Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To ascertain if there is stereoselectivity in peroxisomal proliferation induced by chiral peroxisome proliferators, induction by stereoisomers of 2-methyl-4'-chlorophenoxyacetic acid and 2-methyl-2-(2'-4'-dichlorophenoxy)acetic acid were studied in rat in vivo and in vitro with isolated rat hepatocytes. No significant differences in the inducing potencies of the stereoisomers of the above two phenoxyacetic acid derivatives were found for cyanide-insensitive fatty acyl-CoA oxidizing system, fatty acyl-CoA oxidase, carnitine acetyltransferase or carnitine palmitoyltransferase. There was also no significant difference in the degree of hepatomegaly or lipid-lowering effect between the isomers. The findings with cultured rat hepatocytes agreed with those of the studies in vivo.
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PMID:Lack of stereoselectivity in rat liver peroxisomal enzyme induction by optically active phenoxyacetic acids. 836 50

(E)-2-[2-(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl) propen-1-yl]-4-thiophenecarboxylic acid (AGN 191701) and other retinoid X receptor (RXR)-selective agonists were observed to cause hepatomegaly in rats. The purpose of the present study was to understand the biochemical basis of RXR agonist-induced hepatomegaly. Male Fischer rats were implanted s.c. with osmotic pumps containing 5-bromo-2'-deoxyuridine (BrdU) and treated by gavage with 0,60, or 180 mumol/kg/day of AGN 191701 for 3 days. AGN 191701 caused dose-dependent hepatomegaly in the absence of hepatic necrosis and necrosis and increased hepatocyte BrdU labeling index (LI). To determine if AGN 191701-induced hepatic hyperplasia was sustained, rats were treated by gavage with 60 mumol/kg of AGN 191701 for up to 7 days and exposed to BrdU via osmotic pump on days 1-3 or on days 6-8. Hepatocyte L1 and mitotic index were increased only in rats exposed to BrdU on days 1-3, indicating that AGN 191701-induced hepatocyte proliferation was transient. The receptor specificity of this mitogenic effect was tested by co-treating rats for 2 days with various retinoids and BrdU. 2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-(4-carboxylph enyl)-1,3-dioxolane (SR11237), an RXR-selective agonist, and (E)-5-[2-(5,6,7,8-tetrahydro-3,5,5,8-pentamethyl-2-naphthyl)propen -1-yl]-2-thiophenecarboxylic acid (AGN 191659), a retinoic acid receptor (RAR)/RXR pan-agonist, both increased hepatocyte LI. Two RAR-selective agonist, all-trans-retinoic acid and (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propen -1-yl] benzoic acid (TTNPB), did not affect hepatocyte LI. To determine if RXR agonists have biochemical effects in common with a peroxisome proliferator, various endpoints were measured 24 hr after two daily treatments with AGN 191701, SR11237, or clofibrate. While all three compounds induced hepatic acyl CoA oxidase activity, only clofibrate increased hepatic carnitine acyl transferase activity and lowered serum triglycerides. Taken together, these data show that RXR-selective agonists but not RAR-selective agonists cause hepatomegaly accompanied by hepatocyte mitogenesis in rats. The fact that RXR agonist have some biological effects distinct from RAR agonists and clofibrate suggests that RXR-selective agonists may have unique therapeutic applications.
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PMID:Mitogenic effect of retinoid X receptor agonists in rat liver. 931 79

