Cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) and cholesterol uptake via the LDL receptor influences cholesterol-induced impairment of beta cell function in mice

Kruit, Janine K.; Kremer, Philip H. C.; Dai, Long‐Jun; Tang, Renmei; Ruddle, Piers; Haan, Willeke de; Brunham, Liam R.; Verchere, C. Bruce; Hayden, Michael R.

doi:10.1007/s00125-010-1691-2

Cited by 123 publications

(107 citation statements)

References 30 publications

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“…via LDL receptor) is also an important source of this sterol for islets (Kruit et al 2010). However, it is not only the cholesterol sources, but also their interplay in the mechanisms responsible for its efflux determines cholesterol homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is not only the cholesterol sources, but also their interplay in the mechanisms responsible for its efflux determines cholesterol homeostasis. The cholesterol transporter ABCA1 appears to be a key regulator of cholesterol efflux, because ABCA1 K/K mouse islets presented high cholesterol content with a consequent disruption of GSIS (Kruit et al 2010(Kruit et al , 2011. This negative effect on b-cell function due to accumulation of cholesterol has also been shown in the overactivation of its sources.…”

Section: Discussionmentioning

confidence: 99%

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Distinct pathways of cholesterol biosynthesis impact on insulin secretion

Zuniga-Hertz

Rebelato

Kassan

et al. 2014

Journal of Endocrinology

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Results from previous investigations have indicated that glucose-stimulated insulin secretion (GSIS) is affected by changes in cholesterol and its intermediates, but the precise link between secretion and cholesterol has not been thoroughly investigated. In this study, we show the contribution of both protein isoprenylation and cholesterol-dependent plasma membrane structural integrity to insulin secretion in INS-1E cells and mouse islets. Acute (2 h) inhibition of hydroxyl-methylglutaryl-CoA reductase by simvastatin (SIM) resulted in inhibition of GSIS without reduction in total cellular cholesterol content. This effect was prevented by cell loading with the isoprenyl molecule geranylgeranyl pyrophosphate. Chronic (24 h) inhibition of cholesterol biosynthesis resulted in inhibition of GSIS with a significant reduction in total cellular cholesterol content, which was also observed after the inhibition of cholesterol biosynthesis downstream of isoprenoid formation. Electron paramagnetic resonance analyses of INS-1E cells showed that the SIM-induced reduction in cholesterol increased plasma membrane fluidity. Thus, the blockade of cholesterol biosynthesis resulted in the reduction of availability of isoprenoids, followed by a reduction in the total cholesterol content associated with an increase in plasma membrane fluidity. Herein, we show the different contributions of cholesterol biosynthesis to GSIS, and propose that isoprenoid molecules and cholesterol-dependent signaling are dual regulators of proper b-cell function.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Distinct pathways of cholesterol biosynthesis impact on insulin secretion

Zuniga-Hertz

Rebelato

Kassan

et al. 2014

Journal of Endocrinology

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“…It is noteworthy that these patients did not present the characteristic markers of the metabolic syndrome (including visceral obesity, hypertriglyceridemia, hypertension, and insulin resistance) nor a positive family history of diabetes. The pathophysiology of the Tangier disease model has been confirmed in ABCA1 knock-out animals, which exhibited both an increased development of cardiovascular lesions and a progressive impairment of glucose tolerance [45]. The preserved insulin sensitivity demonstrated in these animals suggests that the impaired glucose regulation is exclusively linked to a direct toxic effect of cholesterol on the beta-cell [44].…”

Section: Dyslipidemia Contributing To Diabetes and Vascular Complicatmentioning

confidence: 91%

“…To this end, various researchers have clearly described specific receptors for LDL-C, namely LRPs, present in pancreatic islets, and they showed that LDL-C particles are incorporated in the metabolic pathway of beta-cells in a highly selective manner [44,45]. However, this increased bioavailability of LDL-C in the pancreatic cell metabolism seems to have a cytotoxic effect, and may cause increased beta-cell apoptosis.…”

Section: Dyslipidemia Contributing To Diabetes and Vascular Complicatmentioning

confidence: 99%

Dyslipidemia and Diabetes: Reciprocal Impact of Impaired Lipid Metabolism and Beta-Cell Dysfunction on Micro- and Macrovascular Complications

Rotella²,

2012

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■ AbstractPatients with diabetes frequently exhibit the combined occurrence of hyperglycemia and dyslipidemia. Published data on their coexistence are often controversial. Some studies provide evidence for suboptimal lifestyle and exogenous hyperinsulinism at "mild insulin resistance" in adult diabetic patients as main pathogenic factors. In contrast, other studies confirm that visceral adiposity and insulin resistance are the basic features of dyslipidemia in type 2 diabetes (T2D). The consequence is an excess of free fatty acids, which causes hepatic gluconeogenesis to increase, metabolism in muscles to shift from glucose to lipid, beta-cell lipotoxicity, and an appearance of the classical "lipid triad", without real hypercholesterolemia. Recently, it has been proposed that cholesterol homeostasis is important for an adequate insulin secretory performance of beta-cells. The accumulation of cholesterol in beta-cells, caused by defective high-density lipoprotein (HDL) cholesterol with reduced cholesterol efflux, induces hyperglycemia, impaired insulin secretion, and beta-cell apoptosis. Data from animal models and humans, including humans with Tangier disease, who are characterized by very low HDL cholesterol levels, are frequently associated with hyperglycemia and T2D. Thus, there is a reciprocal influence of dyslipidemia on beta-cell function and inversely of beta-cell dysfunction on lipid metabolism and micro-and macrovascular complications. It remains to be clarified how these different but mutually influencing adverse effects act in together to define measures for a more effective prevention and treatment of micro-and macrovascular complications in diabetes patients. While the control of circulating low-density lipoprotein (LDL) cholesterol and the level of HDL cholesterol are determinant targets for the reduction of cardiovascular risk, based on recent data, these targets should also be considered for the prevention of betacell dysfunction and the development of type 2 diabetes. In this review, we analyze consolidated data and recent advances on the relationship between lipid metabolism and diabetes mellitus, with particular attention to the reciprocal effects of the two features of the disease and the development of vascular complications.

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“…To the Editor: In a recent issue of Diabetologia, Kruit and colleagues presented an article regarding the role of cholesterol-induced impairment of beta cell function in mice [1]. The authors found that in Ldlr -/-knockout mice, which lack the LDL receptor, islet cholesterol content was normal despite moderate hypercholesterolaemia, and in the presence of very high plasma cholesterol levels induced by a Western-style diet, glucose-stimulated insulin secretion was not reduced.…”

Section: Abca1 Atp-binding Cassette Transporter A1mentioning

confidence: 99%