The Experts below are selected from a list of 6846 Experts worldwide ranked by ideXlab platform
Xinxin Ding - One of the best experts on this subject based on the ideXlab platform.
-
Hepatic Gene Expression Changes in Mouse Models with Liver-specific Deletion or Global Suppression of the NADPH-Cytochrome P450 Reductase Gene MECHANISTIC IMPLICATIONS FOR THE REGULATION OF MICROSOMAL CYTOCHROME P450 AND THE FATTY LIVER PHENOTYPE
The Journal of biological chemistry, 2005Co-Authors: Yan Weng, Concetta Dirusso, Andrew A. Reilly, Paul N. Black, Xinxin DingAbstract:NADPH-cytochrome P450 reductase (CPR) is an essential component for the function of many enzymes, including microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. In liver-Cpr-null (with liver-specific Cpr deletion) and Cpr-low (with reduced CPR expression in all organs examined) mouse models, a reduced serum cholesterol level and an induction of hepatic P450s were observed, whereas hepatomegaly and fatty liver were only observed in the liver-Cpr-null model. Our goal was to identify hepatic gene expression changes related to these phenotypes. Cpr-lox mice (with a floxed Cpr gene and normal CPR expression) were used as the control. Through microarray analysis, we identified many genes that were differentially expressed among the three groups of mice. We also recognized the 12 gene ontology terms that contained the most significantly changed gene expression in at least one of the two mouse models. We further uncovered potential mechanisms, such as an increased activation of constitutive androstane receptor and a decreased activation of peroxisomal proliferator-activated receptor-alpha by precursors of cholesterol biosynthesis, that underlie common changes (e.g. induction of multiple P450s and suppression of genes for fatty acid metabolism) in response to CPR loss in the two mouse models. Additionally, we observed model-specific gene expression changes, such as the induction of a fatty-acid translocase (Cd36 antigen) and the suppression of Carnitine O-Palmitoyltransferase 1 (Cpt1a) and acyl-CoA synthetase long chain family member 1 (Acsl1), that are potentially responsible for the severe hepatic lipidosis and an altered fatty acid profile observed in liver-Cpr-null mice.
Stefano Didonato - One of the best experts on this subject based on the ideXlab platform.
-
molecular characterization of inherited Carnitine palmitoyltransferase ii deficiency
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Franco Taroni, Gaetano Finocchiaro, Elisabetta Verderio, Stefania Fiorucci, Patrizia Cavadini, G Uziel, Eleonora Lamantea, Cinzia Gellera, Stefano DidonatoAbstract:Abstract Deficiency of Carnitine palmitoyltransferase II (CPTase II; palmitoyl-CoA:L-Carnitine O-Palmitoyltransferase, EC 2.3.1.21) is a clinically heterogeneous autosomal recessive disorder of energy metabolism. We studied the molecular basis of CPTase II deficiency in an early-onset patient presenting with hypoketotic hypoglycemia and cardiomyopathy. cDNA and genomic DNA analysis demonstrated that the patient was homozygous for a mutant CPTase II allele (termed ICV), which carried three missense mutations: a G-1203----A transition, predicting a Val-368----Ile substitution (V368I); a C-1992----T transition, predicting an Arg-631----Cys substitution (R631C); and an A-2040----G transition, predicting a Met-647----Val substitution (M647V). Genomic DNA analysis of family members showed that the mutations cosegregated with the disease in the family. However, screening of 59 healthy controls demonstrated that both the V368I and M647V mutations are sequence polymorphisms with allele frequencies of 0.5 and 0.25, respectively. By contrast, the R631C substitution was not detected in 22 normal individuals or in 12 of 14 CPTase II-deficient patients with the adult muscular form. Notably, 2 adult CPTase II-deficient patients were heterozygous for the ICV allele, thus suggesting compound heterozygosity for this and a different mutant allele. The consequences of the three mutations on enzyme activity were investigated by expressing normal and mutated CPTase II cDNAs in COS cells. The R631C substitution drastically depressed the catalytic activity of CPTase II, thus confirming that this is the crucial mutation. Interestingly, the V368I and M647V substitutions, which did not affect enzyme activity alone, exacerbated the effects of the R631C substitution. Biochemical characterization of mutant CPTase II in patient's cells showed that the mutations are associated with (i) severe reduction of Vmax (approximately 90%), (ii) normal apparent Km values, and (iii) decreased protein stability.
Yan Weng - One of the best experts on this subject based on the ideXlab platform.
