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1.
Int J Eat Disord ; 52(4): 462-465, 2019 04.
Article in English | MEDLINE | ID: mdl-30628116

ABSTRACT

Selective eating is a common presenting problem in Avoidant/Restrictive Food Intake Disorder (ARFID). Understanding the etiology of selective eating will lead to the creation of more effective treatments for this problem. Recent reports have linked disgust sensitivity to picky eating, and the field has yet to conceptualize the role that disgust might play in ARFID. Disgust has long been tied to formation of taste aversions and is considered at its core to be a food-related emotion. A brief review of the literature on disgust reveals that disgust has a unique psychophysiological profile compared to other emotions, like anxiety, and that disgust is resistant to extinction procedures. If disgust is implicated in the etiology of selective eating, its presence would have a significant impact on treatment approaches. This article provides an overview of the research on disgust and eating, a clinical example of the treatment challenges that disgust may pose, and an overview of the unique clinical features of disgust as they apply to psychopathology. We pose several research questions related to disgust and selective eating and discuss initial hypotheses for pursing this line of inquiry. Finally, we discuss the possible implications of this line of research for treatment.


Subject(s)
Anxiety/psychology , Disgust , Feeding and Eating Disorders/psychology , Psychopathology/methods , Child , Emotions , Feeding and Eating Disorders/therapy , Humans , Male , Treatment Outcome
2.
Fam Med ; 45(8): 569-71, 2013 Sep.
Article in English | MEDLINE | ID: mdl-24129869

ABSTRACT

BACKGROUND AND OBJECTIVES: Student-produced creative arts journals now exist in several medical schools. The Florida State University College of Medicine (FSUCOM) has created HEAL: Humanism Evolving through Arts and Literature. This study sought to determine what influence, if any, HEAL publications may have on medical students. METHODS: A survey utilizing Likert scale questions was sent to Florida State University medical students. Student responses were tabulated and analyzed using SAS 9.2 and MS Excel. A total of 241 (49.5%) students responded to the survey. RESULTS: About 81% of the respondents enjoyed reading HEAL. Many respondents agreed that HEAL promoted patient-centered care (55.9%) and could prevent burnout (61.8%). Sixty-four percent thought that HEAL helped them to understand their colleagues and classmates. CONCLUSIONS: This survey found that the medical students perceive HEAL as having positive value.


Subject(s)
Education, Medical/methods , Journalism, Medical , Medicine in the Arts , Students, Medical/psychology , Adolescent , Adult , Female , Health Surveys , Humans , Male , Patient-Centered Care , Program Evaluation , Surveys and Questionnaires , Young Adult
3.
J Child Fam Stud ; 22(2): 177-191, 2013 Feb.
Article in English | MEDLINE | ID: mdl-36711028

ABSTRACT

Researchers and practitioners conduct multi-informant assessments of child and family behavior under the assumption that informants have unique perspectives on these behaviors. These unique perspectives stem, in part, from differences among informants in the settings in which they observe behaviors (e.g., home, school, peer interactions). These differences are assumed to contribute to the discrepancies commonly observed in the outcomes of multi-informant assessments. Although assessments often prompt informants to think about setting-specific behaviors when providing reports about child and family behavior, the notion that differences in setting-based behavioral observations contribute to discrepant reports has yet to be experimentally tested. We trained informants to use setting information as the basis for providing behavioral reports, with a focus on parental knowledge of children's whereabouts and activities. Using a within-subjects controlled design, we randomly assigned 16 mothers and adolescents to the order in which they received a program that trains informants to use setting information when providing parental knowledge reports (Setting-Sensitive Assessment), and a control program involving no training on how to provide reports. Relative to the control program, the Setting-Sensitive Assessment training increased the differences between mother and adolescent reports of parental knowledge, suggesting that mothers and adolescents observe parental knowledge behaviors in different settings. This study provides the first experimental evidence to support the assumption that discrepancies arise because informants incorporate unique setting information into their reports.

