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Fausto G Hegardt - One of the best experts on this subject based on the ideXlab platform.
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impaired Ketogenesis is a major mechanism for disturbed hepatic fatty acid metabolism in rats with long term cholestasis and after relief of biliary obstruction
Journal of Hepatology, 2002Co-Authors: Corinne Lang, Fausto G Hegardt, Dolors Serra, Simona Berardi, Markus Schafer, L Krahenbuhl, Stephan KrahenbuhlAbstract:Abstract Background/Aims : Rats with long-term cholestasis have reduced ketosis of unknown origin. Methods : Fatty acid metabolism was studied in starved rats with biliary obstruction for 4 weeks (bile duct ligated rats=BDL rats), and 3, 7, 14, 28 and 84 days after reversal of biliary obstruction by Roux-en-Y anastomosis (RY rats), and in sham-operated control rats. Results : BDL rats had reduced β -hydroxybutyrate concentrations in plasma (0.25±0.10 vs. 0.75±0.20mmol/l) and liver (2.57±0.20 vs. 4.63±0.61 μ mol/g) which increased after restoring bile flow. Hepatic expression and activity of carnitine palmitoyltransferase I (CPT I) or CPT II were unaffected or decreased in BDL rats, respectively, and increased after restoring bile flow. Oxidative metabolism of different substrates by isolated liver mitochondria and activation of palmitate were reduced in BDL rats and recovered 7–14 days after restoring bile flow. Ketogenesis was decreased in mitochondria from BDL rats and recovered 3 months after restoring bile flow. Both mRNA and protein expression of hydroxymethylglutaryl-coenzyme A synthase (HMG-CoA synthase), the rate-limiting enzyme of Ketogenesis, was reduced in livers of BDL rats and increased after reversing biliary obstruction. Conclusions : In BDL rats, impairment of hepatic fatty acid metabolism is multifactorial. After reversing biliary obstruction, reduced activity of HMG-CoA synthase is the major factor.
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Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in Ketogenesis
Biochemical Journal, 1999Co-Authors: Fausto G HegardtAbstract:Cytosolic and mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthases were first recognized as different chemical entities in 1975, when they were purified and characterized by Lane's group. Since then, the two enzymes have been studied extensively, one as a control site of the cholesterol biosynthetic pathway and the other as an important control site of Ketogenesis. This review describes some key developments over the last 25 years that have led to our current understanding of the physiology of mitochondrial HMG-CoA synthase in the HMG-CoA pathway and in Ketogenesis in the liver and small intestine of suckling animals. The enzyme is regulated by two systems: succinylation and desuccinylation in the short term, and transcriptional regulation in the long term. Both control mechanisms are influenced by nutritional and hormonal factors, which explains the incidence of Ketogenesis in diabetes and starvation, during intense lipolysis, and in the foetal-neonatal and suckling-weaning transitions. The DNA-binding properties of the peroxisome-proliferator-activated receptor and other transcription factors on the nuclear-receptor-responsive element of the mitochondrial HMG-CoA synthase promoter have revealed how Ketogenesis can be regulated by fatty acids. Finally, the expression of mitochondrial HMG-CoA synthase in the gonads and the correction of auxotrophy for mevalonate in cells deficient in cytosolic HMG-CoA synthase suggest that the mitochondrial enzyme may play a role in cholesterogenesis in gonadal and other tissues.
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The effect of dexamethasone treatment on the expression of the regulatory genes of Ketogenesis in intestine and liver of suckling rats.