In the course of glycine conjugation, benzoic acid is successively converted into benzoyl-CoA and benzoylglycine by mitochondrial enzymes (i.e. benzoyl-CoA synthetase and benzoyl-CoA/glycine N-acyltransferase, respectively), utilizing ATP, CoA, and glycine. Large doses of benzoate deplete CoA from the liver, suggesting that the supply of CoA may limit the capacity for glycine conjugation. Because fibrates are known to increase hepatic CoA synthesis, we examined whether treatment with fenofibrate or bezafibrate enhanced the capacity of rats to conjugate benzoic acid with glycine. Dietary administration of fenofibrate or bezafibrate (2.5 mmol/kg of feed, for 10 days) increased hepatic CoA levels 8-10-fold, while not affecting hepatic ATP levels; only fenofibrate elevated, albeit moderately, the concentration of glycine in liver. Hepatic mitochondria isolated from fibrate-fed rats, compared with those from controls, exhibited unchanged benzoyl-CoA synthetase activity but higher benzoyl-CoA hydrolase and lower benzoyl-CoA/glycine N-acyltransferase activities. Feeding with either fibrate increased liver mass by 50-60%. Control and fibrate-fed rats were administered benzoate at different doses, one to produce a large demand for CoA (i.e. 2 mmol/kg, iv) and two others to produce smaller demands for CoA (i.e. 1 mmol/kg or 2 mmol/kg plus glycine, iv). Fenofibrate-fed rats, and to a lesser extent bezafibrate-fed animals, exhibited increased glycine conjugation capacity, as indicated by faster disappearance of benzoate from the blood and appearance of benzoylglycine in the blood and urine, compared with controls; however, fibrates were not more effective in rats receiving the benzoate dose that produced the greatest demand for CoA. In contrast, benzoylglycine formation from benzoate (0.1-1 mM) was not enhanced in liver slices from fibrate-fed rats; moreover, it was lower than control levels in slices from bezafibrate-fed animals. Bezafibrate, but not fenofibrate, given to rats in a single dose (0.5 mmol/kg, ip) decreased the elimination and glycine conjugation of benzoate, indicating that bezafibrate is a direct inhibitor of glycine conjugation. In summary, fibrates influence glycine conjugation in a complex manner. Some fibrate-induced alterations (i.e. increased benzoyl-CoA hydrolase and decreased glycine transferase activities and direct inhibition by bezafibrate) can potentially hinder conjugation of benzoate with glycine, thus precluding conclusions regarding whether increased CoA availability enhances glycine conjugation. Fibrate-induced hepatomegaly appears to significantly contribute to the increased glycine conjugation capacity of rats treated with fenofibrate or bezafibrate.
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PMID:Effects of fibrates on the glycine conjugation of benzoic acid in rats. 980 50

Current dietary management of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD; long-chain-(S)-3-hydroxyacyl-CoA:NAD+ oxido-reductase, EC 1.1.1.211) deficiency (LCHADD) is based on avoiding fasting, and minimizing energy production from long-chain fatty acids. We report the effects of various dietary manipulations on plasma and urinary laboratory values in a child with LCHADD. In our patient, a diet restricted to 9% of total energy from long-chain fatty acids and administration of 1.5 g medium-chain triglyceride oil per kg body weight normalized plasma acylcarnitine and lactate levels, but dicarboxylic acid excretion remained approximately ten times normal. Plasma docosahexaenoic acid (DHA, 22:6n-3) was consistently low over a 2-year period; DHA deficiency may be related to the development of pigmentary retinopathy seen in this patient population. We also conducted a survey of metabolic physicians who treat children with LCHADD to determine current dietary interventions employed and the effects of these interventions on symptoms of this disease. Survey results indicate that a diet low in long-chain fatty acids, supplemented with medium-chain triclyceride oil, decreased the incidence of hypoketotic hypoglycaemia, and improved hypotonia, hepatomegaly, cardiomyopathy, and lactic acidosis. However, dietary treatment did not appear to effect peripheral neuropathy, pigmentary retinopathy or myoglobinuria.
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PMID:Dietary management of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). A case report and survey. 1023 7

3-Hydroxy-3-Methylglutaryl coenzyme A lyase (HMG-CoA) deficiency is a rare inborn error of leucine catabolism. The disease is characterized by recurrent episodes of metabolic acidosis, hyperammonemia without ketosis, hypoglycemia, lethargy, hepatomegaly, and seizures. This study has evaluated the magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) findings of three patients with HMG-CoA deficiency. The common findings on all of the MRI scans were multiple, coalescent, marked lesions in periventricular white matter and arcuate fibers, most prominently in frontal or periatrial regions that were superimposed on diffuse, slightly hyperintense subcortical white matter signal. Involvement of the caudate nucleus and the dentate nucleus were observed in the reported patients. MRS studies by both STEAM and PRESS spectra of all patients revealed a decrease in N-acetylaspartate and elevation in both myoinositol and choline. A pathologic peak at 1.33 ppm, which is compatible with lactate, and a particular peak at 2.42 ppm in all patients were also found. The combination of both MRI and MRS findings could be considered as being specific in patients with HMG-CoA lyase deficiency.
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PMID:MRI and MRS in HMG-CoA lyase deficiency. 1037 84