4.
J Homosex ; 53(4): 201-21, 2007.
Article in English | MEDLINE | ID: mdl-18689198

ABSTRACT

BACKGROUND: Evidence suggests there is bias toward lesbian, gay, bisexual, and transgender (LGBT) persons by social workers; unfortunately, little research has been conducted to examine Master of Social Work (MSW) students' views toward these populations. The purpose of this study was to develop an assessment scale to evaluate the attitudes, phobias, and cultural competence of MSW students toward the LGBT populations. METHODS: An assessment scale was developed and administered to MSW students (n = 173) at a Midwestern American university. RESULTS: The majority of MSW students reported low phobia and a positive attitude toward the LGBT populations, yet participants reported having a low level of cultural competence in serving LGBT clients. CONCLUSION: More education and training is needed for MSW students to effectively serve the LGBT populations.


Subject(s)
Attitude of Health Personnel , Bisexuality , Cultural Competency , Homosexuality, Female , Homosexuality, Male , Phobic Disorders/psychology , Social Work/education , Students/psychology , Adult , Female , Humans , Male , Middle Aged , Phobic Disorders/epidemiology , Psychological Tests
5.
J Lipid Res ; 43(7): 1125-32, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12091497

ABSTRACT

The profile of liver acyl-CoAs induced by dietary fats of variable compositions or by xenobiotic hypolipidemic amphipathic carboxylates was evaluated in vivo using a novel electrospray ionization tandem mass spectrometry methodology of high resolution, sensitivity, and reliability. The composition of liver fatty acyl-CoAs was found to reflect the composition of dietary fat. Treatment with hypolipidemic carboxylates resulted in liver dominant abundance of their respective acyl-CoAs accompanied by an increase in liver fatty acyl-CoAs. Cellular effects exerted by dietary fatty acids and/or xenobiotic carboxylic drugs may be transduced in vivo by their respective acyl-CoAs.


Subject(s)
Acyl Coenzyme A/analysis , Dietary Fats/pharmacology , Liver/chemistry , Liver/drug effects , Xenobiotics/pharmacology , Acyl Coenzyme A/metabolism , Animals , Bezafibrate/pharmacology , Diet , Hypolipidemic Agents/pharmacology , Male , Nafenopin/pharmacology , Palmitic Acids/pharmacology , Rats , Sensitivity and Specificity , Spectrometry, Mass, Electrospray Ionization/methods
6.
J Cancer Educ ; 17(2): 101-5, 2002.
Article in English | MEDLINE | ID: mdl-12092852

ABSTRACT

BACKGROUND: Medical organizations are divided on the issue of screening for prostate cancer, yet there is agreement that men should be educated about prostate health. Shared decision making involves patients and practitioners in this process, yet some men need preparatory education prior to the physician encounter. This study assessed the effectiveness of a community prostate health awareness program, focusing on men at risk for prostate cancer. METHODS: Participants were given a pretest and a posttest to assess knowledge gains and impact on short-term intentions to address their prostate health. RESULTS: There was a statistically significant increase in knowledge. Short-term intentions increased for those participants meeting the inclusion criteria. DISCUSSION: Community outreach programs remain an excellent vehicle to educate the public and complement the efforts of health care providers.


Subject(s)
Health Education/standards , Preventive Health Services/standards , Prostatic Diseases/prevention & control , Humans , Male , Michigan , Middle Aged , Program Evaluation , Prostatic Diseases/diagnosis , Prostatic Neoplasms/prevention & control , Time Factors
7.
Ecotoxicol Environ Saf ; 49(2): 122-30, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11386725

