Effects of agalsidase-ß administration on vascular function and blood pressure in familial Anderson-Fabry disease.

Fabry is an X-linked disorder of glycosphingolipid metabolism that is caused by variants of the GLA gene that codes for α-galactosidase A, leading to lysosomal accumulation of globotriaosylceramide in many cell types. As a result, affected patients manifest with an increased risk of developing ischemic stroke, peripheral neuropathy, cardiac dysfunction, and chronic kidney disease. The protective effects of enzyme replacement therapy (ERT), the milestone in Fabry disease treatment, against globotriaosylceramide (GL-3) accumulation and Fabry disease progression are well known. However, the mechanism of action of ERT is not well understood. Since GL-3 also accumulates in the vascular endothelium, we investigated the effects of agalsidase-ß, a recombinant human α-Gal enzyme approved for the treatment of Fabry disease. In this study, vascular function and blood pressure in four adult siblings affected by Fabry disease were evaluated upon agalsidase-ß. In all patients, agalsidase-ß infusion improves flow-mediated dilation and augmentation index. These changes occurred after the first infusion and were then maintained for the whole period of observation, i.e., 1 year, with more pronounced additional increments in flow-mediated dilation after the second agalsidase-ß infusion. Blood pressure was also maintained at optimal levels in all of the patients for the whole period of observation. Our findings show that agalsidase-ß administration can improve vascular function in patients suffering from Fabry disease. Changes in flow-mediated dilation and augmentation index persisted for the whole period of observation (1 year), thus suggesting that early substitutive therapy should be promoted in order to protect the cardiovascular system.

Understanding Plastid Vesicle Transport - Could it Provide Benefit for Human Medicine?

BACKGROUND: In plants, vesicle transport occurs in the secretory pathway in the cytosol, between the membranes of different compartments. Several protein components have been identified to be involved in the process and their functions were characterized. Both cargos and other molecules (such as hormones) have been shown to use vesicle transport, although the major constituents of vesicles are lipids which are transferred from donor to acceptor membranes. In humans, malfunction of the cytosolic vesicle transport system leads to different diseases. METHOD: To better understand and ultimately cure these human diseases, studying other model systems such as yeast can be beneficial. Plants with their cytosolic vesicle transport system could serve as another model system. However, this review focuses on plant vesicles not present in the cytosol but in the chloroplasts, where lipids produced in the surrounding envelope are transported through the aqueous stroma to the thylakoid membranes. Although chloroplast vesicles have found both biochemical and ultrastructural support, only two proteins have been characterized as components of the pathway. However, using bioinformatics a number of other proteins have been suggested as homologs to the cytosolic system. RESULTS & CONCLUSION: Based on these findings vesicles of chloroplasts are likely most similar to the vesicles trafficking from ER to Golgi, or may even be unique, but important experimental support is yet lacking. In this review, proposed vesicle transport components in chloroplasts are presented, and their possible future implementation for human medicine is discussed.

Vitamin E and oxidative stress in abetalipoproteinemia and familial hypobetalipoproteinemia.

Abetalipoproteinemia (ABL) and familial hypobetalipoproteinemia (FHBL) are genetic diseases characterized by low density lipoprotein deficiency. ABL presents early in life with the gastroenterological manifestations of fat malabsorption, steatorrhea, and failure to thrive, and later in life, with progressive ophthalmopathy and neuropathy as a result of deficiency of the fat-soluble vitamins A and E. Heterozygous FHBL subjects are usually asymptomatic, but may develop fatty liver disease. In homozygous (compound heterozygous) FHBL, the clinical and biochemical features are indistinguishable from those of ABL and treatment recommendations are the same: dietary fat restriction to prevent steatorrhea, and long-term high-dose vitamin E and A supplementation to prevent or at least slow the progression of neuromuscular and retinal degenerative disease. Despite their low plasma vitamin E levels, individuals with heterozygous FHBL do not require vitamin E supplementation. There are conflicting reports on whether increased oxidative stress is seen in ABL; these differences may relate to the small size of patient groups as well as differences in patient age and dose of vitamin E supplementation, or the contribution from dietary sources of vitamin E. High density lipoproteins in ABL appear to be severely oxidized yet able to inhibit platelet aggregation by binding to scavenger receptor B1. We review the role of vitamin E and oxidative stress in ABL and FHBL.

LDL but not HDL increases adiponectin release of primary human adipocytes.

