Diabetes is associated with significant changes in plasma concentrations of lipoproteins. We tested the hypothesis that lipoproteins modulate the function and survival of insulin-secreting cells. We first detected the presence of several receptors that participate in the binding and processing of plasma lipoproteins and confirmed the internalization of fluorescent low density lipoprotein (LDL) and high density lipoprotein (HDL) particles in insulin-secreting ␤-cells. Purified human very low density lipoprotein (VLDL) and LDL particles reduced insulin mRNA levels and ␤-cell proliferation and induced a dose-dependent increase in the rate of apoptosis. In mice lacking the LDL receptor, islets showed a dramatic decrease in LDL uptake and were partially resistant to apoptosis caused by LDL. VLDLinduced apoptosis of ␤-cells involved caspase-3 cleavage and reduction in the levels of the c-Jun N-terminal kinase-interacting protein-1. In contrast, the proapoptotic signaling of lipoproteins was antagonized by HDL particles or by a small peptide inhibitor of c-Jun N-terminal kinase. The protective effects of HDL were mediated, in part, by inhibition of caspase-3 cleavage and activation of Akt/protein kinase B. In conclusion, human lipoproteins are critical regulators of ␤-cell survival and may therefore contribute to the ␤-cell dysfunction observed during the development of type 2 diabetes.

Persons who develop hypertriglyceridemia during isotretinoin therapy for acne, as well as their parents, are at increased risk for future hyperlipidemia and the metabolic syndrome.

The neuronal-specific protein complexin I (CPX I) plays an important role in controlling the Ca2+-dependent neurotransmitter release. Since insulin exocytosis and neurotransmitter release rely on similar molecular mechanisms and that pancreatic β-cells and neuronal cells share the expression of many restricted genes, we investigated the potential role of CPX I in insulin-secreting cells. We found that pancreatic islets and several insulin-secreting cell lines express high levels of CPX I. The β-cell expression of CPX I is mediated by the presence of a neuron restrictive silencer element located within the regulatory region of the gene. This element bound the transcriptional repressor REST, which is found in most cell types with the exception of mature neuronal cells and β-cells. Overexpression of CPX I or silencing of the CPX I gene (Cplx1) by RNA interference led to strong impairment in β-cell secretion in response to nutrients such as glucose, leucine and KCl. This effect was detected both in the early and the sustained secretory phases but was much more pronounced in the early phase. We conclude that CPX I plays a critical role in β-cells in the control of the stimulated-exocytosis of insulin.

The terminal differentiation of neuronal and pancreatic ␤-cells requires the specific expression of genes that are targets of an important transcriptional repressor named RE-1 silencing transcription factor (REST). The molecular mechanism by which these REST target genes are expressed only in neuronal and ␤-cells and are repressed by REST in other tissues is a central issue in differentiation program of neuronal and ␤-cells. Herein, we showed that the transcriptional factor Sp1 was required for expression of most REST target genes both in insulin-secreting cells and neuronal-like cells where REST is absent. Inhibition of REST in a non-␤ and a non-neuronal cell model restored the transcriptional activity of Sp1. This activity was also restored by trichostatin A indicating the requirement of histone deacetylases for the REST-mediated silencing of Sp1. Conversely, exogenous introduction of REST blocked Sp1-mediated transcriptional activity. The REST inhibitory effect was mediated through its C-terminal repressor domain, which could interact with Sp1. Taken together, these data show that the inhibition of Sp1 by REST is required for the silencing of its target genes expression in non-neuronal and in non-␤-cells. We conclude that the interplay between REST and Sp1 determines the cell-specific expression of REST target genes.