ABSTRACT

The parent generation of the viviparous blenny, Zoarces viviparus L., were exposed to phytosterols (a) from oogenesis to parturition and (b) from breeding to parturition. The experiments were performed under laboratory conditions in a test unit supplied with continuous renewal of brackish water. After parturition the offspring were further reared either in clean or in phytosterol-contaminated brackish water. The objective was to study the significance of preexposure of the parent on the effects of phytosterols on the offspring in comparison with effects occurring directly on previously unexposed offspring. The phytosterol concentrations used were (a) 0, 10, 20, and 30 microg/L and (b) 0, 10, and 20 microg/L. Offspring exposed in (a) was further reared in clean water and in (b) offspring from parents exposed to 10 microg/L was either exposed further in the same concentration or left in clean water. Offspring from parents exposed to 20 microg/L was further exposed in the same concentration. Finally one group from unexposed parents was exposed to 10 microg/L after birth. The offspring was studied for 6 months after birth. The results showed that blenny offspring are affected by phytosterols at exposure through the parental generation. The results imply that phyto- sterols affect embryological development of the larvae before hatching as well as the levels of circulating hormones of the parent fish. The larvae contained higher levels of phytosterols as did controls and the bile of exposed female fish contained lower levels of phytosterols implying a link between the higher levels in larvae and lower excretion of the females. The growth of the larvae at 10 microg/L was stimulated regardless of whether the larvae were further exposed, indicating that newborn larvae carried within the female are sensitive to exposure to phytosterols.


Subject(s)
Abnormalities, Drug-Induced , Environmental Exposure/adverse effects , Fishes/physiology , Larva/drug effects , Reproduction/drug effects , Sitosterols/toxicity , Animals , Bile/metabolism , Cytochrome P-450 CYP1A1/metabolism , Dose-Response Relationship, Drug , Female , Larva/growth & development , Liver/drug effects , Liver/metabolism , Liver/pathology , Liver Glycogen/metabolism , Male , Organ Size/drug effects , Sitosterols/pharmacokinetics
8.
Ecotoxicol Environ Saf ; 49(2): 144-54, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11386728

ABSTRACT

Juvenile female rainbow trout was exposed for 4.5 months (June to October) to two dilutions of untreated and activated sludge treated whole mill effluent from a pulp mill producing bleached ECF pulp. Two controls were used, on fed ad libitum and a second receiving 0.5% feed of the body weight. All effluent exposed groups were fed ad libitum. Mean weight of the fish was measured monthly. At the end of the experiment a number of physiological and biochemical parameters were analyzed in order to establish the physiological status of the exposed fish in comparison with unexposed fish that obtained ad libitum or restricted amount of feed. The fish exposed to treated effluent grew significantly more than ad libitum control fish until August, whereupon growth retarded in fish exposed to the lower effluent dilution (400 v/v). The growth of fish exposed to untreated effluent did not deviate significantly from the control fed ad libitum. The results from the hematological analysis clearly showed that fish fed restricted amount of feed deviated significantly in most parameters compared with the control fed ad libitum. Fish exposed to treated effluent showed a response pattern similar to that of the control fed restricted amount of feed, whereas the fish exposed to untreated effluent showed a response pattern that did not deviate from that of the ad libitum control. The metabolic parameters suggested that fish exposed to treated effluent had a higher metabolic demand than ad libitum control and that the energy allocation at the end of the experiment was directed to processes other than growth. The responses on hematology were mainly a consequence of the increased energy demand and were not primary effects. The implications of using feed related parameters at field studies are discussed.


Subject(s)
Body Weight/drug effects , Chemical Industry , Industrial Waste/adverse effects , Oncorhynchus mykiss/growth & development , Paper , Water Pollutants, Chemical/adverse effects , Animal Feed , Animals , Bile/chemistry , Bile/drug effects , Bile/metabolism , Body Weight/physiology , Cytochrome P-450 CYP1A1/metabolism , Female , Food Deprivation/physiology , Gonadal Steroid Hormones/blood , Hematologic Tests , Hepatocytes/drug effects , Hepatocytes/enzymology , In Vitro Techniques , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Oncorhynchus mykiss/blood , Oncorhynchus mykiss/metabolism , Phytosterols/analysis , Phytosterols/metabolism , Sewage/adverse effects , Sewage/chemistry , Thyroid Hormones/blood , Vitellogenins/metabolism , Water Purification
9.
Toxicol Lett ; 120(1-3): 9-19, 2001 Mar 31.
Article in English | MEDLINE | ID: mdl-11323157

