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 pl...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 bloodβ-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.展开更多
Importance:Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase deficiency is a rare and underdiagnosed disorder with fewer than 30 patients reported worldwide.The application of whole-exome sequencing in p...Importance:Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase deficiency is a rare and underdiagnosed disorder with fewer than 30 patients reported worldwide.The application of whole-exome sequencing in patients could improve our understanding of this disorder.Objective:To identify the genetic causes and evaluate the phenotype of mitochondrial HMG-CoA synthase deficiency in a pediatric patient with uncommon features that included ketosis and elevated lactate and ammonia.Methods:The proband was referred to the pediatric intensive care unit of Beijing Children's Hospital and selected for molecular testing with whole-exome sequencing.Her parents and sibling also underwent sequencing for segregation information.Results:We identified two novel mutations (c.1347_1351 delAGCCT/p.Ala450Profs*7 and c.1201G>T/ p.Glu401*) in the HMG-CoA synthase-2 gene (HMGCS2,NM_005518.3) in the proband and her brother.Both variants were classified as pathogenic variants according to the American College of Medical Genetics and Genomics/ Association for Molecular Pathology guidelines.Metabolic acidosis in the proband was corrected with continuous renal replacement therapy and she left hospital after 21 days of treatment.Interpretation:Our results extend the genotypic and phenotypic spectrum of HMGCS2 mutation in mitochondrial HMG-CoA synthase deficiency patients and serve as a reminder for physicians to consider mitochondrial HMG-CoA synthase deficiency in newborns and children with coma and hypoketotic hypoglycemia after fasting.展开更多
Adverse nutritional conditions during the perinatal stage are related to early menopause in adulthood;however,the underlying mechanism is still unclear.Herein,we revealed that colostrum-activated ketone body elevation...Adverse nutritional conditions during the perinatal stage are related to early menopause in adulthood;however,the underlying mechanism is still unclear.Herein,we revealed that colostrum-activated ketone body elevation during the postnatal stage regulated primordial follicle reservoir size and then affected ovarian ageing.We found that the expression of the ketogenesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(Hmgcs2)was largely enhanced during primordial follicle pool formation after birth and might be activated in the ovaries by colostrum.Reactive oxygen species(ROS)elevation in the ovaries leads to follicle apoptosis to deplete damaged follicles,while Hmgcs2 deficiency enhances follicle apoptosis and thus decreases the size of the primordial follicle pool and leads to premature ovarian ageing(POA),which might be related to the activation of cellular endogenous antioxidant system.All these defects could be rescued by ketone body administration,which suppressed ROS-activated follicle apoptosis.Our results suggest that the internal metabolic homeostasis of newborn mice is critical for the primordial reservoir and that any intrauterine and perinatal undernutrition could result in POA.展开更多
文摘目的探索3-羟甲基戊二酰辅酶A合酶2(3-hydroxy-3-methylglytaryl-CoA synthetase 2,HMGCS2)在膀胱癌中的表达水平及其与患者临床病理特征的相关性。方法利用GEO数据库筛选肌层浸润性膀胱癌与非肌层浸润性膀胱癌中有显著差异性表达的基因,GEPIA数据库对筛选的公共差异表达基因进行生存分析;Metascape数据库对HMGCS2及其相关基因进行功能富集分析;免疫组化染色检测临床手术切除膀胱癌样本中HMGCS2的蛋白表达情况,卡方检验分析其与患者临床病理特征的关系,Cox回归分析验证其预后效能。结果GEO数据库的转录组数据显示,与非肌层浸润性膀胱癌相比,HMGCS2在肌层浸润性膀胱癌中显著低表达(7.42±2.51 vs 9.38±2.78,P<0.05);GEPIA数据库的生存分析显示,高表达HMGCS2的膀胱癌患者预后较好(总体生存期:风险比HR=0.6,P=0.028;疾病无进展生存期:HR=0.59,P=0.036);KEGG、GO功能富集分析表明,HMGCS2可能参与细胞的脂肪代谢、细胞凋亡及铂类耐药,并涉及mTOR通路的信号转导;卡方检验显示HMGCS2的表达与T分期(P<0.001)、组织学分级(P=0.006)、患者存活状态(P<0.001)及患者疾病无进展状态(P<0.001)显著相关;单因素Cox回归分析显示,HMGCS2与患者的总体生存率及疾病无进展生存率显著相关(总体生存期:HR=0.104,P<0.001;疾病无进展生存期:HR=0.155,P<0.001);多因素Cox回归分析显示,HMGCS2是评估患者预后风险的独立预测因子(总体生存期:HR=0.181,P<0.001;疾病无进展生存期:HR=0.312,P<0.001)。结论HMGCS2在肌层浸润性膀胱癌中低表达,低表达的HMGCS2与患者的不良预后密切相关。
基金supported by the National Key Research and Development Program of China(No.2018YFA0800603)a project(No.19ZR1439000)of the Shanghai Association for Science and Technology to Jianping Ye.
文摘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 bloodβ-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.
文摘Importance:Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase deficiency is a rare and underdiagnosed disorder with fewer than 30 patients reported worldwide.The application of whole-exome sequencing in patients could improve our understanding of this disorder.Objective:To identify the genetic causes and evaluate the phenotype of mitochondrial HMG-CoA synthase deficiency in a pediatric patient with uncommon features that included ketosis and elevated lactate and ammonia.Methods:The proband was referred to the pediatric intensive care unit of Beijing Children's Hospital and selected for molecular testing with whole-exome sequencing.Her parents and sibling also underwent sequencing for segregation information.Results:We identified two novel mutations (c.1347_1351 delAGCCT/p.Ala450Profs*7 and c.1201G>T/ p.Glu401*) in the HMG-CoA synthase-2 gene (HMGCS2,NM_005518.3) in the proband and her brother.Both variants were classified as pathogenic variants according to the American College of Medical Genetics and Genomics/ Association for Molecular Pathology guidelines.Metabolic acidosis in the proband was corrected with continuous renal replacement therapy and she left hospital after 21 days of treatment.Interpretation:Our results extend the genotypic and phenotypic spectrum of HMGCS2 mutation in mitochondrial HMG-CoA synthase deficiency patients and serve as a reminder for physicians to consider mitochondrial HMG-CoA synthase deficiency in newborns and children with coma and hypoketotic hypoglycemia after fasting.
基金supported by the National Key Research and Development Program of China(2018YFC1004703).
文摘Adverse nutritional conditions during the perinatal stage are related to early menopause in adulthood;however,the underlying mechanism is still unclear.Herein,we revealed that colostrum-activated ketone body elevation during the postnatal stage regulated primordial follicle reservoir size and then affected ovarian ageing.We found that the expression of the ketogenesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(Hmgcs2)was largely enhanced during primordial follicle pool formation after birth and might be activated in the ovaries by colostrum.Reactive oxygen species(ROS)elevation in the ovaries leads to follicle apoptosis to deplete damaged follicles,while Hmgcs2 deficiency enhances follicle apoptosis and thus decreases the size of the primordial follicle pool and leads to premature ovarian ageing(POA),which might be related to the activation of cellular endogenous antioxidant system.All these defects could be rescued by ketone body administration,which suppressed ROS-activated follicle apoptosis.Our results suggest that the internal metabolic homeostasis of newborn mice is critical for the primordial reservoir and that any intrauterine and perinatal undernutrition could result in POA.
