Serine metabolism is reportedly involved in immune cell functions, but whether and how serine metabolism regulates macrophage polarization remain largely unknown. Here, we show that suppressing serine metabolism, eith...Serine metabolism is reportedly involved in immune cell functions, but whether and how serine metabolism regulates macrophage polarization remain largely unknown. Here, we show that suppressing serine metabolism, either by inhibiting the activity of the key enzyme phosphoglycerate dehydrogenase in the serine biosynthesis pathway or by exogenous serine and glycine restriction, robustly enhances the polarization of interferon-γ-activated macrophages (M(IFN-γ)) but suppresses that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, serine metabolism deficiency increases the expression of IGF1 by reducing the promoter abundance of S-adenosyl methionine-dependent histone H3 lysine 27 trimethylation. IGF1 then activates the p38-dependent JAK–STAT1 axis to promote M(IFN-γ) polarization and suppress STAT6-mediated M(IL-4) activation. This study reveals a new mechanism by which serine metabolism orchestrates macrophage polarization and suggests the manipulation of serine metabolism as a therapeutic strategy for macrophage-mediated immune diseases.展开更多
The objective of the study is to evaluate and compare the effects of betaine or glycine on carcass trait,meat quality and lipid metabolism of finishing Huan Jiang mini-pigs.Betaine called trimethylglycine is a methyl ...The objective of the study is to evaluate and compare the effects of betaine or glycine on carcass trait,meat quality and lipid metabolism of finishing Huan Jiang mini-pigs.Betaine called trimethylglycine is a methyl derivative of glycine,but few researches were conducted to compare the impact of dietary betaine and glycine on pigs.One hundred and forty-four Huan Jiang mini-pigs(body weight=10.55±0.15 kg;70 d)were randomly divided to 3 treatment groups(basal diet,glycine or betaine).Results indicated that dietary betaine increased the average daily gain(ADG)and final weight(P<0.05).Dietary glycine or betaine markedly reduced average backfat thickness(P<0.05)and heightened lean percentage(P<0.01)compared to the control group.Moreover,in comparison with the control group,betaine significantly improved the redness(a*)and tenderness(shear force)of the longissimus dorsi(LD)muscle(P<0.05),whereas glycine only raised the value of a*of the LD muscle(P<0.05).These results showed that diet supplemented with 0.25%betaine and equimolar amounts of glycine could regulate cascass trait and meat quality of finishing Huan Jiang mini-pigs,and the effect of betaine was superior to that of glycine.展开更多
L-Serine plays a critical role as a building block for cell growth, and thus it is difficult to achieve the direct fermentation of L-serine from glucose. In this study, Corynebacterium glutamicum ATCC 13032 was engine...L-Serine plays a critical role as a building block for cell growth, and thus it is difficult to achieve the direct fermentation of L-serine from glucose. In this study, Corynebacterium glutamicum ATCC 13032 was engineered de novo by blocking and attenuating the conversion of L-serine to pyruvate and glycine, releasing the feedback inhibition by L-serine to 3-phosphoglycerate dehydrogenase (PGDH), in combination with the co-expression of 3-phosphoglycerate kinase (PGK) and feedback-resistant PGDH (PGDHr). The resulting strain, SER-8, exhibited a lower specific growth rate and significant differences in L-serine levels from Phase I to Phase V as determined for fed-batch fermentation. The intracellular L-serine pool reached (14.22±1.41) μmol gCDM 1, which was higher than glycine pool, contrary to fermentation with the wild-type strain. Furthermore, metabolic flux analysis demonstrated that the over-expression of PGK directed the flux of the pentose phosphate pathway (PPP) towards the glycolysis pathway (EMP), and the expression of PGDHr improved the L-serine biosynthesis pathway. In addition, the flux from L-serine to glycine dropped by 24%, indicating that the deletion of the activator GlyR resulted in down-regulation of serine hydroxymethyltransferase (SHMT) expression. Taken together, our findings imply that L-serine pool management is fundamental for sustaining the viability of C. glutamicum, and improvement of C1 units generation by introducing the glycine cleavage system (GCV) to degrade the excessive glycine is a promising target for L-serine production in C. glutamicum.展开更多