ABSTRACT

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the superfamily of nuclear receptors. It binds and is activated by natural polyunsaturated fatty acids, eicosanoids, synthetic thiazolidinediones and related analogues. Biological effects exerted by PPARgamma ligands are mostly concerned with differentiation processes, sensitization to insulin and atherogenesis, and are paradigmatically ascribed to PPARgamma transactivation of PPARgamma-responsive genes. The PPARgamma paradigm and its consequences in humans are analyzed here in terms of the tissue specificity of PPARgamma, loss and gain of function mutants of PPARgamma, PPARgamma-responsive genes and clinical effects of PPARgamma ligands. Differentiation, as well as some of the atherogenic effects induced by PPARgamma ligands, does conform to the PPARgamma paradigm. However, sensitization to insulin as well as some of the antiatherogenic effects of PPARgamma ligands is not accounted for by PPARgamma activation, thus calling for an alternative target for insulin sensitizers.


Subject(s)
Receptors, Cytoplasmic and Nuclear/physiology , Transcription Factors/physiology , Animals , Arteriosclerosis/etiology , Cell Differentiation , Cytokines/physiology , Foam Cells/physiology , Humans , Insulin/pharmacology , Muscle, Smooth, Vascular/cytology , Organ Specificity , Plasminogen Activator Inhibitor 1/physiology
10.
Biochem Pharmacol ; 61(9): 1057-62, 2001 May 01.
Article in English | MEDLINE | ID: mdl-11301038

ABSTRACT

Hepatocyte nuclear factor-4alpha (HNF-4alpha) modulates the expression of liver-specific genes that control the production (e.g. apolipoprotein [apo] A-I and apo B) and clearance (e.g. apo C-III) of plasma lipoproteins. We reported that the CoA thioesters of amphipathic carboxylic hypolipidemic drugs (e.g. clofibric acid analogues currently used for treating hyperlipidemia in humans and substituted long-chain dicarboxylic acids) were formed in vivo, bound to HNF-4alpha, inhibited its transcriptional activity, and suppressed the expression of HNF-4alpha-responsive genes. Hypolipidemic PPARalpha (peroxisome proliferator-activated receptor alpha) activators that were not endogenously thioesterified into their respective acyl-CoAs were shown to be effective in rats but not in humans, implying that the hypolipidemic activity transduced by PPARalpha in rats was PPARalpha-independent in humans. The suppressed acyl-CoA synthase of PPARalpha knockout mice left unresolved the contribution made by the acyl-CoA/HNF-4alpha pathway to the hypolipidemic effect of PPARalpha agonists in rodents. Hence, suppression of HNF-4alpha activity by the CoA thioesters of hypolipidemic "peroxisome proliferators" may account for their hypolipidemic activity independently of PPARalpha activation by their respective free carboxylates. The hypolipidemic activity of peroxisome proliferators is mediated in rats and humans by the PPARalpha and HNF-4alpha pathways, respectively.


Subject(s)
DNA-Binding Proteins , Hypolipidemic Agents/metabolism , Liver/metabolism , Peroxisome Proliferators/metabolism , Phosphoproteins/metabolism , Transcription Factors/metabolism , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , COS Cells , Hepatocyte Nuclear Factor 4 , Humans , Hypolipidemic Agents/pharmacology , Liver/cytology , Liver/drug effects , Palmitic Acids/pharmacology , Peroxisome Proliferators/pharmacology , Phosphoproteins/antagonists & inhibitors , Rats , Receptors, Cytoplasmic and Nuclear/metabolism , Transcription Factors/antagonists & inhibitors , Transcription, Genetic
11.
Am J Physiol Endocrinol Metab ; 279(1): E221-7, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10893343

