Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three children in two families presented in early childhood with episodes of illness associated with fasting which resembled Reye's syndrome: coma, hypoglycemia, hyperammonemia, and fatty liver. One child died with cerebral edema during an episode. Clinical studies revealed an absence of ketosis on fasting (plasma beta-hydroxybutyrate less than 0.4 mmole/liter) despite elevated levels of free fatty acids (2.6-4.2 mmole/liter) which suggested that hepatic fatty acid oxidation was impaired. Urinary dicarboxylic acids were elevated during illness or fasting. Total carnitine levels were low in plasma (18-25 mumole/liter), liver (200-500 nmole/g), and muscle (500-800 nmole/g); however, treatment with L-carnitine failed to correct the defect in ketogenesis. Studies on ketone production from fatty acid substrates by liver tissue in vitro showed normal rates from short-chain fatty acids, but very low rates from all medium and long-chain fatty acid substrates. These results suggested that the defect was in the mid-portion of the intramitochondrial beta-oxidation pathway at the medium-chain acyl-CoA dehydrogenase step. A new assay for the electron transfer flavoprotein-linked acyl-CoA dehydrogenases was used to test this hypothesis. This assay follows the decrease in electron transfer flavoprotein fluorescence as it is reduced by acyl-CoA-acyl-CoA dehydrogenase complex. Results with octanoyl-CoA as substrate indicated that patients had less than 2.5% normal activity of medium-chain acyl-CoA dehydrogenase. The activities of short-chain and isovaleryl acyl-CoA dehydrogenases were normal; the activity of long-chain acyl-CoA dehydrogenase was one-third normal. These results define a previously unrecognized inherited metabolic disorder of fatty acid oxidation due to deficiency of medium-chain acyl-CoA dehydrogenase.
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PMID:Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels. 664 97

An increasing number of women with inborn errors of metabolism are now reaching child-bearing age. For certain disorders there are maternal risks associated with pregnancy. These may be related to an increased likelihood of metabolic decompensation (e.g. disorders of the urea cycle) or to increased stress to systems already compromised by disease (e.g. cardiomyopathy in GSD III). Detrimental effects upon the fetus may also be caused by maternal disease, as occurs with phenylketonuria, or from medication used to treat the mother's condition. Less commonly, fetal inborn errors may adversely effect the mother's health--e.g. fetal long-chain acyl-CoA dehydrogenase deficiency and the maternal HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) and AFLP (acute fatty liver of pregnancy). Because of the rarity of individual disorders, our knowledge of risks associated with pregnancy is limited. Even for more common inborn errors such as phenylketonuria, there remain a number of questions that have not been fully answered.
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PMID:Inborn errors of metabolism and pregnancy. 1086 39

Mitochondrial beta-oxidation of fatty acids is vital for energy production in periods of fasting and other metabolic stress. Human patients have been identified with inherited disorders of mitochondrial beta-oxidation of fatty acids with enzyme deficiencies identified at many of the steps in this pathway. Although these patients exhibit a range of disease processes, Reye-like illness (hypoketotic-hypoglycemia, hyperammonemia and fatty liver) and cardiomyopathy are common findings. There have been several mouse models developed to aid in the study of these disease conditions. The characterized mouse models include inherited deficiencies of very long-chain acyl-CoA dehydrogenase, long-chain acyl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein-alpha, and medium-/short-chain hydroxyacyl-CoA dehydrogenase. Mouse mutants developed, but presently incompletely characterized as models, include carnitine palmitoyltransferase-1a and medium-chain acyl-CoA dehydrogenase deficiencies. In general, the mouse models of disorders of mitochondrial fatty acid beta-oxidation have shown clinical signs that include Reye-like syndrome and cardiomyopathy, and many are cold intolerant. It is expected that these mouse models will provide vital contributions in understanding the mechanisms of disease pathogenesis of fatty acid oxidation disorders and the development of appropriate treatments and supportive care.
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PMID:Mouse models for disorders of mitochondrial fatty acid beta-oxidation. 1191 57

Mice deficient for either long-chain acyl-CoA dehydrogenase (LCAD-/-) or very-long-chain acyl-CoA dehydrogenase (VLCAD-/-) develop hepatic steatosis upon fasting, due to disrupted mitochondrial fatty acid oxidation. Moreover, neither mouse model can maintain core body temperature when exposed to cold. We investigated the effects of fasting and cold exposure on gene expression in these mice. Non-fasted LCAD-/- mice showed gene expression changes indicative of fatty liver, including elevated mRNA levels for peroxisome proliferator-activated receptor-gamma (PPARgamma) and genes involved in lipogenesis. In LCAD-/- and VLCAD-/- mice challenged with fasting and cold exposure, expression of fatty acid oxidation genes was elevated in liver, consistent with increased PPARalpha activity. This effect was not seen in brown adipose tissue, suggesting that expression of these genes may be regulated differently than in liver. The effect of acute cold exposure on expression of fatty acid oxidation genes was measured in peroxisome proliferator-activated receptor (PPAR)-alpha-deficient mice (PPARalpha-/-) and controls. In PPARalpha-/- mice, basal expression of the acyl-CoA dehydrogenases was reduced in liver but was not altered in brown adipose tissue. While cold altered the expression of PPARgamma, sterol-regulatory element binding protein-1 (SREBP-1), ATP citrate lyase, and the uncoupling proteins in brown adipose tissue from both PPARalpha-/- and control mice, fatty acid oxidation genes were unaffected. Thus, while fatty acid oxidation appears critical for non-shivering thermogenesis, expression of the acyl-CoA dehydrogenases is not influenced by cold exposure. Moreover, mitochondrial fatty acid oxidation genes are not regulated by PPARalpha in brown adipose tissue as they are in liver.
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PMID:Differential induction of genes in liver and brown adipose tissue regulated by peroxisome proliferator-activated receptor-alpha during fasting and cold exposure in acyl-CoA dehydrogenase-deficient mice. 1563 94

