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Biomedical subjects

G Franceschini

Publications and source records attributed to G Franceschini.

At least 109 records · Page 6Linked to original sources
PubMed1985

Apolipoprotein AIMilano. Accelerated binding and dissociation from lipids of a human apolipoprotein variant.

The lipid binding properties of apolipoprotein (apo) AIMilano, a molecular variant of human apolipoprotein AI, characterized by the Arg173----Cys substitution, was investigated by the use of dimyristoylphosphatidylcholine liposomes. Both the variant AIMilano and normal AI are incorporated to the same extent in stable complexes isolated by gel filtration, showing similar dimensions and stoichiometries. A higher affinity of apo-AIMilano for dimyristoylphosphatidylcholine is suggested by the faster association rate of the variant apoprotein compared to normal AI; similarly, apo-AIMilano is more readily displaced by guanidine hydrochloride from the isolated dimyristoylphosphatidylcholine-apoprotein complexes. When the secondary structure of apo-AIMilano was investigated by spectrofluoroscopy and circular dichroism, a higher fluorescence peak wavelength and a lower alpha-helical content were detected in the variant apoprotein compared to normal AI. The substitution Arg173----Cys in the AIMilano dramatically alters the amphipathic nature of the modified alpha-helical fragment of apoprotein AI. The association rate with lipids is accelerated by an increased exposure of hydrophobic residues. The reduced stability of the lipid-apoprotein particles is possibly mediated by a reduction in the number of helical segments involved in lipid association. The high flexibility of the AIMilano apolipoprotein in the interaction with lipids may explain its accelerated catabolism and the possibly improved uptake capacities for tissue lipids.

Amino Acid Sequence↗
PubMed1985

Familial disorders of plasma apolipoproteins.

Numerous molecular variants of the protein moiety of human circulating lipoproteins ("apolipoproteins" or "apoproteins") have been described in recent years. Molecular alterations of apolipoproteins may lead to an impaired lipid binding and/or to an accelerated or delayed lipoprotein catabolism. Many variants, particularly those of the E apoprotein system, are associated with premature atherosclerosis. In the case of the Apo AI variants, the concomitant deficiency of Apo AI and Apo CIII leads to severe clinical atherosclerosis. Conversely, molecular variants of Apo AI (several of which come from FRG, i.e. AI-Marburg, -Giessen, -Münster) do not go together with significant clinical abnormalities. The case is different for Tangier disease, characterized by the complete absence of high density lipoproteins, where a dramatic tissue lipid deposition may occur. One molecular variant, Apo AI-Milano, while leading to a significant reduction of HDL, does not seem to be associated with clinical atherosclerosis, but rather with a protection from the disease. The presence of major apolipoprotein abnormalities in familial groups of variable size, provides a molecular explanation for some significant alterations of lipid metabolism. Moreover, it offers, to clinical and basic studies, a useful model for the understanding of the function and metabolism of human apolipoproteins.

Apolipoprotein A-I↗
PubMed1985

Relationship of the phenotypic expression of the A-IMilano apoprotein with plasma lipid and lipoprotein patterns.

The plasma lipoprotein and apolipoprotein profile of 29 adult A-IMilano (A-IM) carriers and 29 age- and sex-matched non-affected subjects of the same kindred was examined, in order to investigate linkages between the lipid and apoprotein abnormalities and the phenotypic expression of the biochemical disorder. Carriers (A-IM+) showed a higher prevalence of hypertriglyceridemia (12 out of 29); they also had lower plasma total cholesterol, esterified cholesterol and phospholipids, compared to non-carriers. Lipoproteins were characterized by a significant enrichment of triglycerides in low and high density fractions (LDL and HDL), and by the expected striking reduction of HDL mass and cholesterolemia. Conversely, no significant alterations of the major circulating apolipoprotein levels, except for apo A-I and apo A-II, were noted in the A-IM+. The increased free cholesterol/esterified cholesterol ratio in plasma (most marked in HDL), was accompanied by a significant reduction of the lecithin cholesterol acyl transferase molar activity. Several correlations pertaining to lipids, lipoproteins and apoproteins were examined: cholesterol and triglycerides in HDL and, more remarkably, apoprotein A-I and C-III levels in plasma were significantly correlated in the A-IM+. While there was no significant prevalence of specific apo E phenotypes, plasma triglycerides and apo C-II levels were highly correlated in the carriers. The A-IM subjects, while in the presence of severe lipoprotein risk factors, may have alternative mechanisms of cholesterol disposal, potentially responsible for the apparently low prevalence of atherosclerosis.