ABSTRACT

Adipose tissue lipolysis and fatty acid reesterification by liver and adipose tissue were investigated in rats fasted for 15 h under basal and calorigenic conditions. The fatty acid flux initiated by adipose fat lipolysis in the fasted rat is mostly futile and is characterized by reesterification of 57% of lipolyzed free fatty acid (FFA) back into adipose triglycerides (TG). About two-thirds of FFA reesterification are carried out before FFA release into plasma, whereas the rest consists of plasma FFA extracted by adipose tissue. Thirty-six percent of the fasting lipolytic flux is accounted for by oxidation of plasma FFA, whereas only a minor fraction is channeled into hepatic very low density lipoprotein-triglycerides (VLDL-TG). Total body calorigenesis induced by thyroid hormone treatment and liver-specific calorigenesis induced by treatment with beta, beta'-tetramethylhexadecanedioic acid (Medica 16) are characterized by a 1.7- and 1.3-fold increase in FFA oxidation, respectively, maintained by a 1.5-fold increase in adipose fat lipolysis. Hepatic reesterification of plasma FFA into VLDL-TG is negligible under both calorigenic conditions. Hence, total body fatty acid metabolism is regulated by adipose tissue as both source and sink. The futile nature of fatty acid cycling allows for its fine tuning in response to metabolic demands.


Subject(s)
Fasting/physiology , Fatty Acids/metabolism , Adipose Tissue/metabolism , Animals , Body Temperature Regulation/physiology , Esterification , Hypolipidemic Agents/pharmacology , Lipolysis/physiology , Liver/metabolism , Liver/physiology , Male , Oxidation-Reduction , Palmitic Acids/pharmacology , Rats , Rats, Inbred Strains , Thyroid Hormones/pharmacology , Triglycerides/metabolism
13.
Biochim Biophys Acta ; 1457(3): 166-74, 2000 Apr 21.
Article in English | MEDLINE | ID: mdl-10773161

ABSTRACT

Calcium-dependent uncoupling of liver mitochondrial oxidative phosphorylation by a non-metabolizable long chain fatty acyl analogue was compared with uncoupling induced by in vivo thyroid hormone treatment. beta,beta'-Methyl-substituted hexadecane alpha, omega-dioic acid (Medica 16) is reported here to induce a saturable 20-30% decrease in liver mitochondrial DeltaPsi, DeltapH and protonmotive force which proceeds in the presence of added Ca(2+) to cyclosporin A-sensitive mitochondrial permeabilization. Ca(2+)-dependent uncoupling by Medica 16 was accompanied by atractylate-enhanced, bongkrekic-inhibited activation of mitochondrial Ca(2+) efflux. The direct mitochondrial effect exerted in vitro by Medica 16 is similar to that induced by in vivo thyroid hormone treatment. Hence, the thyromimetic protonophoric activity of Medica 16 and the uncoupling activity of TH converge onto components of the mitochondrial permeabilization transition pore.


Subject(s)
Hypolipidemic Agents/pharmacology , Ion Channels , Mitochondria, Liver/metabolism , Palmitic Acids/pharmacology , Animals , Hyperthyroidism/metabolism , Hypothyroidism/metabolism , Male , Membrane Proteins/metabolism , Methimazole , Mitochondria, Liver/drug effects , Mitochondrial Membrane Transport Proteins , Mitochondrial Permeability Transition Pore , Proton-Motive Force , Rats , Triiodothyronine , Uncoupling Agents
14.
Ecotoxicol Environ Saf ; 42(1): 40-9, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9931237

