1.Potential implications of ketone body metabolism changes and ketogenic therapy in the treatment of heart failure.
Qiong WANG ; Siyu YAN ; Shuyu KUANG ; Mengmeng ZHOU ; Chunling JIANG
Chinese Critical Care Medicine 2023;35(7):769-772
Heart failure (HF) has become a major challenge in the treatment of global cardiovascular diseases. Great progress has been made in the drug treatment of HF, however, rehospitalization rate and mortality of patients with HF are still high. Hence, there is an urgent need to explore new treatment strategy and new underlying pathogenic mechanisms. In recent years, some researchers have suggested that regulation of ketone body metabolism may become a potentially promising therapeutic approach for HF. Some studies showed that the oxidative utilization of fatty acids and glucose was decreased in the failing heart, accompanied by the increase of ketone body oxidative metabolism. The enhancement of ketone body metabolism in HF is a compensatory change during HF. The failing heart preferentially uses ketone body oxidation to provide energy, which helps to improve the body's cardiac function. This review will discuss the potential significance of ketone body metabolism in the treatment of HF from three aspects: normal myocardial ketone body metabolism, the change of ketone body metabolism in HF, the effect of ketogenic therapy on HF and its treatment.
Humans
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Heart Failure/metabolism*
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Myocardium/metabolism*
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Ketone Bodies/metabolism*
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Cardiovascular Diseases
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Fatty Acids/metabolism*
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Energy Metabolism
3.Sodium butyrate activates HMGCS2 to promote ketone body production through SIRT5-mediated desuccinylation.
Yanhong XU ; Xiaotong YE ; Yang ZHOU ; Xinyu CAO ; Shiqiao PENG ; Yue PENG ; Xiaoying ZHANG ; Yili SUN ; Haowen JIANG ; Wenying HUANG ; Hongkai LIAN ; Jiajun YANG ; Jia LI ; Jianping YE
Frontiers of Medicine 2023;17(2):339-351
Ketone bodies have beneficial metabolic activities, and the induction of plasma ketone bodies is a health promotion strategy. Dietary supplementation of sodium butyrate (SB) is an effective approach in the induction of plasma ketone bodies. However, the cellular and molecular mechanisms are unknown. In this study, SB was found to enhance the catalytic activity of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting enzyme in ketogenesis, to promote ketone body production in hepatocytes. SB administrated by gavage or intraperitoneal injection significantly induced blood ß-hydroxybutyrate (BHB) in mice. BHB production was induced in the primary hepatocytes by SB. Protein succinylation was altered by SB in the liver tissues with down-regulation in 58 proteins and up-regulation in 26 proteins in the proteomics analysis. However, the alteration was mostly observed in mitochondrial proteins with 41% down- and 65% up-regulation, respectively. Succinylation status of HMGCS2 protein was altered by a reduction at two sites (K221 and K358) without a change in the protein level. The SB effect was significantly reduced by a SIRT5 inhibitor and in Sirt5-KO mice. The data suggests that SB activated HMGCS2 through SIRT5-mediated desuccinylation for ketone body production by the liver. The effect was not associated with an elevation in NAD+/NADH ratio according to our metabolomics analysis. The data provide a novel molecular mechanism for SB activity in the induction of ketone body production.
Mice
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Animals
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Butyric Acid/metabolism*
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Ketone Bodies/metabolism*
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Liver/metabolism*
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Hydroxybutyrates/metabolism*
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Down-Regulation
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Sirtuins/metabolism*
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Hydroxymethylglutaryl-CoA Synthase/metabolism*
4.A Rare Cause of Life-Threatening Ketoacidosis: Novel Compound Heterozygous OXCT1 Mutations Causing Succinyl-CoA:3-Ketoacid CoA Transferase Deficiency
Young A KIM ; Seong Heon KIM ; Chong Kun CHEON ; Yoo Mi KIM
Yonsei Medical Journal 2019;60(3):308-311
Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is a rare inborn error of ketone body utilization, characterized by episodic or permanent ketosis. SCOT deficiency is caused by mutations in the OXCT1 gene, which is mapped to 5p13 and consists of 17 exons. A 12-month-old girl presented with severe ketoacidosis and was treated with continuous renal replacement therapy. She had two previously unrecognized mild-form episodes of ketoacidosis followed by febrile illness. While high levels of ketone bodies were found in her blood and urine, other laboratory investigations, including serum glucose, were unremarkable. We identified novel compound heterozygous mutations in OXCT1:c.1118T>G (p.Ile373Ser) and a large deletion ranging from exon 8 to 16 through targeted exome sequencing and microarray analysis. This is the first Korean case of SCOT deficiency caused by novel mutations in OXCT1, resulting in life-threatening ketoacidosis. In patients with unexplained episodic ketosis, or high anion gap metabolic acidosis in infancy, an inherited disorder in ketone body metabolism should be suspected.