Molecular and Cellular Biochemistry, 1998Co-Authors: Gladys Arias, Fausto G Hegardt, Guillermina Asins, Dolors SerraAbstract:The influence of the injection of dexamethasone on Ketogenesis in 12 day old suckling rats was studied in intestine and liver by determining mRNA levels and enzyme activity of the two genes responsible for regulation of Ketogenesis: carnitine palmitoyl transferase I (CPT 1) and mitochondrial HMG-CoA synthase. Dexamethasone produced a 2 fold increase in mRNA and activity of CPT I in intestine, but led to a decrease in mitt HMG-CoA synthase. In liver the mRNA levels and activity of both CPT I and mitt HMG-CoA synthase decreased. Comparison of these values with the ketogenic rate of both tissues following dexamethasone treatment suggests that mitt HMG-CoA synthase could be the main gene responsible for the regulation of Ketogenesis in suckling rats. The changes produced in serum ketone bodies by dexamethasone, with a profile that is more similar to the ketogenic rate in the liver than that in the intestine, indicate that liver contributes more to ketone body synthesis in suckling rats. Two day treatment with dexamethasone produced no change in mRNA or activity levels for CPT I in liver or intestine. While mRNA levels for mitt HMG-CoA synthase changed little, the enzyme activity is decreased in both tissues.
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the effect of fasting refeeding and insulin treatment on the expression of the regulatory genes of Ketogenesis in intestine and liver of suckling rats
Archives of Biochemistry and Biophysics, 1997Co-Authors: Gladys Arias, Fausto G Hegardt, Guillermina Asins, Dolors SerraAbstract:Abstract The influence of fasting/refeeding and insulin treatment on Ketogenesis in 12-day-old suckling rats was studied in intestine and liver by determining mRNA levels and enzyme activity of the two genes responsible for regulation of Ketogenesis: carnitine palmitoyl transferase I (CPT I) and mitochondrial HMG-CoA synthase. Fasting produced hardly any change in mRNA or activity of CPT I in intestine, but led to a decrease in mitochondrial (mit.) HMG-CoA synthase. In liver, while mRNA levels and activity for CPT I increased, neither parameter was changed in HMG-CoA synthase. The comparison of these values with the ketogenic rate of both tissues under the fasting/refeeding treatment shows that HMG-CoA synthase could be the main gene responsible for regulation of Ketogenesis in suckling rats. The small changes produced in serum ketone bodies in fasting/refeeding, with a profile similar to the ketogenic rate of the liver, indicate that liver contributes most to ketone body synthesis in suckling rats under these experimental conditions. Short-term insulin treatment produced increases in mRNA levels and activity in CPT I in intestine, but it also decreased both parameters in mit. HMG-CoA synthase. In liver, graphs of mRNA and activity were nearly identical in both genes. There was a marked decrease in mRNA levels and activity, resembling those values observed in adult rats. As in fasting/refeeding, the ketogenic rate correlated better to mit. HMG-CoA synthase than CPT I, and liver was the main organ regulating Ketogenesis after insulin treatment. Serum ketone body concentrations were decreased by insulin but recovered after the second hour. Long-term insulin treatment had little effect on the mRNA levels for CPT I or mit. HMG-CoA synthase, but both the expressed and total activities of mit. HMG-CoA synthase were reduced by half in both intestine and liver. The ketogenic rate of both organs was decreased to 40% by long-term insulin treatment. The different effects of refeeding and insulin treatment on the expression of both genes, on the ketogenic rate, and on ketone body concentrations are discussed.
Yuka Aoyama - One of the best experts on this subject based on the ideXlab platform.
