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)

There are now nine inherited diseases that have been identified in the pathway of mitochondrial fatty acid oxidation, including LCAD, MCAD, SCAD, and HMG-CoA lyase deficiencies, two forms each of CPT and MAD deficiencies and an incompletely characterized disorder of primary carnitine deficiency. The varied range of clinical manifestations in this new group of diseases should attract the attention not only of general pediatricians (coma, hypoglycemia) but also of pediatric subspecialists in neurology (myopathy), cardiology (cardiomyopathy), and gastroenterology (fatty liver), as well as genetics and metabolism. The presenting features of the genetic defects in fatty acid oxidation fit well with the concept that fatty acid oxidation plays a major role in energy production during prolonged fasting and in working cardiac and skeletal muscle. Life-threatening episodes of coma and hypoglycemia induced by fasting are a common presenting feature in most of the fatty acid oxidation disorders (MCAD, LCAD, and HMG-CoA lyase deficiencies, the infantile form of CPT deficiency, the mild form of MAD deficiency, and in some cases of primary carnitine deficiency). The hypoglycemia in these disorders is most easily explained by the inability of affected patients to use fatty acids as a fuel as a substitute for glucose. It should be stressed, however, that the coma in these disorders may occur from direct toxic effects of fatty acids or fatty acid intermediates before plasma glucose concentrations reach hypoglycemic levels. Severe disturbances of muscle function are a feature in several of the disorders; hypertrophic cardiomyopathy and chronic skeletal muscle weakness occur in both the mild and severe forms of MAD deficiency, in primary carnitine deficiency, and in some patients with LCAD deficiency. In contrast, patients with the adult form of CPT deficiency have normal muscle strength but are prone to episodes of painful rhabdomyolysis induced by prolonged exercise. These manifestations presumably reflect the requirement of working cardiac and skeletal muscle for energy supplied from fatty acid oxidation. In two of the disorders, SCAD deficiency and the severe form of MAD deficiency, chronic CNS toxicity is a dominant feature. The severe effects on the brain in these two disorders may reflect the fact that short-chain fatty acids more readily cross the blood-brain barrier than longer-chain fatty acids.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:New genetic defects in mitochondrial fatty acid oxidation and carnitine deficiency. 331 4

To assess whether genetic factor(s) determine liver triglyceride (TG) levels, a 10-mouse strain survey of liver TG contents was performed. Hepatic TG contents were highest in BALB/cByJ, medium in C57BL/6J, and lowest in SWR/J in both genders. Ninety and seventy-six percent of variance in hepatic TG in males and females, respectively, was due to strain (genetic) effects. To understand the physiological/biochemical basis for differences in hepatic TG among the three strains, studies were performed in males of the BALB/cByJ, C57BL/6J, and SWR/J strains. In vivo hepatic fatty acid (FA) synthesis rates and hepatic TG secretion rates ranked BALB/cByJ approximately C57BL/6J > SWR/J. Hepatic 1-(14)C-labeled palmitate oxidation rates and plasma beta-hydroxybutyrate concentrations ranked in reverse order: SWR/J > BALB/cByJ approximately C57BL/6J. After 14 h of fasting, plasma-free FA and hepatic TG contents rose most in BALB/cByJ and least in SWR/J. beta-Hydroxybutyrate concentrations rose least in BALB/cByJ and most in SWR/J. Adaptation to fasting was most effective in SWR/J and least in BALB/cByJ, perhaps because BALB/cByJ are known to be deficient in SCAD, a short-chain FA oxidizing enzyme. To assess the role of insulin action, glucose tolerance test (GTT) was performed. GTT-glucose levels ranked C57BL/6J > BALB/cByJ approximately SWR/J. Thus strain-dependent (genetic) factors play a major role in setting hepatic TG levels in mice. Processes such as FA production and hepatic export in VLDL on the one hand and FA oxidation on the other, explain some of the strain-related differences in hepatic TG contents. Additional factor(s) in the development of fatty liver in BALB/cByJ remain to be demonstrated.
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PMID:Hepatic triglyceride contents are genetically determined in mice: results of a strain survey. 1559 Nov 60

Recombinant adeno-associated viral vectors pseudotyped with serotype 5 and 8 capsids (AAV5 and AAV8) have been shown to be efficient gene transfer reagents for the liver. We have produced AAV5 and AAV8 vectors that express mouse short-chain acyl-CoA dehydrogenase (mSCAD) cDNA under the transcriptional control of the cytomegalovirus-chicken beta-actin hybrid promoter. We hypothesized that these vectors would produce sufficient hepatocyte transduction (after administration via the portal vein) and thus sufficient SCAD enzyme to correct the phenotype observed in the SCAD-deficient (BALB/cByJ) mouse, which includes elevated blood butyrylcarnitine and hepatic steatosis. Ten weeks after portal vein injection into 8-week-old mice, AAV8-treated livers contained acyl-CoA dehydrogenase activity (14.3 mU/mg) toward butyryl-CoA, compared with 7.6 mU/mg in mice that received phosphate-buffered saline. Immunohistochemistry showed expression of mSCAD within rAAV8-mSCAD-transduced hepatocytes, as seen by light microscopy. A significant reduction of circulating butyrylcarnitine was seen in AAV5-mSCAD- and AAV8-mSCAD-injected mice. Magnetic resonance spectroscopy of fasted mice demonstrated a significant reduction in relative lipid content within the livers of AAV8-mSCAD-treated mice. These results demonstrate biochemical correction of SCAD deficiency after AAV8-mediated SCAD gene delivery.
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PMID:Biochemical correction of short-chain acyl-coenzyme A dehydrogenase deficiency after portal vein injection of rAAV8-SCAD. 1850 Sep 42