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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Niemann-Pick type C (NPC) disease is a multisystem disorder caused primarily by a mutation in the npc1 gene. These studies evaluated the effect of genetic background, deletion of additional genes, and administration of several agents on the age at death in a murine model of this disorder. Such factors as differing strain background or genetic drift within a given background in the npc1 2/2 mouse significantly altered the age at death and the degree of organ disease. Genetic deletion of Siat9 (GM3 synthetase) or Nr1h2 [liver X receptor (LXR)b] shortened the life of the npc1 2/2 animals. Daily treatment of the npc1 2/2 mice with an LXR agonist or administration of a single dose of cyclodextrin, with or without the neurosteroid allopregnanolone, significantly slowed neurodegeneration and increased the lifespan of these animals. These data illustrate that the age at death of the npc1 2/2 mouse can be significantly influenced by many factors, including differences in strain background, other inactivating gene mutations (Siat9 and lxrb), and administration of agents such as LXR agonists and, particularly, cyclodextrin. It is currently not clear which of these effects is nonspecific or which might relate directly to the molecular defect present in the NPC1 syndrome.-

While unesterified cholesterol (C) is essential for remodeling neuronal plasma membranes, its role in certain neurodegenerative disorders remains poorly defined. Uptake of sterol from pericellular fluid requires processing that involves two lysosomal proteins, lysosomal acid lipase (LAL) that hydrolyzes C esters and NPC1. In systemic tissues, inactivation of either protein led to sterol accumulation and cell death, but in the brain, inactivation of only NPC1 caused C sequestration and neurodegeneration. When injected into the CNS of the npc1-/- mouse, HP-β-CD, a compound known to prevent this C accumulation, diffused throughout the brain and was excreted with a T½ of 6.5 h. This agent caused suppression of C synthesis, elevation of C esters, suppression of SREBP2 target genes, and activation of LXR controlled genes. These findings indicated that HP-β-CD promoted movement of the sequestered C from lysosomes to the metabolically active pool of C in the cytosolic compartment of cells in the CNS. The ED50 for this agent in the brain was ∼0.5 mg/kg, and the therapeutic effect lasted more than 7 days. Continuous infusion of HP-β-CD into the ventricular system of npc1-/- animals between 3 and 7 weeks of age normalized the biochemical abnormalities and completely prevented the expected neurodegeneration. These studies support the concept that neurons continuously acquire C from interstitial fluid to permit plasma membrane turnover and remodeling. Inactivation of NPC1 leads to lysosomal C sequestration and neurodegeneration, but this is prevented by the continuous, direct administration of HP-β-CD into the CNS.

Niemann-Pick type C1 (NPC1) disease arises from a mutation inactivating NPC1 protein that normally moves unesterified cholesterol from the late endosomal/lysosomal complex of cells to the cytosolic compartment for processing. As a result, cholesterol accumulates in every tissue of the body causing liver, lung, and CNS disease. Treatment of the murine model of this disease, the npc1 Ϫ/Ϫ mouse, s.c. with ␤-cyclodextrin (4000 mg/kg) one time each week normalized cellular cholesterol metabolism in the liver and most other organs. At the same time, the hepatic dysfunction seen in the untreated npc1 Ϫ/Ϫ mouse was prevented. The severity of cerebellar neurodegeneration also was ameliorated, although not entirely prevented, and the median lifespan of the animals was doubled. However, in contrast to these other organs, lung showed progressive macrophage infiltration with development of lipoid pneumonitis. These studies demonstrated that weekly cyclodextrin administration overcomes the lysosomal transport defect associated with the NPC1 mutation, nearly normalizes hepatic and whole animal cholesterol pools, and prevents the development of liver disease. Furthermore, this treatment slows cerebellar neurodegeneration but has little or no effect on the development of progressive pulmonary disease. (Pediatr Res 68: 309-315, 2010)

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the fastest rising causes of cancer-related deaths in the United States, with disparities observed in cancer incidence and survival between ethnic groups. This report provides updated analyses on race-specific disparities in US HCC trends. METHODS: This large, population-based cohort study was conducted using Surveillance, Epidemiology, and End Results cancer registry data from 2003 to 2011 to investigate race-specific disparities in HCC incidence and survival. Survival was analyzed using Kaplan-Meier methods and multivariate Cox proportional-hazards models. RESULTS: From 2003 to 2011, Asians had the highest HCC incidence, followed by blacks, Hispanics, and non-Hispanic whites. During the same period, Hispanics had the greatest increase in HCC incidence (135.8%), whereas Asians experienced a 5.5% decrease. Although patients aged 65 years had the highest HCC incidence among all racial/ethnic groups, the higher HCC incidence in Asians was observed only for patients ages <50 and 65 years, whereas HCC incidence among patients ages 50 to 64 years was similar among Asians, blacks, and Hispanics. The overall 5-year HCC survival rate was highest among Asians (26.1%; 95% confidence interval [CI], 24.5%-27.6%) and lowest among blacks (21.3%; 95% CI, 19.5%-23.1%). On multivariate regression, Asians (hazard ratio, 0.83; 95% CI, 0.79-0.87; P < .001) and blacks (hazard ratio, 0.94; 95% CI, 0.89-0.99; P 5 .01) had significantly higher survival compared with non-Hispanic whites. CONCLUSIONS: Asians were the only group to demonstrate a declining HCC incidence in the form of a shift from advanced HCC to more localized HCC. These findings most likely reflect improved screening and surveillance efforts for this group. Cancer 2016;122:2512-23. V C 2016 American Cancer Society.KEYWORDS: incidence, liver cancer, racial differences, screening, Surveillance, Epidemiology, and End Results (SEER). INTRODUCTIONHepatocellular carcinoma (HCC) is a leading cause of cancer-related morbidity and mortality worldwide. [1][2][3] In the United States, the incidence of HCC has more than quadrupled, becoming the fastest rising cause of cancer-related deaths. 4,5 Although Asians have the highest overall HCC incidence, when stratified by race/ethnicity, the largest proportional increase in HCC incidence has been observed among Hispanics and blacks. 6,7 These observed differences in HCC trends may reflect race/ethnicity-specific differences in the underlying etiology of HCC, including chronic hepatitis C virus (HCV), chronic hepatitis B virus (HBV), nonalcoholic steatohepatitis, and alcoholic liver disease. 8 For example, the predominant etiology of HCC among Asians is HBV, and improved treatment of HBV over time may contribute to decreased incidence of HCC. In addition, race/ethnicity-specific differences in disease progression and HCC risk may occur even when the underlying liver disease etiology is the same. Disparities in disease progression and HCC risk may warrant more aggressive disease managem...