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deficiency of 3 hydroxybutyrate dehydrogenase bdh1 in mice causes low ketone body levels and fatty liver during fasting
Journal of Inherited Metabolic Disease, 2020Co-Authors: Hiroki Otsuka, Yuka Aoyama, Takeshi Kimura, Mina Nakama, Elsayed Abdelkreem, Hideki Matsumoto, Hidenori Ohnishi, Hideo SasaiAbstract:: D-3-hydroxy-n-butyrate dehydrogenase (BDH1; EC 1.1.1.30), encoded by BDH1, catalyzes the reversible reduction of acetoacetate (AcAc) to 3-hydroxybutyrate (3HB). BDH1 is the last enzyme of hepatic Ketogenesis and the first enzyme of ketolysis. The hereditary deficiency of BDH1 has not yet been described in humans. To define the features of BDH1 deficiency in a mammalian model, we generated Bdh1-deficient mice (Bdh1 KO mice). Under normal housing conditions, with unrestricted access to food, Bdh1 KO mice showed normal growth, appearance, behavior and fertility. In contrast, fasting produced marked differences from controls. Although Bdh1 KO survive fasting for at least 48 hours, blood 3HB levels remained very low in Bdh1 KO mice, and despite AcAc levels moderately higher than in controls, total ketone body (TKB) levels in Bdh1 KO mice were significantly lower than in wild-type (WT) mice after 16, 24 and 48 hours fasting. Hepatic fat content at 24 hours of fasting was greater in Bdh1 KO than in WT mice. Systemic BDH1 deficiency was well tolerated under normal fed conditions but manifested during fasting with a marked increase in AcAc/3HB ratio and hepatic steatosis, indicating the importance of Ketogenesis for lipid energy balance in the liver. This article is protected by copyright. All rights reserved.
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deficiency of 3 hydroxybutyrate dehydrogenase bdh1 in mice causes low ketone body levels and fatty liver during fasting
Journal of Inherited Metabolic Disease, 2020Co-Authors: Hiroki Otsuka, Yuka Aoyama, Takeshi Kimura, Mina Nakama, Elsayed Abdelkreem, Hideki Matsumoto, Yasuhiko Ago, Hidenori OhnishiAbstract:d-3-Hydroxy-n-butyrate dehydrogenase (BDH1; EC 1.1.1.30), encoded by BDH1, catalyzes the reversible reduction of acetoacetate (AcAc) to 3-hydroxybutyrate (3HB). BDH1 is the last enzyme of hepatic Ketogenesis and the first enzyme of ketolysis. The hereditary deficiency of BDH1 has not yet been described in humans. To define the features of BDH1 deficiency in a mammalian model, we generated Bdh1-deficient mice (Bdh1 KO mice). Under normal housing conditions, with unrestricted access to food, Bdh1 KO mice showed normal growth, appearance, behavior, and fertility. In contrast, fasting produced marked differences from controls. Although Bdh1 KO mice survive fasting for at least 48 hours, blood 3HB levels remained very low in Bdh1 KO mice, and despite AcAc levels moderately higher than in controls, total ketone body levels in Bdh1 KO mice were significantly lower than in wild-type (WT) mice after 16, 24, and 48 hours fasting. Hepatic fat content at 24 hours of fasting was greater in Bdh1 KO than in WT mice. Systemic BDH1 deficiency was well tolerated under normal fed conditions but manifested during fasting with a marked increase in AcAc/3HB ratio and hepatic steatosis, indicating the importance of Ketogenesis for lipid energy balance in the liver.
Elsayed Abdelkreem - One of the best experts on this subject based on the ideXlab platform.
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deficiency of 3 hydroxybutyrate dehydrogenase bdh1 in mice causes low ketone body levels and fatty liver during fasting
Journal of Inherited Metabolic Disease, 2020Co-Authors: Hiroki Otsuka, Yuka Aoyama, Takeshi Kimura, Mina Nakama, Elsayed Abdelkreem, Hideki Matsumoto, Hidenori Ohnishi, Hideo SasaiAbstract:: D-3-hydroxy-n-butyrate dehydrogenase (BDH1; EC 1.1.1.30), encoded by BDH1, catalyzes the reversible reduction of acetoacetate (AcAc) to 3-hydroxybutyrate (3HB). BDH1 is the last enzyme of hepatic Ketogenesis and the first enzyme of ketolysis. The hereditary deficiency of BDH1 has not yet been described in humans. To define the features of BDH1 deficiency in a mammalian model, we generated Bdh1-deficient mice (Bdh1 KO mice). Under normal housing conditions, with unrestricted access to food, Bdh1 KO mice showed normal growth, appearance, behavior and fertility. In contrast, fasting produced marked differences from controls. Although Bdh1 KO survive fasting for at least 48 hours, blood 3HB levels remained very low in Bdh1 KO mice, and despite AcAc levels moderately higher than in controls, total ketone body (TKB) levels in Bdh1 KO mice were significantly lower than in wild-type (WT) mice after 16, 24 and 48 hours fasting. Hepatic fat content at 24 hours of fasting was greater in Bdh1 KO than in WT mice. Systemic BDH1 deficiency was well tolerated under normal fed conditions but manifested during fasting with a marked increase in AcAc/3HB ratio and hepatic steatosis, indicating the importance of Ketogenesis for lipid energy balance in the liver. This article is protected by copyright. All rights reserved.