ABSTRACT

Maturing lake trout (Salmo trutta lacustris) of both sexes were exposed to 10 and 20 microg/liter phytosterols, mainly ss-sitosterol, for 4.5 months prior to spawning. Eggs from preexposed females were artificially fertilized with milt from preexposed males in clean water, whereupon the eggs were incubated in clean water until hatching. Yolk sac fry were followed until swim-up, and mortality as well as deformities was recorded. The physiological status of the parent fish was documented, as was the occurrence of phytosterols in bile liquid and gonads. In addition, eggs from preexposed females were fertilized with milt from unexposed males to evaluate the existence of possible sex-linked differences. The results indicate a markedly increased dose-dependent egg mortality, smaller egg size, and lower mean weight of the the yolk sac stage larvae. There was a higher prevalence of deformed or otherwise diseased larvae, especially at the higher dose, but also in the groups where unexposed males were used for fertilization, indicating a female-linked effect mechanism. A causal link between effects on eggs and brood was obtained through a dose-dependent increase in phytosterols in the roe. Several physiological parameters (higher plasma estradiol, higher 7-ethoxyresorufin O-deethylase activity) implied slower maturation of the exposed female fish, whereas indications of accelerated maturation were obtained for the male fish from the same groups. The results indicate that naturally occurring wood-derived compounds in pulp mill effluents may be responsible for reproductive impacts previously observed in fish both in the laboratory and in the receiving waters of pulp mill effluents. The results also suggest that more attention should be paid to process streams emanating from the unbleached part of the mill.


Subject(s)
Ovum/drug effects , Reproduction/drug effects , Sitosterols/toxicity , Sterols/toxicity , Trout , Zygote/drug effects , Animals , Bile/chemistry , Female , Male , Sitosterols/metabolism , Sterols/chemistry , Wood
15.
Ecotoxicol Environ Saf ; 40(3): 184-93, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9679680

ABSTRACT

Effects of effluents from mechanical pulp production on brown trout were studied for 8 weeks at environmentally relevant concentrations. The exposure took place in laboratory-based pools upstream and downstream of the effluent discharge point of an integrated newsprint mill using ground wood/thermomechanical pulp. The mill had no secondary treatment of the wastewater. The pools were supplied with water pumped directly from the river. To determine the relevance of this approach, wild fish were also caught at the respective sites upstream and downstream from the mill. Sublethal effects were assessed using physiological and biochemical parameters including liver histology, hematology, serum biochemistry, and hepatic enzyme assays. Exposure was verified by analyzing water samples, fish bile, and tissues for resin acid concentrations. The downstream experimental fish and captured feral fish displayed responses and changes in physiological parameters similar to those previously observed in laboratory experiments with untreated effluents. The most obvious effects were liver damage and growth inhibition.


Subject(s)
Industrial Waste/adverse effects , Liver/drug effects , Trout/physiology , Water Pollutants, Chemical/adverse effects , Animals , Blood Chemical Analysis , Environmental Exposure , Liver/enzymology , Liver/pathology , Trout/growth & development
16.
Diabetes ; 47(5): 770-8, 1998 May.
Article in English | MEDLINE | ID: mdl-9588449

ABSTRACT

The JCR:LA-cp rat develops an extreme obese/insulin-resistant syndrome such that by 12 weeks of age, there is no longer any insulin-mediated glucose turnover. At 4 weeks of age, obese and lean rats have essentially identical basal and insulin-mediated glucose uptake in skeletal muscle. By 8 weeks of age, however, the obese rats no longer exhibit such intake. Plasma insulin concentrations in the normal fed state show only small increases up to 4 weeks, with a rapid rise to a marked hyperinsulinemia thereafter, with an age at half-development of 5.5 weeks. Plasma triacylglycerol concentrations in fed obese rats are elevated at 3 weeks and rise rapidly thereafter. The triacylglycerol content of skeletal muscle is significantly elevated in the obese rats at 4 weeks of age. Histological examination of Oil Red O-stained muscle tissue and transmission electron microscopy shows the presence of intracellular lipid droplets. Treatment with the potent triacylglycerol-lowering agent MEDICA 16 (beta,beta'-tetramethylhexadecanedioic acid) from 6 weeks of age reduces plasma lipids markedly, but it reduces body weight and insulin resistance only modestly. In contrast, treatment with MEDICA 16 from the time of weaning at 3 weeks of age results in the normalization of food intake and body weight to over 8 weeks of age. The development of hyperinsulinemia is also delayed until 8.5 weeks of age, and insulin levels remain strongly reduced. Plasma triacylglycerol concentrations remain at the same level as in lean rats, and neither an elevated muscle triacylglycerol content nor intracellular lipid droplets are found at 4 weeks of age. The results indicate that insulin resistance develops in the young animals and is not directly due to a genetically determined defect in insulin metabolism. The mechanism of induction instead appears to be related to an exaggerated triacylglycerol metabolism.


