The hairy and enhancer of split 1 is a negative regulator of the repressor element silencer transcription factor.

Silencing of the transcriptional repressor REST is required for terminal differentiation of neuronal and beta-cells. In this study, we hypothesized that REST expression is controlled by hairy and enhancer of split 1 (HES-1), a transcriptional repressor that plays an important role in brain and pancreas development. We identified several N elements (CTNGTG) within the promoter of REST and confirmed that HES-1 associates with the endogenous promoter of REST. Moreover, using a cells model that overexpress HES-1 and a combination of experimental approaches, we demonstrated that HES-1 reduces endogenous REST expression. Taken together, these results indicate that HES-1 is an upstream negative regulator of REST expression.

High risk for hyperlipidemia and the metabolic syndrome after an episode of hypertriglyceridemia during 13-cis retinoic acid therapy for acne: a pharmacogenetic study.

BACKGROUND: Administration of 13-cis retinoic acid (isotretinoin) for acne is occasionally accompanied by hyperlipidemia. It is not known why some persons develop this side effect. OBJECTIVE: To determine whether isotretinoin triggers a familial susceptibility to hyperlipidemia and the metabolic syndrome. DESIGN: Cross-sectional comparison. SETTING: University hospital in Lausanne, Switzerland. PARTICIPANTS: 102 persons in whom triglyceride levels increased at least 1.0 mmol/L (> or =89 mg/dL) (hyperresponders) and 100 persons in whom triglyceride levels changed 0.1 mmol/L (< or =9 mg/dL) or less (nonresponders) during isotretinoin therapy for acne. Parents of 71 hyperresponders and 60 nonresponders were also evaluated. MEASUREMENTS: Waist-to-hip ratio; fasting glucose, insulin, and lipid levels; and apoE genotype. RESULTS: Hyperresponders and nonresponders had similar pretreatment body weight and plasma lipid levels. When reevaluated approximately 4 years after completion of isotretinoin therapy, hyperresponders were more likely to have hypertriglyceridemia (triglyceride level > 2.0 mmol/L [>177 mg/dL]; odds ratio [OR], 4.8 [95% CI, 1.6 to 13.8]), hypercholesterolemia (cholesterol level > 6.5 mmol/L [>252 mg/dL]; OR, 9.1 [CI, 1.9 to 43]), truncal obesity (waist-to-hip ratio > 0.90 [OR, 11.0 (CI, 2.0 to 59]), and hyperinsulinemia (insulin-glucose ratio > 7.2; OR, 3.0 [CI, 1.6 to 5.7]). In addition, more hyperresponders had at least one parent with hypertriglyceridemia (OR, 2.6 [CI, 1.2 to 5.7]) or a ratio of total to high-density lipoprotein cholesterol that exceeded 4.0 (OR, 3.5 [CI, 1.5 to 8.0]). Lipid response to isotretinoin was closely associated with the apoE gene. CONCLUSION: 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.

High prevalence of major cardiovascular risk factors in first-degree relatives of individuals with familial premature coronary artery disease--the GENECARD project.

BACKGROUND: Hypertension, hypercholesterolemia, obesity and smoking are highly prevalent among patients with familial premature coronary artery disease (FP-CAD). Whether these risk factors equally affect other family members remains unknown. METHODS: We examined 222 FP-CAD patients, 158 unaffected sibs, 197 offspring and 94 spouses in 108 FP-CAD families (> or = 2 sibs having survived CAD diagnosed before age 51 (M)/56 (F)), and compared them to population controls. RESULTS: Unaffected sibs had a higher prevalence of hypertension (49% versus 24%, p<0.001), hypercholesterolemia (47% versus 34%, p=0.002), abdominal obesity (35% versus 24%, p=0.006) and smoking (39% versus 24%, p=0.001) than population controls. Offspring had a higher prevalence of hypertension (females), hypercholesterolemia and abdominal obesity than population controls. No difference was observed between spouses and controls. Compared to unaffected sibs, FP-CAD affected sibs had a similar risk factor profile, except for smoking, which was more prevalent (76% versus 39%, p=0.008). CONCLUSIONS: 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.

The repressor element silencing transcription factor (REST)-mediated transcriptional repression requires the inhibition of Sp1.

The terminal differentiation of neuronal and pancreatic beta-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 beta-cells and are repressed by REST in other tissues is a central issue in differentiation program of neuronal and beta-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-beta 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-beta-cells. We conclude that the interplay between REST and Sp1 determines the cell-specific expression of REST target genes.

Complexin I regulates glucose-induced secretion in pancreatic beta-cells.

The neuronal-specific protein complexin I (CPX I) plays an important role in controlling the Ca(2+)-dependent neurotransmitter release. Since insulin exocytosis and neurotransmitter release rely on similar molecular mechanisms and that pancreatic beta-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 beta-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 beta-cells. Overexpression of CPX I or silencing of the CPX I gene (Cplx1) by RNA interference led to strong impairment in beta-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 beta-cells in the control of the stimulated-exocytosis of insulin.

Insulin-secreting beta-cell dysfunction induced by human lipoproteins.

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 beta-cells. Purified human very low density lipoprotein (VLDL) and LDL particles reduced insulin mRNA levels and beta-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. VLDL-induced apoptosis of beta-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 beta-cell survival and may therefore contribute to the beta-cell dysfunction observed during the development of type 2 diabetes.