-
Hepatic Gene Expression Changes in Mouse Models with Liver-specific Deletion or Global Suppression of the NADPH-Cytochrome P450 Reductase Gene MECHANISTIC IMPLICATIONS FOR THE REGULATION OF MICROSOMAL CYTOCHROME P450 AND THE FATTY LIVER PHENOTYPE
The Journal of biological chemistry, 2005Co-Authors: Yan Weng, Concetta Dirusso, Andrew A. Reilly, Paul N. Black, Xinxin DingAbstract:NADPH-cytochrome P450 reductase (CPR) is an essential component for the function of many enzymes, including microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. In liver-Cpr-null (with liver-specific Cpr deletion) and Cpr-low (with reduced CPR expression in all organs examined) mouse models, a reduced serum cholesterol level and an induction of hepatic P450s were observed, whereas hepatomegaly and fatty liver were only observed in the liver-Cpr-null model. Our goal was to identify hepatic gene expression changes related to these phenotypes. Cpr-lox mice (with a floxed Cpr gene and normal CPR expression) were used as the control. Through microarray analysis, we identified many genes that were differentially expressed among the three groups of mice. We also recognized the 12 gene ontology terms that contained the most significantly changed gene expression in at least one of the two mouse models. We further uncovered potential mechanisms, such as an increased activation of constitutive androstane receptor and a decreased activation of peroxisomal proliferator-activated receptor-alpha by precursors of cholesterol biosynthesis, that underlie common changes (e.g. induction of multiple P450s and suppression of genes for fatty acid metabolism) in response to CPR loss in the two mouse models. Additionally, we observed model-specific gene expression changes, such as the induction of a fatty-acid translocase (Cd36 antigen) and the suppression of Carnitine O-Palmitoyltransferase 1 (Cpt1a) and acyl-CoA synthetase long chain family member 1 (Acsl1), that are potentially responsible for the severe hepatic lipidosis and an altered fatty acid profile observed in liver-Cpr-null mice.
Franco Taroni - One of the best experts on this subject based on the ideXlab platform.
-
molecular characterization of inherited Carnitine palmitoyltransferase ii deficiency
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Franco Taroni, Gaetano Finocchiaro, Elisabetta Verderio, Stefania Fiorucci, Patrizia Cavadini, G Uziel, Eleonora Lamantea, Cinzia Gellera, Stefano DidonatoAbstract:Abstract Deficiency of Carnitine palmitoyltransferase II (CPTase II; palmitoyl-CoA:L-Carnitine O-Palmitoyltransferase, EC 2.3.1.21) is a clinically heterogeneous autosomal recessive disorder of energy metabolism. We studied the molecular basis of CPTase II deficiency in an early-onset patient presenting with hypoketotic hypoglycemia and cardiomyopathy. cDNA and genomic DNA analysis demonstrated that the patient was homozygous for a mutant CPTase II allele (termed ICV), which carried three missense mutations: a G-1203----A transition, predicting a Val-368----Ile substitution (V368I); a C-1992----T transition, predicting an Arg-631----Cys substitution (R631C); and an A-2040----G transition, predicting a Met-647----Val substitution (M647V). Genomic DNA analysis of family members showed that the mutations cosegregated with the disease in the family. However, screening of 59 healthy controls demonstrated that both the V368I and M647V mutations are sequence polymorphisms with allele frequencies of 0.5 and 0.25, respectively. By contrast, the R631C substitution was not detected in 22 normal individuals or in 12 of 14 CPTase II-deficient patients with the adult muscular form. Notably, 2 adult CPTase II-deficient patients were heterozygous for the ICV allele, thus suggesting compound heterozygosity for this and a different mutant allele. The consequences of the three mutations on enzyme activity were investigated by expressing normal and mutated CPTase II cDNAs in COS cells. The R631C substitution drastically depressed the catalytic activity of CPTase II, thus confirming that this is the crucial mutation. Interestingly, the V368I and M647V substitutions, which did not affect enzyme activity alone, exacerbated the effects of the R631C substitution. Biochemical characterization of mutant CPTase II in patient's cells showed that the mutations are associated with (i) severe reduction of Vmax (approximately 90%), (ii) normal apparent Km values, and (iii) decreased protein stability.
Francis P Kuhajda - One of the best experts on this subject based on the ideXlab platform.
-
c75 increases peripheral energy utilization and fatty acid oxidation in diet induced obesity
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Jagan N Thupari, Leslie E Landree, Gabriele V Ronnett, Francis P KuhajdaAbstract:C75, a known inhibitor of fatty acid synthase is postulated to cause significant weight loss through decreased hypothalamic neuropeptide Y (NPY) production. Peripherally, C75, an α-methylene-γ-butyrolactone, reduces adipose tissue and fatty liver, despite high levels of malonyl-CoA. To investigate this paradox, we studied the effect of C75 on fatty acid oxidation and energy production in diet-induced obese (DIO) mice and cellular models. Whole-animal calorimetry showed that C75-treated DIO mice had a 50% greater weight loss, and a 32.9% increased production of energy because of fatty acid oxidation, compared with paired-fed controls. Etomoxir, an inhibitor of Carnitine O-Palmitoyltransferase-1 (CPT-1), reversed the increased energy expenditure in DIO mice by inhibiting fatty acid oxidation. C75 treatment of rodent adipocytes and hepatocytes and human breast cancer cells increased fatty acid oxidation and ATP levels by increasing CPT-1 activity, even in the presence of elevated concentrations of malonyl-CoA. Studies in human cancer cells showed that C75 competed with malonyl-CoA, as measured by CPT-1 activity assays. Thus, C75 acts both centrally to reduce food intake and peripherally to increase fatty acid oxidation, leading to rapid and profound weight loss, loss of adipose mass, and resolution of fatty liver. The pharmacological stimulation of CPT-1 activity is a novel finding. The dual action of the C75 class of compounds as fatty acid synthase inhibitors and CPT-1 agonists has therapeutic implications in the treatment of obesity and type II diabetes.