*4.1. ABCA1, Cholesterol and β-Cell Function*

In addition to free fatty acid and triglyceride-mediated lipotoxicity, cholesterol toxicity is known to affect β-cell function and survival. β-cells are remarkably influenced by both intracellular cholesterol content and cholesterol distribution in the plasma membrane. Several transgenic and KO models have shown that increased cholesterol levels in βcells reduce islet function, islet mass, and reduce insulin secretion by interfering with normal insulin secretory pathways [105–109]. In addition, cholesterol is important for maintaining the cholesterol-rich lipid rafts in the β-cell plasma membrane. By mediating the action of voltage-gated calcium channels and SNARE proteins, these lipid rafts mediate secretory stimuli and granule exocytosis/insulin secretion [110–113]. Being a cholesterol transporter affecting intracellular cholesterol concentrations and cholesterol membrane distribution, ABCA1 is thus expected to play a critical role in islet cholesterol homeostasis, β-cell function, insulin resistance and T2D.

Pancreatic β-cell specific *Abca1* KO mice (*Abca1*-P/-P) showed age-related and genedose-dependent accumulation of cholesterol in β-cells. In addition, these mice showed

significantly decreased insulin secretion in response to an acute glucose challenge in vivo, along with progressive glucose tolerance impairment, which was not related to islet development or β-cell mass. The lack of ABCA1 in β-cells was later found to disrupt insulin granule exocytosis [109]. After loading *Abca1*−*/*<sup>−</sup> β-cells with cholesterol, Ca2+ influx in response to glucose stimulation decreased. These cells had a defective depolarization of the membrane and KCl-induced exocytosis. Interestingly, cholesterol depletion rescued the exocytotic defect in β-cells lacking ABCA1, supporting the notion that cholesterol accumulation plays an important role in the dysfunction of insulin secretion [109].

It is noteworthy that mice lacking *Abca1* specifically in β-cells have a more severe impairment in β-cell function compared with mice lacking *Abca1* globally. Because *Abca1*-P/-P mice have higher levels of total plasma cholesterol than global *Abca1* KO mice, the degree of β-cell dysfunction caused by *Abca1* deficiency may be related to the level of plasma cholesterol to which the islets are exposed [105]. Thus, beneficial reductions in plasma lipids may limit the extent of β-cell damage [114].