Adipocytes in obesity have inappropriately low cholesterol while adiponectin release is reduced. Cholesterol shortage may contribute to low adiponectin and 3T3-L1 cells treated with lovastatin have diminished adiponectin in cell supernatants. LDL and HDL deliver cholesterol to adipocytes. LDL but not HDL increases adiponectin in cell supernatants of primary human adipocytes. The effect of LDL is not blocked by receptor associated protein suggesting that members of the LDL-receptor family are not involved. To evaluate whether these in vitro observations translate into changes in systemic adiponectin, adiponectin was measured in serum of three patients before, immediately after and 3d after LDL-apheresis. Whereas circulating lipoproteins are reduced immediately after apheresis adiponectin is not changed. Therefore, acute lowering of lipoproteins does not affect systemic adiponectin also excluding that plenty of adiponectin is bound to lipoprotein particles. Accordingly, levels of adiponectin in purified lipoproteins are quite low. Familial hypobetalipoproteinemia (FHBL) is a rare disorder associated with low plasma LDL. Serum adiponectin is, however, similar compared to healthy controls. Thus, neither LDL nor HDL directly contributes to circulating adiponectin concentrations.

A randomized controlled trial to evaluate the effectiveness of CouPLES: a spouse-assisted lifestyle change intervention to improve low-density lipoprotein cholesterol.

OBJECTIVE: This randomized controlled trial evaluated the effectiveness of a telephone-delivered, spouse-assisted lifestyle intervention to reduce patient LDL-C. METHOD: From 2007 to 2010, 255 outpatients with LDL-C>76 mg/dL and their spouses from the Durham Veterans Affairs Medical Center were randomized to intervention or usual care. The intervention comprised nine monthly goal-setting telephone calls to patients and support planning calls to spouses. Outcomes were assessed at 11 months. RESULTS: Patients were 95% male and 65% White. LDL-C did not differ between groups (mean difference = 2.3 mg/dL, 95% CI = -3.6, 8.3, p = 0.44), nor did the odds of meeting goal LDL-C (OR = 0.95, 95% CI = 0.6, 1.7; p = 0.87). Intakes of calories (p = 0.03), total fat (p = 0.02), and saturated fat (p = 0.02) were lower for the intervention group. Cholesterol and fiber intake did not differ between groups (p = 0.11 and 0.26, respectively). The estimated rate of moderate intensity physical activity per week was 20% higher in the intervention group (IRR = 1.2, 95% CI = 1.0, 1.5, p = 0.06). Most participants did not experience a change in cholesterol medication usage during the study period in the intervention (71.7%) and usual care (78.9%) groups. CONCLUSION: This intervention might be an adjunct to usual primary care to improve adherence to lifestyle behaviors.

Hepatitis C virus-associated hypobetalipoproteinemia is correlated with plasma viral load, steatosis, and liver fibrosis.

OBJECTIVES: A relationship between chronic hepatitis C virus (HCV) infection and lipid metabolism has recently been suggested. The aim of this study was to determine the correlation between lipid profile and virology, histologic lesions, and response to alpha interferon therapy in noncirrhotic, nondiabetic patients with hepatitis C. METHODS: A total of 109 consecutive untreated chronic hepatitis C patients were studied to assess the following: 1) the effects of HCV genotype, viral load, steatosis, hepatic fibrosis, and body mass index (BMI) on lipid profile; and 2) whether lipid parameters could predict response to antiviral therapy. RESULTS: The control group showed a significantly higher apolipoprotein B (apoB) concentration compared with patients with chronic hepatitis C. Hypobetalipoproteinemia (apo B <0.7 g/L) was found in 27 (24.7%) chronic HCV patients and in five (5.3%) control subjects (p = 0.0002). Levels of apo B were negatively correlated with steatosis and HCV viral load (r = -0.22; p = 0.03). This last correlation was strong for non-1 genotype and genotype 3 (r = -0.48; p = 0.0005, and r = -0.47; p = 0.007, respectively) but was not found in genotype 1. In multivariate analysis, low apo B concentration was significantly associated with fibrosis grade 2 or 3 versus grade 0 or 1 (p < 0.001), steatosis >5% (p < 0.001), low body mass index (p < 0.001), and high HCV viral load (p < 0.014). No correlation was found in the 76 treated patients between apo B and response to interferon therapy. CONCLUSIONS: In chronic HCV patients, hypobetalipoproteinemia occurs already in the early stages of HCV infection before the development of liver cirrhosis. The correlation between apo B levels and HCV viral load seems to confirm the interaction between hepatitis C infection and beta-lipoprotein metabolism.

