Marianna Maranghi

Quality of life in ambulatory postmenopausal women: the impact of reduced bone mineral density and subclinical vertebral fractures

Health-related quality of life (HRQOL) in postmenopausal women with osteoporosis has hitherto been mainly assessed in patients with clinically recognized vertebral fractures. Our study aimed to investigate the QOL perception in 361 asymptomatic ambulant postmenopausal women who came to our center for an osteoporosis screening program planned with their general practitioners. The Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO) was administered to all subjects. The participants underwent bone mineral density (BMD) measurements by DXA of either the lumbar spine and/or the femoral neck, as well as X-ray examination of the thoracolumbar spine to identify subclinical vertebral fractures. According to the WHO definition, where subjects are subdivided by BMD values into three groups (women with normal BMD, osteopenia, and osteoporosis), a significant difference was found only for the domains which explore general health perception (p<0.01 by ANOVA) and mental function (p<0.001 by ANOVA). When we segregated both osteopenic and osteoporotic women according to whether or not they had vertebral fractures, a significant difference was found only in osteoporotic patients for domains which explore physical function (p<0.001), social function (p<0.001), general health perception (p<0.02), and total QUALEFFO score (p<0.01). Stepwise multiple logistic regression analysis of the whole sample showed that both vertebral fractures and a low femoral BMD impairs QOL perception, while age did not exert a significant influence. ROC curves analysis demonstrated a low discriminating capacity of individual domains and total QUALEFFO score for both vertebral deformities and BMD categorization. Our results showed that QUALEFFO is not able to discriminate between patients with or without subclinical vertebral fractures. However, some aspects of QOL appear to be impaired in patients with subclinical vertebral fractures or reduced BMD.

Angptl3 Deficiency Is Associated With Increased Insulin Sensitivity, Lipoprotein Lipase Activity, and Decreased Serum Free Fatty Acids

Objective—Angiopoietin-like 3 (Angptl3) is a regulator of lipoprotein metabolism at least by inhibiting lipoprotein lipase activity. Loss-of-function mutations in ANGPTL3 cause familial combined hypolipidemia through an unknown mechanism. Approach and Results—We compared lipolytic activities, lipoprotein composition, and other lipid-related enzyme/lipid transfer proteins in carriers of the S17X loss-of-function mutation in ANGPTL3 and in age- and sex-matched noncarrier controls. Gel filtration analysis revealed a severely disturbed lipoprotein profile and a reduction in size and triglyceride content of very low density lipoprotein in homozygotes as compared with heterozygotes and noncarriers. S17X homozygotes had significantly higher lipoprotein lipase activity and mass in postheparin plasma, whereas heterozygotes showed no difference in these parameters when compared with noncarriers. No changes in hepatic lipase, endothelial lipase, paraoxonase 1, phospholipid transfer protein, and cholesterol ester transfer protein activities were associated with the S17X mutation. Plasma free fatty acid, insulin, glucose, and homeostatic model assessment of insulin resistance were significantly lower in homozygous subjects compared with heterozygotes and noncarriers subjects. Conclusions—These results indicate that, although partial Angptl3 deficiency did not affect the activities of lipolytic enzymes, the complete absence of Angptl3 results in an increased lipoprotein lipase activity and mass and low circulating free fatty acid levels. This latter effect is probably because of decreased mobilization of free fatty acid from fat stores in human adipose tissue and may result in reduced hepatic very low density lipoprotein synthesis and secretion via attenuated hepatic free fatty acid supply. Altogether, Angptl3 may affect insulin sensitivity and play a role in modulating both lipid and glucose metabolism.

High Density Lipoprotein Structural Changes and Drug Response in Lipidomic Profiles following the Long-Term Fenofibrate Therapy in the FIELD Substudy

In a recent FIELD study the fenofibrate therapy surprisingly failed to achieve significant benefit over placebo in the primary endpoint of coronary heart disease events. Increased levels of atherogenic homocysteine were observed in some patients assigned to fenofibrate therapy but the molecular mechanisms behind this are poorly understood. Herein we investigated HDL lipidomic profiles associated with fenofibrate treatment and the drug-induced Hcy levels in the FIELD substudy. We found that fenofibrate leads to complex HDL compositional changes including increased apoA-II, diminishment of lysophosphatidylcholines and increase of sphingomyelins. Ethanolamine plasmalogens were diminished only in a subgroup of fenofibrate-treated patients with elevated homocysteine levels. Finally we performed molecular dynamics simulations to qualitatively reconstitute HDL particles in silico. We found that increased number of apoA-II excludes neutral lipids from HDL surface and apoA-II is more deeply buried in the lipid matrix than apoA-I. In conclusion, a detailed molecular characterization of HDL may provide surrogates for predictors of drug response and thus help identify the patients who might benefit from fenofibrate treatment.

