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J M Hoeg

Publications and source records attributed to J M Hoeg.

At least 73 records · Page 4Linked to original sources
PubMed1988

Tissue-specific expression of apolipoprotein A-I (ApoA-I) is regulated by the 5'-flanking region of the human ApoA-I gene.

We have isolated and characterized a 2.5-kilobase pairs genomic DNA fragment which includes the 5'-flanking region and the first and second exons of the human apolipoprotein (apo) A-I gene. The major transcriptional start site was determined by primer extension analysis and is 235 base pairs (bp) upstream from the AUG translational start codon in liver and 234 bp upstream in the intestine. TATA box-like and CAT box-like sequences and two GC box sequences are present in the intestine 30, 108, 220, and 440 bp upstream, respectively, from the transcriptional start site. Fragments of 570 bp (-487 to +71) and 2.15 kilobase pairs (-2067 to +99) containing the 5'-flanking region of the apoA-I gene were fused upstream to the bacterial chloramphenicol acetyltransferase (CAT) gene. These constructs, designated pA-I(0.6)CAT and pA-I(2.2)CAT, respectively, were introduced into human oral epithelial cells (KB), mouse NIH 3T3 cells, Chinese hamster ovary (CHO) cells, human hepatoma cells (Hep G2), human duodenal epithelial cells (Hutu 80), and human colonic epithelial cells (Caco-2) by calcium phosphate coprecipitation. When compared with control vectors, highly efficient CAT expression of both the pA-I(0.6)CAT and pA-I(2.2)CAT constructs were observed only in cells derived from the liver (Hep G2) and intestine (Caco-2), which is consistent with the tissue specificity of expression of the native gene. Analysis of deletion mutants of the human apoA-I 5'-flanking region revealed that: 1) the region from -250 to -199 bp, from -487 to -413 bp, and -1021 to -691 bp upstream from the transcriptional start site contain sequences required for maximum gene expression; and 2) the regions from -2067 to -1476 bp and -199 to -80 bp contain the sequences required for tissue-specific repression of apoA-I gene expression in non-apoA-I producing cells.

Animals↗
PubMed1988

Abnormal growth hormone secretory dynamics in children with familial hypercholesterolemia.

Growth hormone secretory dynamics and plasma somatomedin C concentrations were assessed in four prepubertal patients with defects in the low-density lipoprotein (LDL) receptor pathway before and after 2 months of treatment with mevinolin, an HMG-CoA reductase inhibitor that reduces intracellular cholesterol. Pre- and posttreatment mean 24-hour growth hormone levels and pulse amplitude were similar and tended to be higher than in age-matched prepubertal controls. Pre- and posttreatment somatomedin C levels were also similar and lower than in age-matched prepubertal controls. All patients responded to growth hormone provocative testing with a peak response of greater than 7 ng/ml, independent of treatment status. Growth velocity was not significantly altered in any patient following 2 months of treatment with mevinolin, and was within the normal range for age. Thus, children with defects in the LDL receptor pathway express abnormalities in growth hormone secretion and somatomedin C generation comparable to those seen in other chronic diseases. Treatment with mevinolin has no apparent effect on these biochemical abnormalities, suggesting that it may not have long-term effects on growth. Regardless of mevinolin therapy, children with defects in the LDL receptor pathway may manifest a degree of growth retardation and, hence, growth rate and skeletal maturation should be closely monitored.

Child↗
PubMed1988

Oral carnitine therapy in children with cystinosis and renal Fanconi syndrome.

