational-group	University of Technology Sydney/Faculty of Health/Graduate School of Health
pubs.organisational-group	University of Technology Sydney/Faculty of Health/Graduate School of Health/GSH.Pharmacy
utslib.copyright.status	closed_access	*
dc.date.updated	2024-10-04T05:27:22Z
pubs.issue	2
pubs.publication-status	Published
pubs.volume	44
utslib.citation.issue	2

Abstract:

BACKGROUND: High cholesterol levels in pancreatic β-cells cause oxidative stress and decrease insulin secretion. β-cells can internalize apo (apolipoprotein) A-I, which increases insulin secretion. This study asks whether internalization of apoA-I improves β-cell insulin secretion by reducing oxidative stress. METHODS: Ins-1E cells were cholesterol-loaded by incubation with cholesterol-methyl-β-cyclodextrin. Insulin secretion in the presence of 2.8 or 25 mmol/L glucose was quantified by radioimmunoassay. Internalization of fluorescently labeled apoA-I by β-cells was monitored by flow cytometry. The effects of apoA-I internalization on β-cell gene expression were evaluated by RNA sequencing. ApoA-I-binding partners on the β-cell surface were identified by mass spectrometry. Mitochondrial oxidative stress was quantified in β-cells and isolated islets with MitoSOX and confocal microscopy. RESULTS: An F1-ATPase β-subunit on the β-cell surface was identified as the main apoA-I-binding partner. β-cell internalization of apoA-I was time-, concentration-, temperature-, cholesterol-, and F1-ATPase β-subunit-dependent. β-cells with internalized apoA-I (apoA-I+ cells) had higher cholesterol and cell surface F1-ATPase β-subunit levels than β-cells without internalized apoA-I (apoA-I- cells). The internalized apoA-I colocalized with mitochondria and was associated with reduced oxidative stress and increased insulin secretion. The IF1 (ATPase inhibitory factor 1) attenuated apoA-I internalization and increased oxidative stress in Ins-1E β-cells and isolated mouse islets. Differentially expressed genes in apoA-I+ and apoA-I- Ins-1E cells were related to protein synthesis, the unfolded protein response, insulin secretion, and mitochondrial function. CONCLUSIONS: These results establish that β-cells are functionally heterogeneous, and apoA-I restores insulin secretion in β-cells with elevated cholesterol levels by improving mitochondrial redox balance.

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http://hdl.handle.net/10453/181192