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deficiency of 3 hydroxybutyrate dehydrogenase bdh1 in mice causes low ketone body levels and fatty liver during fasting
Journal of Inherited Metabolic Disease, 2020Co-Authors: Hiroki Otsuka, Yuka Aoyama, Takeshi Kimura, Mina Nakama, Elsayed Abdelkreem, Hideki Matsumoto, Yasuhiko Ago, Hidenori OhnishiAbstract:d-3-Hydroxy-n-butyrate dehydrogenase (BDH1; EC 1.1.1.30), encoded by BDH1, catalyzes the reversible reduction of acetoacetate (AcAc) to 3-hydroxybutyrate (3HB). BDH1 is the last enzyme of hepatic Ketogenesis and the first enzyme of ketolysis. The hereditary deficiency of BDH1 has not yet been described in humans. To define the features of BDH1 deficiency in a mammalian model, we generated Bdh1-deficient mice (Bdh1 KO mice). Under normal housing conditions, with unrestricted access to food, Bdh1 KO mice showed normal growth, appearance, behavior, and fertility. In contrast, fasting produced marked differences from controls. Although Bdh1 KO mice survive fasting for at least 48 hours, blood 3HB levels remained very low in Bdh1 KO mice, and despite AcAc levels moderately higher than in controls, total ketone body levels in Bdh1 KO mice were significantly lower than in wild-type (WT) mice after 16, 24, and 48 hours fasting. Hepatic fat content at 24 hours of fasting was greater in Bdh1 KO than in WT mice. Systemic BDH1 deficiency was well tolerated under normal fed conditions but manifested during fasting with a marked increase in AcAc/3HB ratio and hepatic steatosis, indicating the importance of Ketogenesis for lipid energy balance in the liver.
Jörn Oliver Sass - One of the best experts on this subject based on the ideXlab platform.
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mimicking ketonuria in the Ketogenesis defect 3 hydroxy 3 methylglutaryl coenzyme a lyase deficiency an artefact in the analysis of urinary organic acids
Journal of Inborn Errors of Metabolism and Screening, 2018Co-Authors: Jörn Oliver Sass, Malkanthi Fernando, Sidney BehringerAbstract:3-Hydroxy-3-methylglutaryl-coenzyme A lyase (HMGCL, HMGCL) deficiency is a rare inborn error of Ketogenesis. Even if the ketogenic enzyme is fully disrupted, an elevated signal for the ketone body ...
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Inborn errors of Ketogenesis and ketone body utilization
Journal of Inherited Metabolic Disease, 2012Co-Authors: Jörn Oliver SassAbstract:Ketone bodies acetoacetate and 3-hydroxy- n -butyric acid are metabolites derived from fatty acids and ketogenic amino acids such as leucine. They are mainly produced in the liver via reactions catalyzed by the ketogenic enzymes mitochondrial 3-hydroxy-3-methylglutary-coenzyme A synthase and 3-hydroxy-3-methylglutary-coenzyme A lyase. After prolonged starvation, ketone bodies can provide up to two-thirds of the brain’s energy requirements. The rate-limiting enzyme of ketone body utilization (ketolysis) is succinyl-coenzyme A:3-oxoacid coenzyme A transferase. The subsequent step of ketolysis is catalyzed by 2-methylactoacetyl-coenzyme A thiolase, which is also involved in isoleucine catabolism. Inborn errors of metabolism affecting those four enzymes are presented and discussed in the context of differential diagnoses. While disorders of Ketogenesis can present with hypoketotic hypoglycemia, inborn errors of ketolysis are characterized by metabolic decompensations with ketoacidosis. If those diseases are considered early and appropriate treatment is initiated without delay, patients with inborn errors of ketone body metabolism often have a good clinical outcome.
