Sodium butyrate activates HMGCS2 to promote ketone body production through SIRT5-mediated desuccinylation / 医学前沿

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.

One case of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency and literature review / 中国基层医药

Objective:To summarize the clinical phenotype and genetic characteristics of one child patient with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (mHS) caused by HMGCS2 gene mutation. Methods:One child patient with mHS who received treatment in Chongqing University Three Gorges Hospital on April 10, 2020 was included in this patient. The child was hospitalized due to cough, shortness of breath and deep coma. After admission, gas chromatography-mass spectrometry of the blood and urine samples and high-throughput whole genome sequencing were performed. The pedigree of the child with gene mutation was analyzed. The child was diagnosed with mHS. Related publications published by June, 2020 were searched in Wanfang database, Chinese Journal Full Text Database, PubMed and HGMD databases using search terms "mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency", "HMGCS2" "mHS deficiency". Forty-three papers addressing mHS deficiency were retrieved. The clinical phenotype and genotypes of the child with HMGCS2 mutation were summarized. Results:As of June 2020, there were 44 children with mHS deficiency, including the child reported in this study. These children consisted of 15 males, 11 females and 18 unknown genders. Among these children, 29 were aged 0-24 months, 4 were aged > 24 months, 6 had no symptoms, and 5 were of unknown age of disease onset. The first symptoms of most children were fever, cough, acute gastroenteritis, and coma. Twenty-seven children had hypoglycemia, 21 children had metabolic acidosis, 15 children developed hepatomegaly, 16 children had increased FFA/D-3-HB, and 10 children were tested 4-hydroxy-6-methyl-2-pyrone positive. The child included in this study had hepatomegaly, elevated alanine aminotransferase and metabolic acidosis. Gas chromatography-mass spectrometry results showed that a variety of metabolites were increased. Tandem mass spectrometry results showed that C40 level was elevated, and long-chain carnitine contents were increased. High-throughput whole genome sequencing results revealed that there were two heterozygous mutations in HMGCS2 gene, (NM_0055) c.559+1G > A; c. 758 T > C heterozygous mutation. Sanger sequencing and parental origin analysis showed that the mutations in this child were from parents. The two gene mutations in this child were new mutations, which have not been reported in China and countries outside China. According to the criteria and guidelines for interpretation of ACMG sequence variation, the variation was determined to be pathogenic. Conclusion:When a child has hypoketotic hypoglycemia and/or metabolic acidosis, increased FFA/D-3-HB and acetylcarnitine levels, mHS deficiency should be considered. HMGCS2 gene examination can help diagnose mHS deficiency.