Adolescent↗
PubMed1985

Familial associations of lipids and lipoproteins in a highly consanguineous population: the Limone sul Garda study.

The impact of genetic factors on the levels of plasma lipids and lipoproteins was evaluated in the total population of a small village. Limone sul Garda, separated up to recent years from neighboring communities, shows a high degree of consanguineity: major blood group phenotypes differ from nearby provinces for at least three gene frequencies. The absence of a difference in plasma lipid correlations between parent-pediatric offspring and parent-adult offspring, is consistent with the uniformity of living habits in the Limone community. Correlation coefficients proved highly significant only for plasma total cholesterol (range of r: 0.223 to 0.359). Differently from other reports, correlations for low density and high density cholesterolemias (LDL and HDL-C) were mostly nonsignificant in the parent-offspring comparisons. Similarly, only intersibling correlations for triglycerides (TG) were statistically significant. As indicated in other genetic studies on plasma lipoprotein levels (also in the Limone sul Garda study), TG and HDL-C were negatively correlated, whereas the correlation was positive between TG and LDL-C levels. The examined population does not, therefore, show a metabolic behavior at variance from other investigated groups. This study, offering a unique opportunity for enucleating genetic from environmental factors, suggests that most familial clusterings of lipoprotein concentrations are environmentally determined, whereas total cholesterolemia is controlled by autosomal mechanisms, without significant variations between sexes.

ABO Blood-Group System↗
PubMed1985

Cimetidine increases HDL-cholesterol, particularly in the HDL3 subfraction.

Changes in high-density lipoprotein (HDL) cholesterol levels were monitored in five patients treated with cimetidine for gastrointestinal disturbances. A progressive rise of HDL cholesterolemia, statistically significant after four weeks of treatment and highly so after eight weeks (+ 25.4%) was noted. The composition of HDL2 varied insignificantly, whereas a marked rise of HDL3 cholesterol (+ 23.4%) and protein (+ 13.9%) was observed at the end of eight weeks. Cimetidine seems to act in a similar way as microsomal enzyme inducers, in spite of the described inhibition of specific pathways in drug metabolism; recent evidence shows that cytochrome P-450 turnover is delayed after cimetidine. Whatever the mechanism(s), H2 receptors may play a role in the cholesterol removal from tissues.

Adult↗
PubMed1985

AIMilano apoprotein identification of the complete kindred and evidence of a dominant genetic transmission.

The AIMilano apoprotein variant is associated with a marked reduction of high density lipoprotein (HDL) cholesterol levels and with increased triglyceridemia. In spite of the low HDL-cholesterol (HDL-Ch), carriers do not generally show clinical signs of atherosclerosis. The biochemical disorder is linked to a molecular change in apoprotein AI, that is, an arg----cys substitution in the 173 position, thus allowing the formation of AIMilano-AIMilano dimers and AIMilano-AII complexes. The origin of the variant gene has been located in Limone sul Garda, a small community in Northern Italy (about 1,000 individuals). This community has a genetic, biochemical, and clinical individuality, consequent to its isolation up to a few years ago; the citizens show highly uniform alimentary habits and elevated consanguinity. The complete population of the small village was sampled, and, by the use of an analytical isoelectric focusing technique for the detection of the mutant, a total of 33 living carriers, ranging in age from 2 to 81 yrs, were identified. Analysis of the genealogic tree of the complete family groups showed that the apoprotein (apo) AIMilano is transmitted as an autosomal dominant trait, all carriers coming from a single mating couple, living in the eighteenth century. The carriers are heterozygous for the apoprotein variant.