11 children with either cystinosis or Lowe's syndrome had a reduced content of plasma and muscle carnitine due to renal Fanconi syndrome. After treatment with oral L-carnitine, 100 mg/kg per d divided every 6 h, plasma carnitine concentrations became normal in all subjects within 2 d. Initial plasma free fatty acid concentrations, inversely related to free carnitine concentrations, were reduced after 7-20 mo of carnitine therapy. Muscle lipid accumulation, which varied directly with duration of carnitine deficiency (r = 0.73), improved significantly in three of seven rebiopsied patients after carnitine therapy. One Lowe's syndrome patient achieved a normal muscle carnitine level after therapy. Muscle carnitine levels remained low in all cystinosis patients, even though cystinotic muscle cells in culture took up L-[3H]carnitine normally. The half-life of plasma carnitine for cystinotic children given a single oral dose approximated 6.3 h; 14% of ingested L-carnitine was excreted within 24 h. Studies in a uremic patient with cystinosis showed that her plasma carnitine was in equilibrium with some larger compartment and may have been maintained by release of carnitine from the muscle during dialysis. Because oral L-carnitine corrects plasma carnitine deficiency, lowers plasma free fatty acid concentrations, and reverses muscle lipid accumulation in some patients, its use as therapy in renal Fanconi syndrome should be considered. However, its efficacy in restoring muscle carnitine to normal, and the optimal dosage regimen, have yet to be determined.

Administration, Oral↗
PubMed1988

Apolipoprotein B synthesized by Hep G2 cells undergoes fatty acid acylation.

Apolipoprotein B is the principal protein associated with cholesterol transport in the blood and has been proposed to play a central role in human atherogenesis. The unique hydrophobic nature of this large (512 kDa), glycosylated apolipoprotein differs from that of the other apolipoproteins. Since another apolipoprotein, apolipoprotein A-I, has been recently shown to have covalently bound fatty acids, potential fatty acid acylation of apolipoprotein B was investigated. The human hepatoma cell line, Hep G2, synthesizes apoB-100 and secretes the apolipoprotein into the culture medium. After a 24-hr incubation with [14C]palmitate and [14C]stearate, the label was incorporated into apoB-100 when assessed by a sodium dodecyl sulfate polyacrylamide gel electrophoresis, autoradiography, immunoblot analysis, and immunoprecipitation. Hydroxylamine treatment, which hydrolyzes ester and thioester bonds, removed the radiolabel. ApoB-100 isolated from Hep G2 cells by ultracentrifugation and preparative sodium dodecyl sulfate gel electrophoresis was hydrolyzed and analyzed by gas-liquid chromatography-mass spectrometry. In contrast to circulating apoB in low density lipoproteins, both palmitate and stearate were present in newly synthesized apoB-100. These results establish that newly synthesized apoB-100 undergoes covalent acylation with palmitate and stearate. The acylation of apoB may play an important role in lipoprotein particle secretion. In addition, derangements in apoB fatty acid acylation may lead to dyslipoproteinemia.

Acylation↗
PubMed1987

3-Hydroxy-3-methylglutaryl--coenzyme A reductase inhibitors in the treatment of hypercholesterolemia.

A new class of drugs, which inhibit de novo cholesterol biosynthesis, significantly reduces the blood cholesterol concentrations in hypercholesterolemic patients. Four separate inhibitors have lowered plasma total cholesterol and low-density lipoprotein (LDL) levels in humans by 20% to 40%: mevastatin (Compactin), lovastatin (mevinolin), pravastatin (CS-514, Eptastatin, and SQ 31000), and simvastatin (Synvinolin, MK-733). In addition to lowering total and LDL cholesterol concentrations, the plasma concentration of the potentially atherogenic B apolipoprotein is also reduced by 20% to 40%. The reduction in the levels of circulating atherogenic lipoprotein particles occurs as a result of decreased synthesis and enhanced removal of LDLs by the LDL receptor pathway in hepatocytes. Moreover, the levels of high-density lipoprotein cholesterol, which are inversely related to atherosclerosis, increase in concentration with treatment by these drugs. If the short-term safety of these drugs extends to ongoing long-term studies and if cardiovascular morbidity and mortality are affected by their use, this class of hypolipidemic agent will markedly facilitate the effective treatment of hypercholesterolemia.

Adult↗
PubMed1987

Comparison of six pharmacologic regimens for hypercholesterolemia.

Six sequential clinical trials were conducted over 5 years to evaluate the safety and efficacy of different treatment regimens for hypercholesterolemia. Of all the study participants, 11 patients were evaluated in all 6 clinical trials using the following regimens: neomycin, neomycin/niacin, cholestyramine, cholestyramine/neomycin, lovastatin and lovastatin/neomycin. All 6 regimens significantly (p less than 0.05) reduced both total and low-density lipoprotein cholesterol concentrations by 25 to 42% from baseline levels. Only neomycin/niacin, cholestyramine and lovastatin significantly increased the high-density lipoprotein (HDL) cholesterol concentration, reducing the total cholesterol/high-density lipoprotein cholesterol ratio to less than 4.7. Thus, all 6 tested regimens were effective in modifying the plasma lipoprotein concentrations in type II hyperlipoproteinemia, but neomycin/niacin, cholestyramine and lovastatin had the most favorable impact. Only lovastatin treatment was free of adverse effects.

