The metabolic syndrome contributes to cardiovascular morbidity and mortality. 1-4 Data from the National Health and Nutrition Examination Survey (NHANES) 1999-2006 reported a metabolic syndrome prevalence of 34%. 5 Understanding updated prevalence trends may be important given the potential effect of the metabolic syndrome and its associated health complications on the aging US population. We investigated trends in the prevalence of the metabolic syndrome through 2012.

Niemann-Pick type C disease is largely attributable to an inactivating mutation of NPC1 protein, which normally aids movement of unesterified cholesterol (C) from the endosomal/lysosomal (E/L) compartment to the cytosolic compartment of cells throughout the body. This defect results in activation of macrophages in many tissues, progressive liver disease, and neurodegeneration. In the npc1 ؊/؊ mouse, a model of this disease, the whole-animal C pool expands from 2,082 to 4,925 mg/kg body weight (bw) and the hepatic C pool increases from 132 to 1,485 mg/kg bw between birth and 49 days of age. A single dose of 2-hydroxypropyl-␤-cyclodextrin (CYCLO) administered at 7 days of age immediately caused this sequestered C to flow from the lysosomes to the cytosolic pool in many organs, resulting in a marked increase in cholesteryl esters, suppression of C but not fatty acid synthesis, down-regulation of genes controlled by sterol regulatory element 2, and up-regulation of many liver X receptor target genes. There was also decreased expression of proinflammatory proteins in the liver and brain. In the liver, where the rate of C sequestration equaled 79 mg⅐d ؊1 ⅐kg ؊1 , treatment with CYCLO within 24 h increased C movement out of the E/L compartment from near 0 to 233 mg⅐d ؊1 ⅐kg ؊1 . By 49 days of age, this single injection of CYCLO resulted in a reduction in whole-body C burden of >900 mg/kg, marked improvement in liver function tests, much less neurodegeneration, and, ultimately, significant prolongation of life. These findings suggest that CYCLO acutely reverses the lysosomal transport defect seen in NPC disease.cholesterol ͉ lysosome ͉ cyclodextrin ͉ liver X receptor

SummaryMutations in methyl CpG binding protein 2 (MECP2) cause Rett Syndrome, the most severe autism spectrum disorder. Re-expressing Mecp2 in symptomatic Mecp2 null mice dramatically improves function and longevity, providing hope that therapeutic intervention is possible in humans. To identify pathways in disease pathology for therapeutic intervention, a dominant ENU mutagenesis suppressor screen was carried out in Mecp2 null mice. Five suppressors that ameliorate symptoms of Mecp2 loss were isolated. Here we show that a stop codon mutation in squalene epoxidase (Sqle), a rate-limiting enzyme in cholesterol biosynthesis underlies suppression in one line. Subsequently, we show that lipid metabolism is perturbed in the brain and liver of Mecp2 null males. Consistently, statin drugs improve systemic perturbations of lipid metabolism, alleviate motor symptoms and confer increased longevity in Mecp2 mutant mice. The genetic screen therefore points to cholesterol homeostasis as a potential target for the treatment of Rett patients.

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