The level and species of plasma non-esterified fatty acids are not related to elevated plasma apolipoprotein B levels in familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL), the leading cause of familial hyperlipidemia with premature coronary artery disease, has been associated with insulin resistance and elevated plasma levels of apolipoproten B (apoB) and non-esterified fatty acids (NEFA). Becaus dietary fats affect plasma cholesterol levels, and specific saturated fatty acids (FA) are particularly potent stimulators in vitro of apoB secretio from hepatocytes, we hypothesized that FCHL patients would exhibit elevations in plasma levels of total FA or specific saturated species. Five families containing 12 FCHL subjects (5 adults, 7 children and 8 normals (5 adults, 3 children) were assessed by dietary, anthropometric, and plasma measurements (glucose, insulin, lipoproteins, total NEFA, and specific FA types).

Age-related changes in cardiovascular disease risk factors of hypercholesterolemic children.

Objective: To describe the age-related changes in cardiovascular disease risk factors in young, hypercholesterolemic (HC) children.

Methods: Hypercholesterolemic (n = 227) and nonhypercholesterolemic (NHC) (n = 80) children between the ages of 4 and 10 years were identified. Height, weight, skin-fold and blood pressure measurements, and total cholesterol levels were measured.

One-year follow-up of nutrition education for hypercholesterolemic children.

Objectives: This study evaluated retention of the effect of a home-based, practitioner-initiated nutrition education model.

Methods: Children with elevated low-density lipoprotein (LDL) cholesterol levels were randomly assigned to one of two nutrition interventions or to an at-risk control group. Intervention effects were evaluated 3, 6, and 12 months postbaseline.

Effects of family history of heart disease, apolipoprotein E phenotype, and lipoprotein(a) on the response of children's plasma lipids to change in dietary lipids.

We examined the effects of family history of coronary artery disease (CAD), apolipoprotein E (apo E) phenotype, and lipoprotein(a) [Lp(a)] on the response of plasma lipids to change in dietary lipid intake after 3 mo of nutrition education in 125 children aged 4-10 y. The subjects were healthy children with elevated low-density-lipoprotein (LDL)-cholesterol concentrations who participated in the Children's Health Project, a nutrition-education program designed to lower plasma cholesterol by means of dietary modifications in accordance with recommendations of the National Cholesterol Education Program. Dietary and plasma lipids were measured by three 24-h recalls and assessments of two fasting plasma samples collected before and 3 mo after the start of intervention.

Kinetics of retinyl esters during postprandial lipemia in man: a compartmental model.

Orally ingested vitamin A (retinol) is incorporated into intestinal chylomicrons (CHYLO) in the form of retinyl esters (RE) along with newly absorbed dietary triglycerides (TG). As the intestinal lipoproteins undergo hydrolysis in the circulation, the majority of the RE remain with the secreted intestinal particles and have been used as a marker for intestinally derived lipoproteins during the early phase of the postprandial state. A multicompartmental model was developed for the kinetics of RE during postprandial lipemia in individuals with normal lipid levels (n = 16) and in patients with hyperlipidemia (n = 44).

Met-HGF/SF: tumorigenesis, invasion and metastasis.

Hepatocyte growth factor/scatter factor (HGF/SF) is synthesized by mesenchymal cells and is a paracrine effector of cells, predominantly epithelial, that express the Met tyrosine kinase receptor. We have demonstrated that autocrine Met-HGF/SF expression in mouse fibroblasts results in transformation and tumorigenesis. HGF/SF-treated cells expressing Met can respond in a variety of ways: mitogenically, by scattering (motility), and by forming branching tubules in gel matrices (branching morphogenesis).

The influence of age and relative weight on the presentation of familial combined hyperlipidemia in childhood.

Background: Familial combined hyperlipidemia (FCHL) has been described as the leading cause of familial hyperlipidemia. FCHL is dominantly inherited, occurs in at least 1% of the population, and is responsible for about 10% of premature coronary artery disease (CAD).

Objective: Because FCHL in childhood is not well characterized, we evaluated the interrelationships among age, percentage of ideal body weight (%IBW) and plasma lipoprotein levels in FCHL children (age 2-18 years), exploring the possibility that obesity and age may influence the presentation of FCHL in childhood.

A 5' splice-region mutation and a dinucleotide deletion in the lysosomal acid lipase gene in two patients with cholesteryl ester storage disease.

Cholesteryl ester storage disease (CESD) results from inherited deficiencies of the lysosomal hydrolase, acid lipase (LAL; E.C. 3.