Acid-Base Equilibrium
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Acidosis
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Blood Glucose
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Exome
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Exons
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Female
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Humans
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Infant
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Ketone Bodies
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Ketosis
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Metabolism
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Microarray Analysis
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Renal Replacement Therapy
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Transferases
5.Effects of interleukin-1beta on nitric oxide production and ATP synthesis in rat surplus hepatocytes after partial hepatectomy.
Wei TU ; Song HU ; Man ZHAO ; Wen-zhi QU ; Zuo-fu YU ; Wen-yu SUN
Acta Academiae Medicinae Sinicae 2007;29(5):631-637
OBJECTIVETo detect the nitric oxide (NO) production and energy metabolism of the interleukin (IL)-1beta-treated residual hepatocytes from rats after partial hepatectomy.
METHODSForty rats were equally divided into partial hepatectomies (PH) group and control group. In the control group the rats were otherwise matched and underwent sham surgeries. The residual hepatocytes were separated by the collagenase perfusion method. The hepatocytes were cultured with cytokines such as IL-1beta. The production of NO in the two groups were measured with Griess reagent method, the production of inducible nitric oxide synthase (iNOS) protein detected with Western blot, the content of the nucleotide in the hepatocytes detected with high-performance liquid chromatography, and the content of the ketone body in the hepatocytes of the two groups determined with the enzymatic method. Afterwards the ketone body ratio (acetoacetate/beta-hydroxy butyrate, KBR) was calculated.
RESULTSThe production of NO in the PH group was twice as much as that in the Sham group. IL-1beta decreased the content of ATP and the KBR in the hepatocytes of both groups, and the decrease magni tude in the PH group was significantly larger than that in the Sham group. After the injection of L-arginine, the production of NO in the hepatocytes in the PH group increased, and the level of ATP and KBR decreased. N(G)-methyl-L-arginine (L-NMMA), the inhibitor of NO synthase, inhibited the production of NO and reversed the decrease of ATP and KBR.
CONCLUSIONAfter partial hepatectomy, increased NO production in the hepatocytes after the treatment of interleukin-1beta may disturb the function of mitochondria by inhibiting the synthesis of ATP.
Adenosine Triphosphate ; biosynthesis ; Animals ; Arginine ; pharmacology ; Cells, Cultured ; Hepatectomy ; Hepatocytes ; metabolism ; Interleukin-1beta ; pharmacology ; Ketone Bodies ; biosynthesis ; Nitric Oxide ; antagonists & inhibitors ; biosynthesis ; Nitric Oxide Synthase ; antagonists & inhibitors ; Rats ; omega-N-Methylarginine ; pharmacology
6.Effect of ketogenic diet on hippocampus mossy fiber sprouting and GluR5 expression in kainic acid induced rat model.
Xiang-ping XU ; Ruo-peng SUN ; Rui-feng JIN
Chinese Medical Journal 2006;119(22):1925-1929
3-Hydroxybutyric Acid
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blood
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Animals
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Dietary Carbohydrates
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administration & dosage
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Dietary Fats
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administration & dosage
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Dietary Proteins
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administration & dosage
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Disease Models, Animal
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Epilepsy
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diet therapy
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metabolism
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pathology
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Hippocampus
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metabolism
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Kainic Acid
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Ketone Bodies
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metabolism
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Male
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Mossy Fibers, Hippocampal
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pathology
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RNA, Messenger
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analysis
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Rats
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Rats, Sprague-Dawley
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Receptors, Kainic Acid
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analysis
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genetics