Subject(s)
Hypertriglyceridemia/drug therapy , Hypolipidemic Agents/pharmacology , Insulin Resistance/genetics , Obesity/genetics , Palmitic Acids/pharmacology , Triglycerides/physiology , Animals , Deoxyglucose/pharmacokinetics , Hypertriglyceridemia/genetics , Insulin/blood , Metabolic Clearance Rate , Microscopy, Electron , Muscles/metabolism , Muscles/ultrastructure , Rats , Rats, Inbred Strains , Syndrome , Tissue Distribution , Triglycerides/blood
17.
Nature ; 392(6675): 512-6, 1998 Apr 02.
Article in English | MEDLINE | ID: mdl-9548258

ABSTRACT

Dietary fatty acids specifically modulate the onset and progression of various diseases, including cancer, atherogenesis, hyperlipidaemia, insulin resistances and hypertension, as well as blood coagulability and fibrinolytic defects; their effects depend on their chain length and degree of saturation. Hepatocyte nuclear factor-4alpha (HNF-4alpha) is an orphan transcription factor of the superfamily of nuclear receptors and controls the expression of genes that govern the pathogenesis and course of some of these diseases. Here we show that long-chain fatty acids directly modulate the transcriptional activity of HNF-4alpha by binding as their acyl-CoA thioesters to the ligand-binding domain of HNF-4alpha. This binding may shift the oligomeric-dimeric equilibrium of HNF-4alpha or may modulate the affinity of HNF-4alpha for its cognate promoter element, resulting in either activation or inhibition of HNF-4alpha transcriptional activity as a function of chain length and the degree of saturation of the fatty acyl-CoA ligands. In addition to their roles as substrates to yield energy, as an energy store, or as constituents of membrane phospholipids, dietary fatty acids may affect the course of a disease by modulating the expression of HNF-4alpha-controlled genes.


Subject(s)
Acyl Coenzyme A/metabolism , Dietary Fats/metabolism , Phosphoproteins/metabolism , Repressor Proteins , Saccharomyces cerevisiae Proteins , Transcription Factors/metabolism , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , COS Cells , Coenzyme A Ligases/genetics , Coenzyme A Ligases/metabolism , DNA/metabolism , DNA-Binding Proteins/metabolism , Enhancer Elements, Genetic , Escherichia coli , Esters/metabolism , Fatty Acids/metabolism , Fatty Acids, Nonesterified/metabolism , Hepatocyte Nuclear Factor 4 , Humans , Ligands , Palmitoyl-CoA Hydrolase/genetics , Palmitoyl-CoA Hydrolase/metabolism , Phosphoproteins/agonists , Phosphoproteins/antagonists & inhibitors , Rats , Recombinant Fusion Proteins/metabolism , Transcription Factors/agonists , Transcription Factors/antagonists & inhibitors , Transcription, Genetic , Transfection
18.
J Biol Chem ; 273(7): 3937-42, 1998 Feb 13.
Article in English | MEDLINE | ID: mdl-9461579

ABSTRACT

Mitochondria uncoupling by fatty acids in vivo is still questionable, being confounded by their dual role as substrates for oxidation and as putative genuine uncouplers of oxidative phosphorylation. To dissociate between substrate and the uncoupling activity of fatty acids in oxidative phosphorylation, the uncoupling effect was studied here using a nonmetabolizable long chain fatty acyl analogue. beta,beta'-Methyl-substituted hexadecane alpha,omega-dioic acid (MEDICA 16) is reported here to induce in freshly isolated liver cells a saturable oligomycin-insensitive decrease in mitochondrial proton motive force with a concomitant increase in cellular respiration. Similarly, MEDICA 16 induced a saturable decrease in membrane potential, proton gradient, and proton motive force in isolated liver and heart mitochondria accompanied by an increase in mitochondrial respiration. Uncoupling by MEDICA 16 in isolated mitochondria was partially suppressed by added atractyloside. Hence, fatty acids may act as genuine uncouplers of cellular oxidative phosphorylation by interacting with specific mitochondrial proteins, including the adenine nucleotide translocase.