Abstract-Serum or plasma levels of Lp(a) vary widely between individuals and are higher in Africans and their descendants compared with white persons. In whites, high serum levels of Lp(a) are associated with the premature development of atherosclerosis. In both ethnic groups, serum Lp(a) levels are highly genetically determined and only a few environmental or physiological factors, like testosterone or estrogen, have been shown to lower serum Lp(a) levels. In whites, alcohol consumption is associated with lower serum Lp(a) levels. However, the mechanism underlying this association and whether it holds true for blacks is not known. To address these questions, we analyzed serum Lp(a) levels in 333 middle-aged males of African descent from the Seychelles Islands (Indian Ocean). In addition, we analyzed the size of the apo(a) isoforms and the serum levels of albumin and sex hormones in a subset of 279 subjects. Serum Lp(a) levels were similar in teetotalers (median, 32.5 mg/dL; nϭ42) and occasional drinkers (median, 34.1 mg/dL; nϭ112). In contrast, individuals consuming 10 to 80 g of ethanol/d (nϭ83) and heavy drinkers (Ͼ80 g of ethanol/d, nϭ96) had a 9% and 32% lower median Lp(a) level than teetotalers, respectively (Pϭ0.01). The size distribution of the apo(a) isoforms and the mean serum levels of albumin, estradiol, and luteinizing hormone were similar in teetotalers and occasional drinkers compared with moderate and heavy drinkers. These latter 2 groups had lower serum levels of testosterone and sex hormone-binding globulin. These data indicate that alcohol intake is associated in a dosedependent manner with lower serum Lp(a) levels in males of African descent and that this association is not related to the size of the apo(a) isoforms, to the synthetic function of the liver, or to sex hormone biochemical status.

Hypertension, obesity and hypercholesterolemia are highly prevalent among first-degree relatives, but not spouses, of patients with FP-CAD. These persons deserve special medical attention due to their familial/genetic susceptibility to atherogenic metabolic abnormalities. In these families, smoking may be the trigger for FP-CAD.

Extravascular coagulation and diminished fibrinolysis are processes that contribute to the pathology of both inflammatory arthritis and atherosclerosis. We hypothesized that, given its homology with plasminogen, apolipoprotein (apo) (a), the distinctive glycoprotein of the atherogenic lipoprotein (Lp) (a), may be equally implicated in inflammatory arthritis. We detected the presence of apo(a) as part of Lp(a) in human arthritic synovial fluid. The abundance of apo(a) in synovial fluid rose in proportion to plasma apo(a) levels and was higher in inflammatory arthritides than in osteoarthritis. In addition, apo(a) immunoreactive material, but not apo(a) transcripts, was detected in inflammatory arthritic synovial tissues. These data indicated that synovial fluid apo(a) originates from circulating Lp(a) and that diffusion of Lp(a) through synovial tissue is facilitated in inflammatory types of arthritis. In synovial tissues, apo(a) co-localized with fibrin. These observations could be reproduced in a model of antigen-induced arthritis, using transgenic mice expressing human Lp(a). Although in this mouse model the presence of apo(a) did not change the severity of arthritis, the co-localization of apo(a) with fibrin in synovial tissue suggests that, in humans, apo(a) may modulate locally the fibrinolytic activity and may thus contribute to the persistence of intra-articular fibrin in inflammatory arthritis. Patients suffering from rheumatic diseases are at increased risk for cardiovascular morbidity and mortality, 1,2 suggesting that common factors may promote the development of both atherosclerosis and arthritis.

Fragments of apolipoprotein(a) [apo(a)], the distinctive glycoprotein of lipoprotein(a) [Lp(a)], are present in human plasma and urine and have been implicated in the development of atherosclerosis. The mechanism responsible for the generation of apo(a) fragments in vivo is poorly understood. In this study, we examined the plasma levels of Lp(a) and apo(a) fragments [or free apo(a)] and urinary apo(a) in 15 subjects who underwent cardiac surgery necessitating cardiopulmonary bypass. We also measured the plasma concentration and activity of polymorphonuclear elastase, an Lp(a)-cleaving enzyme in vitro, and plasma levels of C-reactive protein. Despite a marked activation of polymorphonuclear cells and a pronounced inflammatory response, as documented by an 8-fold and a 35-fold increase in plasma levels of polymorphonuclear elastase and C-reactive protein, respectively, the proportion of plasma free apo(a) to Lp(a) and urinary excretion of apo(a) remained unchanged over a 7-day period after surgery, and polymorphonuclear elastase activity remained undetectable in plasma. No fragmentation of apo(a) was observed ex vivo in plasma samples collected before and after surgery. These data indicate that in this model, apo(a) is not fragmented in plasma and are consistent with the hypothesis that apo(a) fragments result from a constitutively active tissue mechanism that is not modified by cardiac surgery with cardiopulmonary bypass.