ABCA12 regulates insulin secretion from β‐cells

Ursino, Gloria; Fu, Ying; Cottle, Denny L; Mukhamedova, Nigora; Jones, Lynelle K.; Low, Hann; Tham, Ming Shen; Gan, Wan Jun; Mellett, Natalie A.; Das, Partha Pratim; Weir, Jacquelyn M.; Ditiatkovski, Michael; Fynch, Stacey; Thorn, Peter; Thomas, Helen E.; Meikle, Peter J.; Parkington, Helena C.; Smyth, Ian; Sviridov, Dmitri

doi:10.15252/embr.201948692

Cited by 13 publications

(11 citation statements)

References 48 publications

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“…This is supported by the reduced number of insulin granules docked at the plasma membrane in -cells from isolated islets from -ROCK1 -/mice, which is associated with a decrease in the first phase of insulin release during glucose stimulation. Consistent with this view, previous reports link several proteins such as TRB3 [36], ABCA12 [38] and LKB1 [39] with modulating insulin granules and plasma membrane docking dynamics in the regulation of GSIS. The mechanism(s) underlying insulin granules mobilization could involve in F-actin remodeling in response to glucose stimulation [40].…”

Section: Discussionsupporting

confidence: 66%

ROCK1 regulates insulin secretion from β-cells

Sung

Lim

Kim

et al. 2021

Preprint

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Objective: The endocrine pancreatic β-cells play a pivotal role in the maintenance of whole-body glucose homeostasis and its dysregulation is a consistent feature in all forms of diabetes. However, knowledge of intracellular regulators that modulate b-cell function remains incomplete. We investigated the physiological role of ROCK1 in the regulation of insulin secretion and glucose homeostasis. Methods: Mice lacking ROCK1 in pancreatic β-cells (RIP-Cre; ROCK1loxP/loxP, β-ROCK1-/-) were studied. Glucose and insulin tolerance tests as well as glucose-stimulated insulin secretion (GSIS) were measured. Insulin secretion response to a direct glucose or pyruvate or pyruvate kinase (PK) activator stimulation in isolated islets from β-ROCK1-/- mice or β-cell lines with knockdown of ROCK1 were also evaluated. Proximity ligation assay was performed to determine the physical interactions between PK and ROCK1. Results: Mice with a deficiency of ROCK1 in pancreatic β-cells exhibited significantly increased blood glucose levels and reduced serum insulin without changes in body weight. Interestingly, β-ROCK1-/- mice displayed progressive impairment of glucose tolerance while maintaining insulin sensitivity mostly due to impaired GSIS. Consistently, GSIS was markedly decreased in ROCK1-deficient islets and ROCK1 knockdown INS-1 cells. Concurrently, ROCK1 blockade led to a significant decrease in intracellular calcium levels, ATP levels, and oxygen consumption rates in isolated islets and INS-1 cells. Treatment of ROCK1-deficient islets or ROCK1 knockdown β-cells either with pyruvate or a PK activator rescued the impaired GSIS. Mechanistically, we observed that ROCK1 binding to PK is greatly enhanced by glucose stimulation in β-cells. Conclusions: Our findings demonstrate that β-cell ROCK1 is essential for glucose-stimulated insulin secretion and maintenance of glucose homeostasis and that ROCK1 acts as an upstream regulator of glycolytic pyruvate kinase signaling.

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Section: Discussionsupporting

confidence: 66%

ROCK1 regulates insulin secretion from β-cells

Sung

Lim

Kim

et al. 2021

Preprint

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“…Lipids play important roles in ISG maturation. The cholesterol content of insulin granules is high, at least in part through the action of granule-localized ABC cholesterol transporters [64,65]. β-Cells lacking the ABCG1/ ABCA12 cholesterol transporters or treated with cholesterol synthesis inhibitors present with enlarged ISG and exhibit reduced glucose-stimulated insulin secretion [64][65][66].…”