The Met-HGF/SF autocrine signaling mechanism is involved in sarcomagenesis.

Hepatocyte growth factor/scatter factor (HGF/SF) can elicit a wide variety of effects upon cells expressing its receptor, the tyrosine kinase proto-oncogene product Met, including mitogenicity, motility, and morphogenesis. Normally, met expression is restricted to epithelial cells and is activated in a paracrine fashion by HGF/SF secreted from cells of mesenchymal origin. In this chapter, we review data showing that: (i) met over-expression in HGF/SF-expressing NIH/3T3 fibroblasts leads to sarcomagenesis and metastasis via an autocrine mechanism; (ii) Met-HGF/SF autocrine signalling occurs to a low level in normal fibroblasts and to a much greater extent in human sarcomas and sarcoma cell lines; (iii) met expression is enhanced as p53-deficient fibroblasts are passaged in vitro and (iv) met and HGF/SF over-expression are selected for during tumorigenesis of p53-deficient late-passage fibroblasts.

Reduction of elevated LDL-cholesterol levels of 4- to 10-year-old children through home-based dietary education.

Objective: To assess the effects of a home-based, parent-child autotutorial (PCAT) dietary education program on the dietary knowledge, lipid consumption, and plasma low density lipoprotein-cholesterol (LDL-C) of 4- to 10-year-old children with elevated plasma LDL-C.

Methods: "At-risk" children (screening total cholesterol, (TC), exceeded 4.55 mmol/L and average LDL-C from two fasting samples was between 2.

Familial combined hyperlipidemia in children: clinical expression, metabolic defects, and management.

The first evidence that elevation of plasma levels of cholesterol is a risk factor for the development of atherosclerosis in children came from the Bogalusa Heart Study in 1986, which reported an association between aortic fatty streaks in 3- to 26-year-old subjects and increased plasma levels of low-density lipoprotein cholesterol (LDL-C). The most compelling evidence of a cause-and-effect relationship has come from the multicenter cooperative study called the Pathobiological Determinants of Atherosclerosis in Youth. When the investigators examined the abdominal aorta and the right coronary artery of adolescents and young adults who had died of trauma, they found a significant relationship between the sum of the very low density lipoprotein (VLDL) plus LDL-C level and both fatty streaks and raised atherosclerotic lesions.

Familial combined hyperlipidemia in children: clinical expression, metabolic defects, and management.

Familial combined hyperlipidemia (FCHL) is a dominantly inherited hyperlipidemia that occurs in at least 1% of the adult population and is responsible for 10% of premature coronary artery disease. In families referred for evaluation because of primary hyperlipidemia in a child, FCHL is expressed three times more commonly than familial hypercholesterolemia and half of the siblings are affected. Several metabolic defects apparently are associated with the FCHL phenotype.

An inhibitory Raf-1 mutant suppresses expression of a subset of v-raf-activated genes.

The proto-oncogene Raf-1 is a cytoplasmic serine/threonine kinase implicated in the signaling process in cell proliferation. To determine if Raf-1 is sufficient and necessary to transmit mitogenic signals to growth-responsive genes, we examined the effect of constitutively activated (v-raf) or inhibitory (Raf-C4) Raf-1 proteins on reporter gene activation in transient expression assays of NIH 3T3 cells. In serum-starved cells, v-raf strongly activated transcription from the promoters of the immediate-early genes c-fos and egr-2, as well as the proximal or B promoter of the late growth response gene rep-3 (rep-3b).

Use of cholestyramine in the treatment of children with familial combined hyperlipidemia.

We studied the effectiveness of and compliance with the use of cholestyramine in children with heterozygous familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCHL). During a 10-year period, 673 children (aged 10.5 +/- 4.

A quality assurance program for the measurement of capillary blood cholesterol levels in private pediatric practices. The Children's Health Project.

Objective: To develop an easy to use quality assurance program for the measurement of capillary blood cholesterol levels in private pediatric practices. The program needed to comply with the guidelines laid down by the National Cholesterol Education Program.

Design: Intervention study.

The effect of lovastatin on very low-density lipoprotein apolipoprotein B production by the liver in familial combined hyperlipidaemia.

Overproduction of very low-density lipoprotein apolipoprotein B by the liver is a metabolic marker for familial combined hyperlipidaemia, a common inherited disorder of lipoprotein metabolism. Four subjects with familial combined hyperlipidaemia had rates of apolipoprotein B production which were 2-7 times normal, using a protocol in which [15N]glycine was used to label newly synthesized hepatic proteins. Following 4-6 months of therapy with lovastatin, very low-density lipoprotein apolipoprotein B production in all four subjects had returned to the normal range.

