ABCA1 implicated in control of β-cell cholesterol homeostasis

New data indicate that ABCA1 (ATP-binding cassette transporter subfamily A member 1), which facilitates the delivery of cholesterol from cells to lipid-poor apolipoprotein A-I in the extracellular space, plays a key role in β-cell cholesterol homoeostasis and insulin secretion.1 Cholesterol accumulation, resulting from the absence of β-cell ABCA1, may be implicated in β-cell dysfunction in type 2 diabetes.

Researchers investigated the role of ABCA1 in β-cell function using a mouse model lacking β-cell ABCA1 (ABCA1–P/-P). The ABCA1-P/-P mice developed impaired glucose tolerance within 8 weeks, and plasma insulin levels during glucose tolerance tests were significantly lower than in control mice (ABCA1+/+). Glucose challenge (3 mg/kg bodyweight) showed that plasma insulin levels were lower after 2 minutes in ABCA1-P/-P mice than control mice, indicating that ABCA1 is essential for the first phase of glucose-stimulated insulin secretion in vivo. Similar findings were reported in response to L-arginine (0.3 mg/kg), suggesting that the absence of β-cell ABCA1 leads to a generalised insulin secretory defect. Reduction in insulin secretion in ABCA1-P/-P mice could not be explained by differences in β-cell mass or changes in morphology, abundance or size of the islets compared with control mice. Insulin sensitivity in ABCA1-P/-P mice was similar to that of control mice.

Islets isolated from ABCA1-P/-P mice showed significant increases in total and free cholesterol and cholesterol ester levels, although levels of HDL cholesterol and triglycerides did not differ from those measured in islets of control mice. However islets from mice lacking ABCA1 globally showed no increase in total and free cholesterol or cholesterol ester compared with controls, suggesting that absence of β-cell ABCA1 leads to greater cholesterol accumulation and more severe impairment of glucose tolerance. Expression of ABCG1, a cholesterol transporter essential for preventing excess accumulation of cellular cholesterol, was increased in vitro in ABCA1-P/-P mice to compensate for the loss of β-cell ABCA1. In addition, insulin secretion was also significantly reduced in islets from mice lacking β-cell ABCA1.

Treatment with rosiglitazone, a peroxisome proliferator-activated receptor γ agonist known to activate ABCA1 in macrophages,2 restored glucose tolerance in control mice fed a high-fat diet, but not in ABCA1-P/-P mice fed a high-fat diet. Findings that rosiglitazone lowered free cholesterol levels in islets isolated from control mice but not in islets from ABCA1-P/-P mice suggests that this may contribute to the failure to respond to rosiglitazone in mice lacking β-cell ABCA1.

The researchers concluded that ABCA1 plays a key functional role in mediating cholesterol homeostasis in β-cells, and that absence of β-cell function leads to defective insulin secretion and impairment of glucose tolerance. These findings suggest that cholesterol accumulation may contribute to β-cell dysfunction in type 2 diabetes. Strategies that target β-cell ABCA1 may prove useful in the treatment of type 2 diabetes.

References

1. Brunham LR, Kruit JK, Pape TD et al. β-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment. Nat Med 2007;13:340-7.

2. Chinetti G et al. PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med 2001;7:53-8.

Commentary

This interesting study shows for the first time that pancreatic β-cell function is closely linked to one of the key regulators of HDL metabolism, ABCA1. The findings, which demonstrate that cholesterol accumulation in pancreatic islets inhibits insulin secretion, are consistent with lipotoxicity being a key determinant of β-cell dysfunction in type 2 diabetes.

The results also show that there is a compensatory upregulation of β-cell ABCG1 in the absence of ABCA1. When taken together these results suggest that increasing β- cell ABCA1 or ABCG1 expression may be beneficial in type 2 diabetes. However, this would be the case only if there was a corresponding increase in the level of extracellular cholesterol acceptors (lipid-free/lipid-poor apolipoprotein A-I in the case of ABCA1 and spherical HDL in the case of ABCG1). Given that cholesterol export from β-cells does not contribute significantly to plasma HDL cholesterol levels, it follows that the acceptor level may not have to be increased by much to have an effect, making this a potentially appealing therapeutic approach.

An observation of particular interest in this study was that when challenged with a high-fat diet, mice gain weight at the same rate irrespective of whether or not they are deficient in β-cell ABCA1. This highlights the fact that the development of type 2 diabetes has a strong genetic component.

While the relevance of these results for humans is not known, they do indicate that we should be looking to broaden our horizons when considering strategies for reducing the incidence of type 2 diabetes.