Adult↗
PubMed1987

Definition and management of hyperlipoproteinemia.

The results of recent large, prospective clinical trials have established that the reduction of plasma total and low density lipoprotein cholesterol concentrations in certain hyperlipidemic patients reduced their risk for developing symptomatic cardiovascular disease. Attention has now been turned to both defining which individuals should be treated and how best to treat those patients. Utilizing the concepts of human lipid, lipoprotein, and apolipoprotein metabolism that have evolved over the past 20 years, the metabolism of the plasma lipoproteins can be effectively modulated in the majority of hyperlipoproteinemic patients. In addition to summarizing human lipoprotein metabolism, this article outlines a step-by-step approach to the treatment of hyperlipoproteinemia.

Adolescent↗
PubMed1987

The effect of mevinolin on steroidogenesis in patients with defects in the low density lipoprotein receptor pathway.

Adrenal steroidogenesis is dependent upon cholesterol derived from both de novo biosynthesis and uptake of plasma lipoproteins through the low density lipoprotein (LDL) receptor pathway. Recent studies have demonstrated that patients homozygous for familial hypercholesterolemia have a mild impairment in cortisol secretion during maximal ACTH stimulation. Mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, has been used clinically to inhibit de novo cholesterol synthesis in patients with familial hypercholesterolemia. In this study we examined hypothalamic-pituitary-adrenal function in seven patients with defects in the LDL receptor pathway, both before and during treatment with oral mevinolin (20 mg, twice a day), to assess whether inhibition of cholesterol synthesis influences steroidogenesis under basal conditions and in response to ovine CRH and exogenous ACTH. Two months after initiation of therapy, high density lipoprotein cholesterol levels were significantly elevated, and LDL cholesterol levels were reduced, although not normalized. Basal and ovine CRH-stimulated adrenocortical function were normal in all patients both before and during therapy. Plateau plasma cortisol concentrations achieved during maximal ACTH stimulation were lower than those in control subjects in all patients both before and during therapy. All patients, however, had an approximately 3-fold increase over basal values. These results suggest that treatment of patients with defects in the LDL receptor pathway with mevinolin improves the plasma lipid profile and does not result in adrenal dysfunction or further exacerbation of the mild impairment of adrenal function during maximal ACTH stimulation.

Adrenal Cortex↗
PubMed1987

Testicular function in type II hyperlipoproteinemic patients treated with lovastatin (mevinolin) or neomycin.

Steroid synthesis requires cholesterol derived from de novo synthesis or plasma lipoproteins. Low density lipoproteins appear to be the major contributor of cholesterol for steroid synthesis in man. Patients with disorders of low density lipoproteins or the low density lipoprotein receptor have reduced cortisol production in response to ACTH. Therapeutic agents designed to lower plasma cholesterol could, therefore, adversely affect steroid hormone production. Lovastatin (mevinolin) is a new hypolipidemic agent which blocks cholesterol synthesis by competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. In beagle dogs, lovastatin at 40-180 times the clinically effective dose in man, has been associated with an increase in spontaneous testicular atrophy. Accordingly, the effect of lovastatin on testicular function and lipoprotein levels was studied in 16 hyperlipidemic men in a randomized, double blind, cross-over study with another hypolipidemic agent, neomycin. Serum testosterone, PRL, LH, and FSH; LHRH-stimulated LH and FSH concentrations; and testicular size were measured, and semen analyses were made. We found no evidence that lovastatin had adverse effects on testicular function despite significant alterations in plasma lipoprotein concentrations.

Adult↗
PubMed1986

The method of determination must be considered in interpreting blood cholesterol levels.