Hipocolesterolemia familiar en la infancia / Familiar hypocholesterolemia during childhood

Mientras los estados hiperlipémicos se manifestarán sintomáticamente en la edad adulta, los trastornos que cursan con hipocolesterolemia , pueden dar síntomas desde los primeros años de la vida.Los trastornos hipocolesterolémicos se dividen en: aquellos con valores reducidos de lipoproteínas de alta densidad (HDL), rara vez sintomáticos en la infancia; los hipocolesterolémicos secundarios a un déficit de lipoproteínas, como resultado de una enfermedad subyacente; y los hipocolesterolémicos que cursan con valores bajos de quilomicrones (QM), lipoproteínas de muy baja densidad (VLDL) y lipoproteínas de baja densidad (LDL). Estos últimos son el grupo de mayor interés en pediatría porque en él se engloban una serie de enfermedades hereditarias con manifestaciones ya desde la infancia. Todas ellas son consecuencia de un déficit de la apoproteína B (Apo-B) transportadora en el plasma de dichas lipoproteínas. Se presenta el caso de una familia con 4 hijos; en que el padre y 3 hermanos son portadores de hipobetalipoproteinemia forma heterocigota. La presentación de esta familia permite la revisión de todas las enfermedades hereditarias hipocolesterolémicas (AU)

Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C.

BACKGROUND/AIMS: Steatosis could be the result of HCV (hepatitis C virus)-induced hypobetalipoproteinemia in patients with chronic hepatitis C. The aim of this study was to assess serum levels of main constituents of betalipoproteins and their relationship with steatosis in patients with chronic hepatitis C without known risk factors for steatosis. PATIENTS: One-hundred male patients with untreated biopsy proven non-cirrhotic chronic hepatitis C were included. Twenty-nine of these patients were further treated with interferon. RESULTS: Cholesterol concentration was significantly lower in patients compared to three control groups: reference male population, patients with chronic hepatitis B or with non-alcoholic fatty liver. In multivariate analysis, low apolipoprotein B concentration was an independent factor related with the degree of steatosis. Hypobetalipoproteinemia and degree of steatosis were significantly associated with infection with genotype 3. Among treated patients, only sustained virological responders had a significant increase of cholesterol (5.6 +/- 1 vs. 4.7 +/- 1.3 mmol/l; P = 0.03) and apolipoprotein B concentrations (113 +/- 19 vs. 75 +/- 14 mg/dl; P = 0.05). CONCLUSION: In chronic hepatitis C, hypobetalipoproteinemia is prevalent and associated with steatosis, especially in patients infected with genotype 3. The correction of hypobetalipoproteinemia following HCV eradication suggests that HCV itself could induce hypobetalipoproteinemia and steatosis.

Liver fibrosis in a patient with familial homozygous hypobetalipoproteinaemia: possible role of vitamin supplementation.

A case of apolipoprotein B-related disorder is reported in which liver fibrosis developed without long term administration of medium chain triglycerides, previously incriminated in the pathogenesis of this lesion. The patient was a young woman in whom the diagnosis of familial homozygous hypobetalipoproteinaemia was made at the age of 21. A first liver specimen taken at diagnosis revealed steatosis, hypertrophic Golgi apparatus and proliferating smooth endoplasmic reticulum. The patient was treated with vitamin A and E supplementation only. Two years later, a second liver biopsy, carried out because of increased serum alanine aminotransferase concentrations, showed fibrosis, mild cytolysis and marked mitochondrial alterations. Hepatic level of vitamin A was increased. This finding supports the hypothesis that liver disease observed in our patient might be an adverse effect of vitamin supplementation. Our observation underlines the importance of including liver function tests in the follow up of patients with apolipoprotein B-related disorders.

Metabolic studies on the hypolipidaemic effect of guar gum.

The hypolipidaemic effect of guar gum (30 g/day) was examined in a double blind placebo-controlled crossover study in 9 patients with primary hyperlipidaemia. The treatment periods were of six weeks duration. Cholesterol levels in low density lipoprotein (LDL) were decreased by 11.5% and in intermediate density lipoprotein (IDL) by 10.7%. Plasma cholesterol levels were reduced by 9.6% (P less than 0.05). Kinetic studies using autologous 125I-labelled LDL showed a decrease of 21.6% in plasma LDL apo B pool size (P less than 0.05) that resulted from a 39.1% increase in its fractional rate of catabolism. The kinetic effects of guar gum on LDL metabolism appear similar to that of bile acid binding resins in that LDL apo B fractional catabolism is greatly increased while there is a slight increase in production rate.