Lipoproteins and β-Cell Functions: From Basic to Clinical Data

Corresponding author: Dae Ho Lee Department of Internal Medicine, Wonkwang University School of Medicine & Hospital, 895 Muwang-ro, Iksan 570-974, Korea E-mail: [email protected] Cholesterol loading to β-cells was shown to increase neuronal nitric oxide synthase (NOS) dimerization, which decreases glucokinase activity [1] and also inhibits glucose-stimulated phosphatidylinositol 4,5-bisphosphate hydrolysis and the closure of KATP channels [2]. Thus, islets exposed to physiologic levels of low density lipoprotein (LDL) show a decrease in glucose-stimulated insulin secretion in a LDL receptor-dependent manner [2,3]. LDL-cholesterol (LDL-C) concentrations as low as 0.8 and 1 mM can inhibit the proliferation of islet cells by 50% to 70% [3]. This inhibition of cultured islets proliferation occurs in β-cells independently of LDL receptor [3]. In addition to the adverse effects on insulin secretion and proliferation, LDL has a negative impact on β-cell survival when it is modified or present at very high concentrations [3-5]. Oxidized LDL induces the JNK pathway and the subsequent activation of AP1, thereby leading to impaired insulin synthesis and increased apoptosis [4]. Very low density lipoprotein (VLDL)-mediated apoptosis of β-cells is also associated with an increase in JNK activity [5]. Considering the above-mentioned negative effects of LDL on β-cell functions, cholesterol seems to be very bad for β-cells. However, not only cellular cholesterol content, but also a delicate balance of cholesterol concentrations between different subcellular compartments needs to be finely tuned for optimal β-cell functionality [6]. ATP-binding cassette transporter G1 (ABCG1) plays an important role in the enrichment of insulin secretory granules with cholesterol and the partitioning of cholesterol between different cellular compartments rather than for cholesterol efflux from the β-cells [7,8] while ABCA1 mediates the efflux of cholesterol and phospholipids to an extracellular apolipoprotein acceptor. Mice with ABCA1 deficiency in β-cells have characteristic phenotypes including cholesterol accumulation in islet, normal plasma cholesterol levels, markedly impaired glucose tolerance (IGT), and defective insulin secretion, without influencing insulin sensitivity [9]. On hyperglycemic clamp study, the first phase insulin secretion rate was shown to be significantly lower in Tangier heterogygotes with loss-of-function mutations in ABCA1 than in control subjects [10]. The lack of β-cell ABCA1 results in impaired depolarization-induced exocytotic fusion of insulin granules, disturbances in membrane microdomain organization, and alteration in Golgi and insulin granule morphology, suggesting that elevated islet cholesterol accumulation directly impairs granule fusion and insulin secretion [6]. Physiologic levels of high density lipoprotein (HDL) protein may or may not increase basal and glucose-stimulated insulin secretion from β-cells, depending on experimental conditions [3,6]. HDL protects β-cells from endoplasmic reticulum stress, basal apoptosis, and apoptosis induced by various stressful conditions, including glucose, cytokines, VLDL, and oxidized LDL [3,6,11]. Inducible NOS is expressed in β-cells and mediate the proapoptotic effect of glucose and cytokines, but its basal and stimulated expression in islets is suppressed by HDL [3]. Furthermore, the downstream target of activated inducible NOS, namely the death receptor Fas, is downregulated by HDL, whereas antiapoptotic Fas-associated death domain-like interEditorial Obesity and metabolic syndrome