Compounds that cause peroxisome proliferation in rats and mice have been reported to interfere with mitochondrial (mt) bioenergetics and possibly biogenesis. The purpose of this investigation was to establish whether proliferation of peroxisomes and mitochondria are necessarily related. Perfluorooctanesulfonate (PFOS) and N-ethyl perfluorooctanesulfonamido ethanol (N-EtFOSE) were investigated as peroxisome proliferators in comparison to perfluorooctanoic acid (PFOA). Three parameters were chosen to assess peroxisome proliferation, stimulation of lauroyl CoA oxidase activity, reduction of serum cholesterol concentration, and hepatomegaly. mt Biogenesis was assessed through cytochrome oxidase activity, cytochrome content and mitochondrial DNA (mtDNA) copy number. PFOA, PFOS, or N-EtFOSE was administered via a single i.p. injection at 100 mg/kg in male rats, and measurements were made 3 days later. In this model, PFOS and PFOA share similar potencies as peroxisome proliferators, whereas N-EtFOSE showed no activity. mt Endpoints were altered only in the PFOA treatment group, which consisted of a decrease cytochrome oxidase activity in liver tissue and an increase in the mtDNA copy number. None of the perfluorooctanoates significantly altered mt cytochrome content following acute in vivo treatment. These data demonstrate that acute administration of PFOS or PFOA causes hepatic peroxisome proliferation in rats. However, stimulation of mt biogenesis is not a characteristic response of all peroxisome proliferators.
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PMID:Perfluorooctanoate, perflourooctanesulfonate, and N-ethyl perfluorooctanesulfonamido ethanol; peroxisome proliferation and mitochondrial biogenesis. 1187 71

The fomesafen and 2,4-D amine herbicide induce cytotoxic effects at hepatic level in rats, such as: hepatomegaly, hyperplasia and increase in the enzymes activity which participate in the processes of peroxisomal beta-oxidation of fatty acids. In this work, the effect of vitamin E and C was evaluated, as well as, the dexamethasone in the modulation of these hepatotoxic effects. Sprague-Dawley rats were treated with the herbicides and with the agents to be evaluated. The different treatments were given during 15 days orally route. The herbicides combined with the dexamethasone and antioxidant agents were administrated only and simultaneously with the herbicides. Once concluded the different treatment, the rats were weighed and sacrificed. It was evaluated the liver size and liver fragments were obtained to determine the enzymatic activity of Fatty Acyl CoA-oxidase (FACO) and cellular number. The results showed that the hepatomegaly induced by fomesafen was inhibited by the vitamins and by the dexamethasone, while any effect was not observed in the group of rats treated with 2,4-D amine. None of the agents modulated the FACO activity induced by herbicides in treated rats. However, the dexamethasone showed a protective effect in the hyperplasia induced by two herbicides. The hepatotoxic effects induced by the herbicides responded to a different mechanism due to the differences of the effects observed at the antioxidant agents. On the other hand, the inhibition of the cellular proliferation by the dexamethasone does not keep relation with the responsible mechanisms of inducing the oxidant stress into FACO activity. Under experimental conditions of this study, the use of these agents does not guarantee protection against the hepatotoxic effects induced by the herbicides.
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PMID:[Participation of dexamethasone and E and C vitamins in the modulation of the hepatotoxic effect induced by fomesafen and 2,4-D amino herbicides, in rats ]. 1221 1

Peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor superfamily and are intimately involved in lipid metabolism and energy homeostasis. Activation of these receptors in rodents can lead to hepatomegaly and ultimately hepatic carcinogenesis although the mechanisms by which these processes occur are poorly understood. To further our understanding of these processes and to discriminate between different PPAR mediated signalling pathways, a proteomic approach has been undertaken to identify changes in protein expression patterns in Sprague Dawley rat liver following dosing with a PPARalpha agonist (Wyeth 14643), a PPARgamma agonist (Troglitazone) and a compound with mixed PPARalpha/gamma agonist activity (SB-219994). Using one-and-two-dimensional electrophoresis of tissue lysates a diverse range of protein abundance changes was observed in these tissues. Whilst a number of these proteins have PPAR response elements (PPREs) in their respective promoters, another group was detected whose expression has been documented to be sensitive to peroxisome proliferator administration. Most notably within these groups, proteins involved in lipid catabolism displayed increased expression following drug administration. A further subset of proteins, with less obvious biological implications, also showed altered expression patterns. Where available, sequences upstream of the coding regions of genes not previously known to have PPREs were searched with positional consensus matrices for the presence of PPREs in an attempt to validate these changes. Using such an approach putative PPARgamma and PPARdelta response elements were discovered upstream of the tubulin beta coding region. There was limited overlap in observed protein abundance changes between the three groups, and where this was the case (cytosolic epoxide hydrolase, peroxisomal bifunctional enzyme, hydroxymethyl glutaryl CoA, synthase, long chain acyl-CoA thioesterase), expression of these proteins had previously been shown to be under the control of PPAR activity.
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PMID:Protein expression changes in the Sprague Dawley rat liver proteome following administration of peroxisome proliferator activated receptor alpha and gamma ligands. 1268 17

Effective therapies for the treatment of obesity, a key element of metabolic syndrome, are urgently needed but currently lacking. Stearoyl-CoA desaturase-1 (SCD1) is the rate-limiting enzyme catalyzing the conversion of saturated long-chain fatty acids into monounsaturated fatty acids, which are major components of triglycerides. In the current study, we tested the efficacy of pharmacological inhibition of SCD1 in controlling lipogenesis and body weight in mice. SCD1-specific antisense oligonucleotide inhibitors (ASOs) reduced SCD1 expression, reduced fatty acid synthesis and secretion, and increased fatty acid oxidization in primary mouse hepatocytes. Treatment of mice with SCD1 ASOs resulted in prevention of diet-induced obesity with concomitant reductions in SCD1 expression and the ratio of oleate to stearoyl-CoA in tissues and plasma. These changes correlated with reduced body adiposity, hepatomegaly and steatosis, and postprandial plasma insulin and glucose levels. Furthermore, SCD1 ASOs reduced de novo fatty acid synthesis, decreased expression of lipogenic genes, and increased expression of genes promoting energy expenditure in liver and adipose tissues. Thus, SCD1 inhibition represents a new target for the treatment of obesity and related metabolic disorders.
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PMID:Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase-1. 1674 73

Detection of hepatic carnitine palmitoyltransferase I (CPT IA) deficiency by metabolite screening may be problematic. The urine organic acid profile is generally said to be normal and no abnormal or increased acylcarnitine species are evident on bloodspot tandem MS examination. We diagnosed CPT IA deficiency presenting with acute encephalopathy +/- hypoglycemia and hepatomegaly in one Bukharan Jewish and two Palestinian Arab infants from consanguineous families. CPT1A mutation analysis identified two novel nonsense mutations, c.1737C>A (Y579X) and c.1600delC (L534fsX), extending the known genetic heterogeneity in this disorder. A distinctive organic aciduria was observed in all three patients, even several days after initiation of treatment and resolution of symptoms. Abnormal findings included a hypoketotic dicarboxylic aciduria with prominence of the C12 dicarboxylic (dodecanedioic) acid. This C12 dicarboxylic aciduria suggests that CPT I may play a role in uptake of long-chain dicarboxylic acids by mitochondria after their initial shortening by beta-oxidation in peroxisomes. In addition, increased excretion of 3-hydroxyglutaric acid was detected in all three patients, a finding previously observed only in glutaric aciduria type 1, ketosis, and short-chain hydroxyacyl-CoA dehydrogenase deficiency. Examination of urine organic acids with awareness of these metabolic findings may lead to improved diagnosis of this seemingly rare disorder.
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PMID:Novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase I deficiency. 1614 4


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