Effect of type 2 diabetes mellitus caveolin‑3 K15N mutation on glycometabolism

Huang, Yiyuan; Deng, Yufeng; Shang, Lina; Yang, Lihui; Huang, Juanjuan; Ma, Jing; Liao, Xianshan; Zhou, Hui; Xian, Jing; Gao, Liang; Huang, Qin

doi:10.3892/etm.2019.7840

Cited by 6 publications

(5 citation statements)

References 59 publications

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“…Mice that lack caveolin-3 (cav3), a skeletal muscle-specific scaffolding protein critical in the formation of caveolae on the plasma membrane, exhibit skeletal muscle insulin resistance due to plasma membrane-specific effects on the IR (41,42). Overexpression of dominant-negative cav3 leads to decreased glucose uptake and glycogen synthesis in C2C12 cells, which is attributed to decreased Akt phosphorylation (43)(44)(45). Conversely, an increase in wildtype cav3 expression is sufficient to enhance Akt phosphorylation and glucose uptake (46).…”

Section: How Does the Inhibition Of The Lands Cycle Promote Greater Imentioning

confidence: 99%

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

Ferrara¹,

Rong²,

Maschek³

et al. 2021

Journal of Clinical Investigation

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Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals that are insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PL) that were differentially-abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lyso-PC/PC, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.

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Section: How Does the Inhibition Of The Lands Cycle Promote Greater Imentioning

confidence: 99%

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

Ferrara¹,

Rong²,

Maschek³

et al. 2021

Journal of Clinical Investigation

View full text Add to dashboard Cite

show abstract

“…Mice that lack caveolin-3 (cav3), a skeletal muscle-specific scaffolding protein critical in the formation of caveolae on the plasma membrane, exhibit skeletal muscle insulin resistance due to plasma membrane-specific effects on the IR (41, 42). Overexpression of dominant-negative cav3 leads to decreased glucose uptake and glycogen synthesis in C2C12 cells, which is attributed to decreased Akt phosphorylation (43–45). Conversely, an increase in wildtype cav3 expression is sufficient to enhance Akt phosphorylation and glucose uptake (46).…”

Section: Resultsmentioning

confidence: 99%

The Lands cycle modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

Ferrara

Rong²,

Maschek

et al. 2019

Preprint

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39 Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but 40 the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A 41 comprehensive lipidomic analyses of primary myocytes from lean insulin-sensitive (LN) and 42 obese insulin-resistant (OB) individuals revealed several species of lysophospholipids (lyso-PL) 43 that were differentially-abundant. These changes coincided with greater expression of 44 lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid 45 transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 46 (LPCAT3-MKO) exhibited greater muscle lyso-PC/PC, concomitant with greater insulin 47 sensitivity in vivo and insulin-stimulated skeletal muscle glucose uptake ex vivo. Absence of 48 LPCAT3 reduced phospholipid packing of the cellular membranes and increased plasma 49membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by 50 modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal 51 muscle Lands cycle, whose consequence might induce the disruption of plasma membrane 52 organization that suppresses muscle insulin action. 53Notably, the increase occurred at the level of the insulin receptor (IR), a node that is localized in 131 the phospholipid-rich plasma membrane. Consequently, LPCAT3 deletion enhanced insulin-132 stimulated glycogen synthesis ( Figure 2H), suggesting that this intervention increases skeletal 133 muscle insulin sensitivity in vitro (due to low GLUT4:GLUT1 stoichiometry, insulin-stimulated 134 glucose uptake is not an ideal surrogate for insulin sensitivity in C2C12 myotubes). LPCAT3 135 knockdown also enhanced insulin signaling in HSkMC from obese subjects ( Figure 2G). 136 137The organization and clustering of plasma membrane microdomains is linked to the induction of 138 tyrosine-kinase signaling events, such as IR signaling (29-31). Because LPCAT3 deletion 139

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“…A previous study demonstrated that a variety of mutations were present in the CAV-3 gene among 1–1000 patients with T2DM. A previous assessment of patients with newly developed T2DM demonstrated that K15N muta tion located in the N-terminus of caveolin-3 may lead to changes in caveolin-3 secondary structure, thus causing decreased recombinant caveolin-3 expression [ 97 ]. It has been found that decreased expression and reduced localization of caveolin-3 by CAV-3-P104L mutation inhibited glucose uptake and glycogen synthesis [ 98 ].…”

Section: Caveolin-3 and Metabolic Perturbationmentioning

confidence: 99%

Caveolin-3 and Arrhythmias: Insights into the Molecular Mechanisms

Qiu

Wang

et al. 2022

JCM

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Caveolin-3 is a muscle-specific protein on the membrane of myocytes correlated with a variety of cardiovascular diseases. It is now clear that the caveolin-3 plays a critical role in the cardiovascular system and a significant role in cardiac protective signaling. Mutations in the gene encoding caveolin-3 cause a broad spectrum of clinical phenotypes, ranging from persistent elevations in the serum levels of creatine kinase in asymptomatic humans to cardiomyopathy. The influence of Caveolin-3(CAV-3) mutations on current density parallels the effect on channel trafficking. For example, mutations in the CAV-3 gene promote ventricular arrhythmogenesis in long QT syndrome 9 by a combined decrease in the loss of the inward rectifier current (IK1) and gain of the late sodium current (INa-L). The functional significance of the caveolin-3 has proved that caveolin-3 overexpression or knockdown contributes to the occurrence and development of arrhythmias. Caveolin-3 overexpression could lead to reduced diastolic spontaneous Ca2+ waves, thus leading to the abnormal L-Type calcium channel current-induced ventricular arrhythmias. Moreover, CAV-3 knockdown resulted in a shift to more negative values in the hyperpolarization-activated cyclic nucleotide channel 4 current (IHCN4) activation curve and a significant decrease in IHCN4 whole-cell current density. Recent evidence indicates that caveolin-3 plays a significant role in adipose tissue and is related to obesity development. The role of caveolin-3 in glucose homeostasis has attracted increasing attention. This review highlights the underlining mechanisms of caveolin-3 in arrhythmia. Progress in this field may contribute to novel therapeutic approaches for patients prone to developing arrhythmia.

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Effect of type 2 diabetes mellitus caveolin‑3 K15N mutation on glycometabolism

Cited by 6 publications

References 59 publications

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

The Lands cycle modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

Caveolin-3 and Arrhythmias: Insights into the Molecular Mechanisms

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