Based on the results of recent clinical trials, physicians have been encouraged to screen and treat patients for hypercholesterolemia. Since the data from the Lipid Research Clinics (LRC) have been used to define the patient population that should be treated, a comparison of LRC cholesterol results with those obtained with two commonly used clinical laboratory instruments was performed. Both the Technicon SMAC and the Du Pont aca had positive bias compared with the LRC method. Therefore, many patients with cholesterol concentrations greater than 265 mg/dL (6.85 mmol/L) as determined by these routinely used methods have markedly lower levels determined by LRC methods. These findings not only indicate that rigorous interlaboratory standardization is required to conform to LRC reference values, but they also suggest that the clinician should be aware of these methodological considerations when the decision to treat hypercholesterolemia is made.

Autoanalysis↗
PubMed1986

Human preproapolipoprotein C-II. Analysis of major plasma isoforms.

Apolipoprotein C-II plays a major role in lipid metabolism as a cofactor for lipoprotein lipase, the enzyme involved in the hydrolysis of triglyceride-rich lipoproteins. Apo-C-II is initially synthesized as a 101 amino acid protein that undergoes subsequent cotranslational cleavage of a signal peptide. Post-translational processing of apo-C-II has not been previously described. In this manuscript we identify four major plasma isoforms of apo-C-II by two-dimensional gel electrophoresis and immunoblot analysis that result from post-translational modification of apo-C-II. Neuraminidase studies have shown that two of these isoforms are early secreted sialic acid containing glycoproteins. Amino acid compositional and amino-terminal analysis have established that the major plasma isoform of apo-C-II is proapo-C-II. Proapo-C-II undergoes proteolytic cleavage of its amino-terminal hexapeptide to generate the mature form of apo-C-II. Thus, apo-C-II appears to be secreted as a carbohydrate containing proprotein that then undergoes deglycosylation and proteolytic cleavage to generate mature apo-C-II, a minor isoform in plasma. An improved understanding of the structural relationship of the various plasma isoforms of apo-C-II will help to elucidate the mechanisms involved in normal, as well as defective, processing of apo-C-II.

Amino Acids↗
PubMed1986

Metabolism of low-density lipoproteins by cultured hepatocytes from normal and homozygous familial hypercholesterolemic subjects.

The profoundly elevated concentrations of low-density lipoproteins (LDL) present in homozygous familial hypercholesterolemia lead to symptomatic cardiovascular disease and death by early adulthood. Studies conducted in nonhepatic tissues demonstrated defective cellular recognition and metabolism of LDL in these patients. Since mammalian liver removes at least half of the LDL in the circulation, the metabolism of LDL by cultured hepatocytes isolated from familial hypercholesterolemic homozygotes was compared to hepatocytes from normal individuals. Fibroblast studies demonstrated that the familial hypercholesterolemic subjects studied were LDL receptor-negative (less than 1% normal receptor activity) and LDL receptor-defective (18% normal receptor activity). Cholesterol-depleted hepatocytes from normal subjects bound and internalized 125I-labeled LDL (Bmax = 2.2 micrograms LDL/mg cell protein). Preincubation of normal hepatocytes with 200 micrograms/ml LDL reduced binding and internalization by approx. 40%. In contrast, 125I-labeled LDL binding and internalization by receptor-negative familial hypercholesterolemic hepatocytes was unaffected by cholesterol loading and considerably lower than normal. This residual LDL uptake could not be ascribed to fluid phase endocytosis as determined by [14C]sucrose uptake. The residual LDL binding by familial hypercholesterolemia hepatocytes led to a small increase in hepatocyte cholesterol content which was relatively ineffective in reducing hepatocyte 3-hydroxy-3-methylglutaryl-CoA reductase activity. Receptor-defective familial hypercholesterolemia hepatocytes retained some degree of regulatable 125I-labeled LDL uptake, but LDL uptake did not lead to normal hepatocyte cholesterol content or 3-hydroxy-3-methylglutaryl-CoA reductase activity. These combined results indicate that the LDL receptor abnormality present in familial hypercholesterolemia fibroblasts reflects deranged hepatocyte LDL recognition and metabolism. In addition, a low-affinity, nonsaturable uptake process for LDL is present in human liver which does not efficiently modulate hepatocyte cholesterol content or synthesis.

Albumins↗