Genotype at a major locus with large effects on apolipoprotein B levels predicts familial combined hyperlipidemia.

A sample enriched for familial combined hyperlipidemia (FCHL) was examined for evidence of an association between genotype at an apolipoprotein B (apoB) elevating locus defined by complex segregation analysis and FCHL. Complex segregation analysis detected a locus with a large effect on plasma apoB levels and was used to compute the most probable genotype of family members. None of the 35 normolipidemic adults carried a copy of the allele associated with elevated apoB levels, yet 58% of the 109 adults with FCHL carried 1 (29%) or 2 (28%) copies.

krox 20 messenger RNA and protein expression in the adult central nervous system.

krox 20 is an inducible immediate early response gene. To determine if krox 20 has a physiological role in the adult central nervous system (CNS), this study sought to demonstrate the presence of krox 20 in adult rat brain. RNA analysis showed the presence of krox 20 transcripts in the CNS, including the cortex.

Determinants of fasting plasma triglyceride levels: metabolism of hepatic and intestinal lipoproteins.

The contribution of the kinetics of exogeneous and endogenous lipoproteins in determining the level of triglyceride in fasting plasma was assessed in a group of 19 normolipidaemic and hypertriglyceridaemic subjects. From data derived during a 9-h infusion of [15N]-glycine, we have assessed very low density lipoprotein apolipoprotein B production, and from data analysed by kinetic modelling obtained following ingestion of retinol and triolein, we have assessed chylomicron and chylomicron remnant clearance in a group of 19 normolipidaemic and hypertriglyceridaemic subjects. A strong positive correlation was observed between the fasting plasma triglyceride level and the reciprocal of the apolipoprotein B fractional synthetic rate (r = 0.

Cell cycle analysis of Krox-20, c-fos, and JE expression in proliferating NIH3T3 fibroblasts.

We have shown that early growth response genes which were identified on the basis of their expression during the G0 to G1 transition can also be induced in proliferating fibroblasts. The expression of Krox-20 and c-fos mRNAs increased dramatically upon stimulation of cell populations of increasing density and correlated with the percentage of cells in the G0-G1 stages of the cell cycle. However, fractionation of serum-stimulated cultures into cell cycle stage-specific subpopulations using fluorescence-activated cell sorting revealed that the levels of Krox-20 and c-fos mRNAs were equal in all stages of the cell cycle.

Familial combined hyperlipidaemia: use of stable isotopes to demonstrate overproduction of very low-density lipoprotein apolipoprotein B by the liver.

We have assessed very low-density lipoprotein apolipoprotein B production, using [15N]glycine as an endogenous marker in a 9-hour primed constant infusion protocol, in four adult male subjects with familial combined hyperlipidaemia and in four normolipidaemic adult male controls. The mean very low-density lipoprotein apolipoprotein B absolute synthetic rate was significantly greater in the familial combined hyperlipidaemic subjects than in control subjects (26.31 +/- 8.

Measurement of (C13)arginine incorporation into apolipoprotein B-100 in very low density lipoproteins and low density lipoproteins in normal subjects using (13C)sodium bicarbonate infusion and isotope ratio mass spectrometry.

We describe a new stable isotope technique for the in vivo study of hepatic plasma protein synthesis in humans. The method involves the infusion of (13C)sodium bicarbonate for 1 h and the measurement of the isotopic enrichment of (13C)arginine in newly synthesized apolipoprotein B of very low density lipoproteins (VLDL-apoB) and low density lipoproteins (LDL-apoB) in blood samples taken over a 5-6 h period from the commencement of the infusion. Isotope ratio mass spectrometry was utilized to measure 13CO2 enrichment following hydrolysis of these proteins and conversion of the guanidinium carbon of arginine in the hydrolysate to carbon dioxide by sequential incubation with arginase and urease.

Identification of the serum-responsive transcription initiation site of the zinc finger gene Krox-20.

The Krox-20 gene is rapidly and transiently induced when quiescent 3T3 cells are stimulated to reenter the proliferative cycle. We identified the major serum-responsive transcription initiation site and found that it differs from the initiation sites previously identified for the Krox-20 gene. Transcripts from the major serum-responsive initiation site increased at least 40-fold in serum-stimulated cells compared with logarithmically growing cells.