Poor Glycemic Control Is an Independent Risk Factor for Low HDL Cholesterol in Patients With Type 2 Diabetes

OBJECTIVE To determine whether the association observed between poor glycemic control and low HDL cholesterol in type 2 diabetes is dependent on obesity and/or hypertriglyceridemia. RESEARCH DESIGN AND METHODS We performed a cross-sectional study of 1,819 patients with type 2 diabetes and triglycerides <400 mg/dl enrolled at three diabetes centers in Italy. The risk for low HDL cholesterol was analyzed as a function of A1C levels. Odds ratios (ORs) were calculated after adjustment for confounding factors. RESULTS A 1% increase in A1C significantly increased the risk for low HDL cholesterol (OR 1.17 [95% CI 1.1–1.2], P = 0.00072); no changes were observed when age, sex, smoking, and lipid-lowering therapy were included in the model (1.17 [1.1–1.2], P = 0.00044). The association remained strong after adjustments for obesity and hypertriglyceridemia in multivariate analysis (1.12 [1.05–1.18], P = 0.00017). CONCLUSIONS Poor glycemic control appears to be an independent risk factor for low HDL cholesterol in type 2 diabetes.

A novel de novo germ‐line V292M mutation in the extracellular region of RET in a patient with phaeochromocytoma and medullary thyroid carcinoma: functional characterization

Context  In multiple endocrine neoplasia (MEN), rearranged during transfection (RET), gene testing has been extensively exploited to characterize tumour aggressiveness and optimize the diagnostic and clinical management.

Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis

Angiopoietin-like 3 (ANGPTL3) regulates lipoprotein metabolism by modulating extracellular lipases. Loss-of function mutations in ANGPTL3 gene cause familial combined hypolipidemia (FHBL2). The mode of inheritance and hepatic and vascular consequences of FHBL2 have not been fully elucidated. To get further insights on these aspects, we reevaluated the clinical and the biochemical characteristics of all reported cases of FHBL2. One hundred fifteen FHBL2 individuals carrying 13 different mutations in the ANGPTL3 gene (14 homozygotes, 8 compound heterozygotes, and 93 heterozygotes) and 402 controls were considered. Carriers of two mutant alleles had undetectable plasma levels of ANGPTL3 protein, whereas heterozygotes showed a reduction ranging from 34% to 88%, according to genotype. Compared with controls, homozygotes as well as heterozygotes showed a significant reduction of all plasma lipoproteins, while no difference in lipoprotein(a) [Lp(a)] levels was detected between groups. The prevalence of fatty liver was not different in FHBL2 subjects compared with controls. Notably, diabetes mellitus and cardiovascular disease were absent among homozygotes. FHBL2 trait is inherited in a codominant manner, and the lipid-lowering effect of two ANGPTL3 mutant alleles was more than four times larger than that of one mutant allele. No changes in Lp(a) were detected in FHBL2. Furthermore, our analysis confirmed that FHBL2 is not associated with adverse clinical sequelae. The possibility that FHBL2 confers lower risk of diabetes and cardiovascular disease warrants more detailed investigation.

The angiopoietin-like protein 3: A hepatokine with expanding role in metabolism

Purpose of review Cumulating evidence are revealing roles of angiopoietin-like proteins (ANGPTLs) in lipid, glucose, and energy metabolism. In this review, we discuss the recent developments in understanding the specific role in metabolic processes of the liver-derived ANGPTL3. Recent findings Several groups have reported clinical and metabolic characterization of individuals with loss-of-function variants in ANGPTL3 showing familial combined hypolipidemia, a syndrome characterized by marked reduction of all plasma lipoproteins. Their findings indicate that in humans, ANGPTL3 has a broader action on apoB and apoA-I-containing lipoproteins, as well as on free fatty acid and adipose tissue metabolism. Summary The identification of loss-of-function ANGPTL3 mutation is shedding light on a possible role of ANGPTL3 at the crossroads of lipoproteins, fatty acids, and glucose metabolism, thus making ANGPTL3 an attractive protein to target the cardio-metabolic risk.