Normal function of the peroxisome proliferator-activated receptor alpha (PPARalpha) is crucial for the regulation of hepatic fatty acid metabolism. Fatty acids serve as ligands for PPARalpha, and when fatty acid levels increase, activation of PPARalpha induces a battery of fatty acid-metabolizing enzymes to restore fatty acid levels to normal. Hepatic fatty acid levels are increased during ethanol consumption. However, results of in vitro work showed that ethanol metabolism inhibited the ability of PPARalpha to bind DNA and activate reporter genes. This observation has been further studied in mice. Four weeks of ethanol feeding of C57BL/6J mice also impairs fatty acid catabolism in liver by blocking PPARalpha-mediated responses. Ethanol feeding decreased the level of retinoid X receptor alpha (RXRalpha) as well as the ability of PPARalpha/RXR in liver nuclear extracts to bind its consensus sequence, and the levels of mRNAs for several PPARalpha-regulated genes were reduced [long-chain acyl coenzyme A (acyl-CoA) dehydrogenase and medium-chain acyl-CoA dehydrogenase] or failed to be induced (acyl-CoA dehydrogenase, liver carnitine palmitoyl-CoA transferase I, very long-chain acyl-CoA synthetase, very long-chain acyl-CoA dehydrogenase) in livers of the ethanol-fed animals. Consistent with this finding, ethanol feeding did not induce the rate of fatty acid beta-oxidation, as assayed in liver homogenates. Inclusion of WY14,643, a PPARalpha agonist, in the diet restored the DNA-binding activity of PPARalpha/RXR, induced mRNA levels of several PPARalpha target genes, stimulated the rate of fatty acid beta-oxidation in liver homogenates, and prevented fatty liver in ethanol-fed animals. Blockade of PPARalpha function during ethanol consumption contributes to the development of alcoholic fatty liver, which can be overcome by WY14,643.
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PMID:Molecular mechanisms of alcoholic fatty liver: role of peroxisome proliferator-activated receptor alpha. 1567 Jun 63

Patients with very long-chain acyl-CoA dehydrogenase (VLCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)/mitochondrial trifunctional protein (MTP) deficiency, disorders of the mitochondrial long-chain fatty acid oxidation, can present with hypoketotic hypoglycemia, rhabdomyolysis, and cardiomyopathy. In addition, patients with LCHAD/MTP deficiency may suffer from retinopathy and peripheral neuropathy. Until recently, there was no indication of intrauterine morbidity in these disorders. This observation was in line with the widely accepted view that fatty acid oxidation (FAO) does not play a significant role during fetal life. However, the high incidence of the gestational complications acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, and low platelets syndrome observed in mothers carrying a LCHAD/MTP-deficient child and the recent reports of fetal hydrops due to cardiomyopathy in MTP deficiency, as well as the high incidence of intrauterine growth retardation in children with LCHAD/MTP deficiency, suggest that FAO may play an important role during fetal development. In this study, using in situ hybridization of the VLCAD and the LCHAD mRNA, we report on the expression of genes involved in the mitochondrial oxidation of long-chain fatty acids during early human development. Furthermore, we measured the enzymatic activity of the VLCAD, LCHAD, and carnitine palmitoyl-CoA transferase 2 (CPT2) enzymes in different human fetal tissues. Human embryos (at d 35 and 49 of development) and separate tissues (5-20 wk of development) were used. The results show a strong expression of VLCAD and LCHAD mRNA and a high enzymatic activity of VLCAD, LCHAD, and CPT2 in a number of tissues, such as liver and heart. In addition, high expression of LCHAD mRNA was observed in the neural retina and CNS. The observed pattern of expression during early human development is well in line with the spectrum of clinical signs and symptoms reported in patients with VLCAD or LCHAD/MTP deficiency.
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PMID:Long-chain fatty acid oxidation during early human development. 1584 37