Section: Ca 2+mentioning

confidence: 99%

“…The cholesterol content of insulin granules is high, at least in part through the action of granule-localized ABC cholesterol transporters [64,65]. β-Cells lacking the ABCG1/ ABCA12 cholesterol transporters or treated with cholesterol synthesis inhibitors present with enlarged ISG and exhibit reduced glucose-stimulated insulin secretion [64][65][66]. The mechanism of cholesterol action is not clear, but it has been shown that cholesterol transport is needed to protect newly formed ISG against lysosomal degradation [28].…”

Section: Ca 2+mentioning

confidence: 99%

Insulin granule biogenesis and exocytosis

Omar‐Hmeadi

Idevall‐Hagren

2020

Cell. Mol. Life Sci.

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Insulin is produced by pancreatic β-cells, and once released to the blood, the hormone stimulates glucose uptake and suppresses glucose production. Defects in both the availability and action of insulin lead to elevated plasma glucose levels and are major hallmarks of type-2 diabetes. Insulin is stored in secretory granules that form at the trans-Golgi network. The granules undergo extensive modifications en route to their release sites at the plasma membrane, including changes in both protein and lipid composition of the granule membrane and lumen. In parallel, the insulin molecules also undergo extensive modifications that render the hormone biologically active. In this review, we summarize current understanding of insulin secretory granule biogenesis, maturation, transport, docking, priming and eventual fusion with the plasma membrane. We discuss how different pools of granules form and how these pools contribute to insulin secretion under different conditions. We also highlight the role of the β-cell in the development of type-2 diabetes and discuss how dysregulation of one or several steps in the insulin granule life cycle may contribute to disease development or progression.

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“…Disease development was profiled using a custom-made skin-related Nanostring GX array (see Data S1 ) which confirmed an ∼50% loss of Abca12 transcript and a reduction in Abca1 mRNA consistent with previous reports ( Figure 3 H). 12 Using a previously characterized antibody, 15 no ABCA12 protein was detectable by immunofluorescence analysis, suggesting that the persistent transcript was non-functional ( Figure 3 I). Of the 95 genes included in the Nanostring array, 57 were found to be significantly dysregulated upon Abca12 deletion, including the downregulation of differentiation markers ( Krt10 and Lor ) and the upregulation of wounding and proliferation markers ( Krt5 , Krt14 , Krt6a/b , and Krt16 ) ( Data S1 ).…”

Section: Resultsmentioning

confidence: 98%

Topical Aminosalicylic Acid Improves Keratinocyte Differentiation in an Inducible Mouse Model of Harlequin Ichthyosis

Cottle

Ursino

Jones

et al. 2020

Cell Reports Medicine

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Summary Mutations in the lipid transport protein ABCA12 cause the life-threatening skin condition harlequin ichthyosis (HI), which is characterized by the loss of skin barrier function, inflammation, and dehydration. Inflammatory responses in HI increase disease severity by impairing keratinocyte differentiation, suggesting amelioration of this phenotype as a possible therapy for the condition. Existing treatments for HI are based around the use of retinoids, but their value in treating patients during the neonatal period has been questioned relative to other improved management regimens, and their long-term use is associated with side effects. We have developed a conditional mouse model to demonstrate that topical application of the aminosalicylic acid derivatives 5ASA or 4ASA considerably improves HI keratinocyte differentiation without the undesirable side effects of the retinoid acitretin and salicylic acid (aspirin). Analysis of changes in gene expression shows that 4ASA in particular elicits compensatory upregulation of a large family of barrier function-related genes, many of which are associated with other ichthyoses, identifying this compound as a lead candidate for developing topical treatments for HI.

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ABCA12 regulates insulin secretion from β‐cells

Cited by 13 publications

References 48 publications

ROCK1 regulates insulin secretion from β-cells

ROCK1 regulates insulin secretion from β-cells

Insulin granule biogenesis and exocytosis

Topical Aminosalicylic Acid Improves Keratinocyte Differentiation in an Inducible Mouse Model of Harlequin Ichthyosis

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