BRAFV600E mutation and expression of proangiogenic molecular markers in papillary thyroid carcinomas

OBJECTIVE Tyrosine kinase inhibitors (TKIs) are evaluated for treatment of radioiodine refractory thyroid cancer. Their effects in this setting are based on blockade of proangiogenic signaling mediated by receptors for vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGF). Most TKIs also block other cancer-relevant kinases, such as B-type Raf kinase (BRAF), which are constitutively activated in approximately half of papillary thyroid carcinomas (PTCs), but the impact of these effects is not clear. DESIGN The aim of our study was to investigate the impact of BRAF(V600E) on proangiogenic gene expression and microvascular features of PTCs. METHODS mRNA levels for VEGFA, VEGF receptors, and coreceptors (VEGFRs 1, 2, and 3, neuropilin-1), and PDGF receptor β (PDGFRβ or PDGFRB) were measured with real-time PCR in BRAF(V600E) (n=55) and wild-type BRAF (BRAF-wt; n=35) PTCs. VEGF and VEGFR protein expression and microvessel densities (MVD) and lymphatic vessel densities (LVDs) were assessed by immunohistochemistry in 22 of the 90 PTCs (including 11 BRAF(V600E) cases). Angiogenic gene expression was also studied in vitro after induction/silencing of the BRAF(V600E) mutation in thyrocyte lines. RESULTS Transcript levels of proangiogenic factors were significantly lower in BRAF(V600E) PTCs versus BRAF-wt PTCs (P<0.0001), but MVD and LVDs were not significantly different. VEGFA mRNA levels in thyroid cell lines decreased when BRAF(V600E) mutation was induced (P=0.01) and increased when it was silenced (P=0.01). CONCLUSIONS Compared with BRAF-wt PTCs, those harboring BRAF(V600E) exhibit downregulated VEGFA, VEGFR, and PDGFRβ expression, suggesting that the presence of BRAF mutation does not imply a stronger prediction of response to drugs targeting VEGF and PDGFB signaling pathways.

Dietary omega-3 polyunsaturated fatty acid intake is related to a protective high-density lipoprotein subspecies profile independent of genetic effects: A monozygotic twin pair study

BACKGROUND Studies on diet and high-density lipoprotein (HDL) subspecies distribution are limited. OBJECTIVE We examined the relationship between macronutrient composition and lipoprotein particle size and HDL subspecies independent of genetic effects by studying monozygotic (MZ) twins. METHODS 24 healthy MZ twin pairs aged 23-33 years were identified from two longitudinal population-based studies, FinnTwin16 and FinnTwin12. Total energy and nutrient intake were assessed with 3-day food records and physical activity was measured by the Baecke index. HDL subspecies distribution was determined by non-denaturing gradient gel electrophoresis. Associations between diet composition and HDL mean particle size were determined by multivariate nutrient density models adjusted for confounding variables. RESULTS Substituting one energy percentage from omega-3 polyunsaturated fatty acids (n-3 PUFAs) for a corresponding amount of energy from other type of fats was related to changes in the relative proportions of the HDL subspecies 2b, 3a and 3b toward a larger mean particle size in men (β ± SE: 1.00 ± 0.26 nm, p = 0.004) and women (β ± SE: 0.90 ± 0.21 nm, p = 0.001). This association remained significant in analyses controlling for genetic and shared environmental influences using within-pair differences of the measures in MZ twin pairs (β ± SE: 0.37 ± 0.14 nm, p = 0.019). Twins with the higher n-3 PUFA intake had significantly higher proportions of large HDL(2b) particles and lower proportions of smaller-sized HDL(3a) and HDL(3b) particles as compared to their co-twins with lower intakes (p < 0.05). CONCLUSIONS Our data suggest that n-3 PUFA intake is associated with a favorable change in the distribution of HDL subspecies towards larger particles independent of genetic and shared environmental factors.

Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism

The consequences of angiopoietin-like protein 3 (ANGPTL3) deficiency on postprandial lipid and lipoprotein metabolism has not been investigated in humans. We studied 7 homozygous (undetectable circulating ANGPTL3 levels) and 31 heterozygous (50% of circulating ANGPTL3 levels) subjects with familial combined hypolipidemia (FHBL2) due to inactivating ANGPTL3 mutations in comparison with 35 controls. All subjects were evaluated at fasting and during 6 h after a high fat meal. Postprandial lipid and lipoprotein changes were quantified by calculating the areas under the curve (AUCs) using the 6 h concentration data. Plasma changes of β-hydroxybutyric acid (β-HBA) were measured as marker of hepatic oxidation of fatty acids. Compared with controls, homozygotes showed lower incremental AUCs (iAUCs) of total TG (−69%, P < 0.001), TG-rich lipoproteins (−90%, P < 0.001), apoB-48 (−78%, P = 0.032), and larger absolute increase of FFA (128%, P < 00.1). Also, heterozygotes displayed attenuated postprandial lipemia, but the difference was significant only for the iAUC of apoB-48 (−28%; P < 0.05). During the postprandial period, homozygotes, but not heterozygotes, showed a lower increase of β-HBA. Our findings demonstrate that complete ANGPTL3 deficiency associates with highly reduced postprandial lipemia probably due to faster catabolism of intestinally derived lipoproteins, larger expansion of the postprandial FFA pool, and decreased influx of dietary-derived fatty acids into the liver. These results add information on mechanisms underlying hypolipidemia in FHBL2.