Adolescent↗
PubMed1985

Reversible increase of the apo CII/apo CIII-1 ratio in the very low density lipoproteins after procetofen treatment in hypertriglyceridemic patients.

Procetofen, a new hypolipidemic drug with a powerful cholesterol and triglyceride lowering activity, was administered to hypertriglyceridemic patients, in an effort to determine the major lipoprotein and apoprotein changes, thus providing an insight of the drug's mechanism of action. The twenty-six selected patients (13 type IIB and 13 type IV) were given 100 mg tid of the compound for 9 weeks. Procetofen lowered triglycerides in plasma (-50%) and in all lipoprotein classes (-30-50%) in both patient groups; an 18% reduction of low density lipoprotein cholesterol levels also occurred in type IIB patients. High density lipoprotein cholesterol generally increased significantly, with a maximum of 11% in type IV patients. Plasma apolipoproteins showed a pattern of changes, characteristic of each hyperlipoproteinemia phenotype, reversible after the end of drug treatment. Apoprotein B decreased 16% in type IIB patients, but was not modified in type IV. Conversely, apoprotein CII increased significantly in the very low density lipoproteins of both groups of treated subjects, with a reduction of CIII-1. These findings support the hypothesis that procetofen may act primarily as a stimulator of the catabolism of triglyceride rich lipoproteins. On the other hand, the significant reduction of total and low density lipoprotein cholesterol levels in type IIB, also indicates that other mechanisms, possibly related to changes in the direct liver secretion of apoprotein B or to remnant removal, may be operative with this new drug.

Adult↗
PubMed1985

Effects of storage on the distribution of high density lipoprotein subfractions in human sera.

The current growing interest in the separation of the high density lipoprotein (HDL) subfractions suggested a comparative analysis of the HDL2 and HDL3 distribution in fresh and stored serum samples. Human sera were processed by rate zonal ultracentrifugation in a swinging bucket rotor, immediately after collection and after a 7-day storage at 4 degrees C, both in the presence and in the absence of 5.1 M sodium bromide. Samples stored in absence of salt show a marked decrease of the HDL3 mass, a reduction of its flotation rate, and significant changes in the lipid composition. The HDL2 concentration and composition are not altered by storage. The reported findings indicate that significant HDL3 modifications may occur in serum samples stored at 4 degrees C; these changes can be prevented by the addition of high concentrations of salt before storage.

Adult↗
PubMed1984

Pantethine reduces plasma cholesterol and the severity of arterial lesions in experimental hypercholesterolemic rabbits.

Pantethine (P), a coenzyme A precursor, was administered to cholesterol-fed rabbits (0.5% cholesterol diet + 1% pantethine) for 90 days. At the end of treatment, plasma total cholesterol levels were reduced 64.7% and the HDL/total cholesterol ratio increased in P-treated animals; a significant rise of the apo A-I/A-II ratio was detected in HDL. VLDL lipid and protein levels were, on the other hand, reduced by P. The cholesterol-ester content of both liver and aortic tissues was not significantly affected by P. Although the total aortic area with evident plaques was reduced only 18.2%, the microscopical examination of sections from the major vessels of P-treated animals, showed a reduction in the severity of lesions, both in the aorta and in the coronary arteries. These findings suggest that P, in addition to significantly lowering plasma cholesterol levels in rabbits on an experimental diet, may modify lipid deposition in major arteries, possibly by affecting lipoprotein composition and/or exerting an arterial protective effect.

Animals↗
PubMed1984

Increased plasma and aortic triglycerides in rabbits after acute administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Administration of a single nonlethal dose (20 micrograms/kg) of 2,3,7,8-tetrachlorodibenzo-p-dioxin to New Zealand male rabbits, both on a standard and on a cholesterol (0.5% in the diet) regimen, resulted in a significant increase of plasma triglyceride levels. Triglycerides were particularly raised in the very low-density lipoprotein fraction; no significant apolipoprotein changes, as assessed by an analytical isoelectrofocusing procedure, could be determined. Concomitant to the increased triglyceridemia, aortic triglycerides were also significantly elevated in 2,3,7,8-tetrachlorodibenzo-p-dioxin-pretreated rabbits, both on the standard and on the cholesterolemic regimen. These findings suggest that 2,3,7,8-tetrachlorodibenzo-p-dioxin, possibly by inhibiting triglyceride breakdown, may induce an atherogenic form of hypertriglyceridemia in a standard experimental model of atherosclerosis.