Alterations in mitochondrial function have been implicated in the pathogenesis of insulin resistance and type 2 diabetes. However, it is unclear whether the reduced mitochondrial function is a primary or acquired defect in this process. To determine whether primary defects in mitochondrial beta-oxidation can cause insulin resistance, we studied mice with a deficiency of long-chain acyl-CoA dehydrogenase (LCAD), a key enzyme in mitochondrial fatty acid oxidation. Here, we show that LCAD knockout mice develop hepatic steatosis, which is associated with hepatic insulin resistance, as reflected by reduced insulin suppression of hepatic glucose production during a hyperinsulinemic-euglycemic clamp. The defects in insulin action were associated with an approximately 40% reduction in insulin-stimulated insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity and an approximately 50% decrease in Akt2 activation. These changes were associated with increased PKCepsilon activity and an aberrant 4-fold increase in diacylglycerol content after insulin stimulation. The increase in diacylglycerol concentration was found to be caused by de novo synthesis of diacylglycerol from medium-chain acyl-CoA after insulin stimulation. These data demonstrate that primary defects in mitochondrial fatty acid oxidation capacity can lead to diacylglycerol accumulation, PKCepsilon activation, and hepatic insulin resistance.
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PMID:Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. 1794 18

To screen target proteins of oxidative stress which mediate the effects of exercise on preventing nonalcoholic fatty liver disease (NAFLD), the methods for selecting carbonylated proteins were modified, and carbonylated proteins were profiled. The results showed that treadmill training reduced oxidative stress and the levels of intrahepatic triglyceride (IHTG). The changes in IHTG showed a significant positive correlation with oxidative stress as indicated by malondialdehyde level. Further results from proteomics illustrated that 17 functional proteins were susceptible to oxidative modification, and exercise protected three proteins from carbonylation. The latter three proteins may serve as both direct target proteins of oxidative stress and mediators contributing to the beneficial effects of exercise. In particular, a long-chain specific acyl-CoA dehydrogenase (ACADL) which was a key enzyme in lipid metabolism was not carbonylated and with higher activities in exercise group. These findings indicate that this modified technique is practical and powerful in selecting carbonylated proteins. Long-term treadmill training is effective in ameliorating oxidative stress and preventing the accumulation of IHTG. Among the 17 target proteins of oxidative modification, three proteins contribute to the beneficial effects of exercise. Preventing ACADL from carbonylation may be involved in the physiological mechanism of exercise-induced NAFLD improvement.
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PMID:Proteomic profile of carbonylated proteins in rat liver: exercise attenuated oxidative stress may be involved in fatty liver improvement. 2350 22

Korean pine nut oil (PNO) has been reported to influence weight gain and lipid metabolism. We examined whether PNO replacement in a high-fat diet (HFD) can ameliorate HFD-induced hepatic steatosis. Five-week-old male C57BL mice were fed control diets containing 10% of the energy from fat from PNO or soybean oil (SBO) (PC, SC) or HFDs with 45% of the energy from fat, with 10% from PNO or SBO and 35% from lard (PHFD, SHFD), for 12 weeks. Body weight gain and amount of white adipose tissue were lower in PHFD (10% and 18% lower, respectively) compared with SHFD. Hepatic triacylglycerol (TG) level was significantly lower in PHFD than the SHFD (26% lower). PNO consumption upregulated hepatic ACADL mRNA levels. The hepatic PPARG mRNA level was lower in the PC than in the SC. Expression of the sirtuin (SIRT) 3 protein in white adipose tissue was down-regulated in the SHFD and restored in the PHFD to the level in the lean control mice. SIRT 3 was reported to be upregulated under conditions of caloric restriction (CR) and plays a role in regulating mitochondrial function. PNO consumption resulted in lower body fat and hepatic TG accumulation in HFD-induced obesity, which seemed to be associated with the CR-mimetic response.
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PMID:Korean Pine Nut Oil Attenuated Hepatic Triacylglycerol Accumulation in High-Fat Diet-Induced Obese Mice. 2680 79

We previously showed that the mitochondrial fatty acid oxidation enzyme long-chain acyl-CoA dehydrogenase (LCAD) is expressed in alveolar type II pneumocytes and that LCAD-/- mice have altered breathing mechanics and surfactant defects. Here, we hypothesized that LCAD-/- mice would be susceptible to influenza infection. Indeed, LCAD-/- mice demonstrated increased mortality following infection with 2009 pandemic influenza (A/CA/07/09). However, the mortality was not due to increased lung injury, as inflammatory cell counts, viral titers, and histology scores all showed non-significant trends toward milder injury in LCAD-/- mice. To confirm this, LCAD-/- were infected with a second, mouse-adapted H1N1 virus (A/PR/8/34), to which they responded with significantly less lung injury. While both strains become increasingly hypoglycemic over the first week post-infection, LCAD-/- mice lose body weight more rapidly than wild-type mice. Surprisingly, while acutely fasted LCAD-/- mice develop hepatic steatosis, influenza-infected LCAD-/- mice do not. They do, however, become more hypothermic than wild-type mice and demonstrate increased blood lactate values. We conclude that LCAD-/- mice succumb to influenza from bioenergetic starvation, likely due to increased reliance upon glucose for energy.
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PMID:Increased mortality from influenza infection in long-chain acyl-CoA dehydrogenase knockout mice. 2945 21


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