Shawn C Burgess - One of the best experts on this subject based on the ideXlab platform.
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progressive adaptation of hepatic Ketogenesis in mice fed a high fat diet
American Journal of Physiology-endocrinology and Metabolism, 2010Co-Authors: Nishanth E Sunny, Matthew J Potthoff, Santhosh Satapati, Shawn C Burgess, Roshi Mehdibeigi, Chandra Springrobinson, Joao A G Duarte, Jeffrey D BrowningAbstract:Hepatic Ketogenesis provides a vital systemic fuel during fasting because ketone bodies are oxidized by most peripheral tissues and, unlike glucose, can be synthesized from fatty acids via mitochondrial β-oxidation. Since dysfunctional mitochondrial fat oxidation may be a cofactor in insulin-resistant tissue, the objective of this study was to determine whether diet-induced insulin resistance in mice results in impaired in vivo hepatic fat oxidation secondary to defects in Ketogenesis. Ketone turnover (μmol/min) in the conscious and unrestrained mouse was responsive to induction and diminution of hepatic fat oxidation, as indicated by an eightfold rise during the fed (0.50+/−0.1)-to-fasted (3.8+/−0.2) transition and a dramatic blunting of fasting ketone turnover in PPARα−/− mice (1.0+/−0.1). C57BL/6 mice made obese and insulin resistant by high-fat feeding for 8 wk had normal expression of genes that regulate hepatic fat oxidation, whereas 16 wk on the diet induced expression of these genes and stimulated the function of hepatic mitochondrial fat oxidation, as indicated by a 40% induction of fasting Ketogenesis and a twofold rise in short-chain acylcarnitines. Together, these findings indicate a progressive adaptation of hepatic Ketogenesis during high-fat feeding, resulting in increased hepatic fat oxidation after 16 wk of a high-fat diet. We conclude that mitochondrial fat oxidation is stimulated rather than impaired during the initiation of hepatic insulin resistance in mice.
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fgf21 induces pgc 1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Matthew J Potthoff, Takeshi Inagaki, Santhosh Satapati, Xunshan Ding, Regina Goetz, Moosa Mohammadi, Brian N Finck, David J Mangelsdorf, Steven A Kliewer, Shawn C BurgessAbstract:The liver plays a crucial role in mobilizing energy during nutritional deprivation. During the early stages of fasting, hepatic glycogenolysis is a primary energy source. As fasting progresses and glycogen stores are depleted, hepatic gluconeogenesis and Ketogenesis become major energy sources. Here, we show that fibroblast growth factor 21 (FGF21), a hormone that is induced in liver by fasting, induces hepatic expression of peroxisome proliferator-activated receptor γ coactivator protein-1α (PGC-1α), a key transcriptional regulator of energy homeostasis, and causes corresponding increases in fatty acid oxidation, tricarboxylic acid cycle flux, and gluconeogenesis without increasing glycogenolysis. Mice lacking FGF21 fail to fully induce PGC-1α expression in response to a prolonged fast and have impaired gluconeogenesis and Ketogenesis. These results reveal an unexpected relationship between FGF21 and PGC-1α and demonstrate an important role for FGF21 in coordinately regulating carbohydrate and fatty acid metabolism during the progression from fasting to starvation.