Subject(s)
Mitochondria, Liver/drug effects , Palmitic Acids/pharmacology , Uncoupling Agents/pharmacology , Animals , Atractyloside/pharmacology , Cell Respiration/drug effects , Cells, Cultured , Fatty Acids/pharmacology , Flow Cytometry , Hydrogen-Ion Concentration , Membrane Potentials/drug effects , Mitochondria, Heart/drug effects , Mitochondrial ADP, ATP Translocases/metabolism , Oligomycins/pharmacology , Oxidative Phosphorylation/drug effects , Oxygen/metabolism , Palmitic Acid/pharmacology , Rats
19.
Toxicol Lett ; 102-103: 85-90, 1998 Dec 28.
Article in English | MEDLINE | ID: mdl-10022237

ABSTRACT

Amphipathic carboxylates collectively defined as peroxisome proliferators (PP) induce in rodents a pleiotropic effect, mediated by the peroxisome proliferator-activated receptor alpha (PPAR alpha). Treatment with PP results in rodents in hypolipidemia, peroxisome proliferation and liver hypertrophy and hyperplasia leading to non-genotoxic hepatocarcinogenesis. In contrast to rodents, the hypolipidemic effect exerted by PP in humans is not accompanied by peroxisome proliferation nor by induction of peroxisomal beta-oxidation or other activities induced by PP in rodents. Non-responsiveness in humans may be ascribed to a missing liver component in the PPAR alpha transduction pathway specifically involved with transcriptional modulation of chromosomal PPAR alpha responsive genes. Hence, biological effects exerted by PP in the human liver are likely to be mediated by a transduction pathway independent of PPAR alpha.


Subject(s)
Liver/drug effects , Peroxisome Proliferators/toxicity , Receptors, Cytoplasmic and Nuclear/physiology , Transcription Factors/physiology , Animals , Humans , Hypolipidemic Agents/pharmacology , Peroxisome Proliferators/pharmacology , Rats , Species Specificity
20.
Diabetes ; 46(12): 1958-64, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9392480

ABSTRACT

Beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) consists of a nonmetabolizable long-chain fatty acid designed to probe the effect exerted by fatty acids on insulin sensitivity. The effect of MEDICA 16 was evaluated in insulin-resistant Zucker (fa/fa) rats in terms of liver, muscle, and adipose tissue response to clamped euglycemic hyperinsulinemia in vivo. Nontreated Zucker rats were insulin resistant, maintaining basal rates of total-body glucose disposal, glucose production in liver, free fatty acid (FFA) flux into plasma, and FFA reesterification in adipose tissue, irrespective of the insulin levels induced. MEDICA 16 treatment resulted in an insulin-induced decrease in hepatic glucose production, together with an insulin-induced increase in total-body glucose disposal. Intracellular reesterification of lipolysed FFA in adipose tissue was specifically activated by MEDICA 16, resulting in a pronounced decrease in FFA release, with a concomitant decrease in plasma FFA. In conclusion, MEDICA 16 treatment results in the sensitization of liver, muscle, and adipose tissue to insulin in an animal model for obesity-induced insulin resistance.


Subject(s)
Hypolipidemic Agents/pharmacology , Insulin Resistance , Insulin/pharmacology , Obesity/metabolism , Palmitic Acids/pharmacology , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Blood Glucose/metabolism , Cholesterol/blood , Fatty Acids, Nonesterified/blood , Glucose/biosynthesis , Glucose Clamp Technique , Insulin/blood , Kinetics , Liver/drug effects , Liver/metabolism , Muscles/drug effects , Muscles/metabolism , Palmitic Acid/blood , Rats , Rats, Zucker , Triglycerides/blood
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