Animals↗
PubMed1983

[Separation of high density lipoproteins (HDL) using zonal ultracentrifugation in patients with apolipoprotein AI Milano variant].

Investigations of HDL with zonal ultracentrifugation were carried out in three patients with apolipoprotein AIMilano. HDL in patients with AIMilano apolipoprotein are characterized by the practically total absence of HDL2. The HDL3 peak is broader than normal. In spite of the marked reduction or practically total absence of HDL2, which is believed to be a protective factor against atherosclerosis, our patients show no signs of clinical atherosclerosis.

Adult↗
PubMed1982

High density lipoprotein-3 heterogeneity in subjects with the apo-AIMilano variant.

The structure of high density lipoproteins (HDL) isolated from subjects with the AIMilano (AIM) apoprotein variant was studied by the use of the cross-linking reagent dimethylsuberimidate. The HDL2 subfraction is markedly reduced, as compared to control subjects; the HDL3 subfraction, on the other hand, shows a marked heterogeneity, being characterized by at least three particle subpopulations, identified as HDL3-I, HDL3-II, and HDL3-III. The HDL3 fraction purified from the AI Milano subjects eluted as a symmetrical peak from a 6% agarose column, corresponding to a unimodal particle size distribution. The content of the different HDL3 particles, detected by cross-linking, varied widely along the elution profile, the tail of the peak being enriched in anomalous particles of very small size (HDL3-III). Apoprotein compositional studies indicated that these small HDL3-III may be enriched in the AIM monomer, the larger particles containing more AIM-AII complexes and AIM dimers. All the anomalous HDL3 particles are triglyceride enriched, with a decreased cholesterol ester content. They may be an intermediate product in the cholesterol transfer chain between HDL and very low density lipoproteins, or be generated during interconversion of HDL. These particles may have a functional role in tissue cholesterol homeostasis; their unusual compositional changes may help explain the protection of the studied subjects from tissue cholesterol deposition, in spite of the marked decrease of the total HDL fraction.

Amino Acids↗
PubMed1982

Plasma lipid and lipoprotein changes in hypertensive patients treated with propranolol and prazosin.

The effects of propranolol and prazosin on plasma lipoproteins in patients with essential hypertension were evaluated according to a crossover protocol of two 8-week periods with a washout of 4 to 6 weeks. Eleven patients with moderate hypertension (greater than 90 but less than or equal to 144 mm Hg, diastolic) and slightly overweight (+10% to +/- +30%, according to Metropolitan Life Insurance tables) were selected. No dietary changes were prescribed. Plasma cholesterol, triglycerides (TG), and lipoprotein changes were monitored at the beginning of each sequence and at 2-, 4- and 8-week intervals. Prazosin, when given first, did not essentially modify any of the metabolic parameters, except for a slight elevation in plasma apoprotein AI levels, i.e., the main protein component of high density lipoprotein (HDL); propranolol caused a significant rise in total TG and very low density lipoprotein TG (VLDL-TG) levels (+37.3% and +23.9%, respectively). Somewhat lower total TG (+19.6%) and vLDL (17.8%) TG elevations were noted when propranolol was given first; plasma glucose was also significantly raised (+12.8%). Triglyceride and glucose levels returned to normal upon changing to prazosin. Total plasma- and lipoprotein-associated cholesterol levels were essentially unchanged with either drug; similarly, no significant changes were detected in total plasma apoprotein B (the main protein component of LDL and also VLDL), a component of apoprotein AI levels. Uric acid levels were slightly raised on propranolol. There was an 8.8% reduction in uric acid levels when the medication changed from propranolol to prazosin.

Apoproteins↗