鞘脂(sphingolipids)是生物细胞中最主要的膜脂之一,同时也作为信号分子介导细胞生长、增殖、迁移及死亡等重要的生理反应,异常鞘脂代谢经常与心血管疾病、糖尿病、癌症、神经变性病以及自身免疫性疾病等相关。丝氨酸棕榈酰转移酶(serin...鞘脂(sphingolipids)是生物细胞中最主要的膜脂之一,同时也作为信号分子介导细胞生长、增殖、迁移及死亡等重要的生理反应,异常鞘脂代谢经常与心血管疾病、糖尿病、癌症、神经变性病以及自身免疫性疾病等相关。丝氨酸棕榈酰转移酶(serine palmitoyltransferase,SPT)及其复合物是鞘脂从头合成途径的起始酶和关键酶,催化L-丝氨酸与棕榈酰辅酶A缩合形成3-酮二氢鞘氨醇,之后再经过一系列反应生成神经酰胺和其它重要的鞘脂,在鞘脂代谢和稳态调节方面发挥重要作用。本文基于国内外对SPT的研究,综述了SPT的构型、活性位点、底物结合位点等关键的结构信息,尤其近2年的研究发现,SPT是一种组成极其复杂的酶,各个亚基之间存在错综复杂的相互作用和高度调控。SPT具有重要的生物学功能,包括参与胚胎发育、调节内环境稳态、诱导细胞凋亡和参与机体免疫调节等。SPT还可以通过调节酶活性影响鞘脂代谢,进而影响血管疾病和肿瘤的发生发展,并有潜力成为肿瘤诊断和治疗的关键分子。此外,SPT突变体与神经变性病密切相关,本文着重介绍了遗传性感觉与自主神经病变1型(hereditary sensory and autonomic neuropathy type 1,HSAN1)和早发性肌萎缩侧索硬化症(amyotrophic lateral sclerosis,ALS)的病变机制及最新的治疗手段,为深入了解该酶及其参与的鞘脂代谢提供理论参考,同时也为今后的功能研究和药物研发奠定基础。展开更多
基金This research was supported by grants from the Tianjin Municipal Natural Science Foundation of China(20JCYBJC00220,QY)from the National Natural Science Foundation of China:81672710(QY),81872239(QY),82073051(TW),81874055(TW),and 81902900(LS).
文摘Serine metabolism is reportedly involved in immune cell functions, but whether and how serine metabolism regulates macrophage polarization remain largely unknown. Here, we show that suppressing serine metabolism, either by inhibiting the activity of the key enzyme phosphoglycerate dehydrogenase in the serine biosynthesis pathway or by exogenous serine and glycine restriction, robustly enhances the polarization of interferon-γ-activated macrophages (M(IFN-γ)) but suppresses that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, serine metabolism deficiency increases the expression of IGF1 by reducing the promoter abundance of S-adenosyl methionine-dependent histone H3 lysine 27 trimethylation. IGF1 then activates the p38-dependent JAK–STAT1 axis to promote M(IFN-γ) polarization and suppress STAT6-mediated M(IL-4) activation. This study reveals a new mechanism by which serine metabolism orchestrates macrophage polarization and suggests the manipulation of serine metabolism as a therapeutic strategy for macrophage-mediated immune diseases.
基金the National Key R&D Program(2018YFD0500405)the National Nature Science Foundation of China(31972582,U19A2037)+7 种基金the Changsha Natural Science Funds for Distinguished Young Scholar(kq2009020)Special funds for the construction of innovative provinces in Hunan Project(2019NK2193,2019RS3022)Open Fund of Key Laboratory of Agro-ecological Processes in Subtropical Region,Chinese Academy of Sciences(ISA2020203)the‘Strategic Priority Research Program’of the Chinese Academy of Sciences(XDA24030204)the Science and technology projects of Changsha City(kq1801059)Hunan Province Key Laboratory of Animal Nutritional Physiology and Metabolic Process(2018TP1031)the General Program of National Natural Science Foundation of China(31872985)the Earmarked Fund for China Agriculture Research System(CARS-35).
文摘The objective of the study is to evaluate and compare the effects of betaine or glycine on carcass trait,meat quality and lipid metabolism of finishing Huan Jiang mini-pigs.Betaine called trimethylglycine is a methyl derivative of glycine,but few researches were conducted to compare the impact of dietary betaine and glycine on pigs.One hundred and forty-four Huan Jiang mini-pigs(body weight=10.55±0.15 kg;70 d)were randomly divided to 3 treatment groups(basal diet,glycine or betaine).Results indicated that dietary betaine increased the average daily gain(ADG)and final weight(P<0.05).Dietary glycine or betaine markedly reduced average backfat thickness(P<0.05)and heightened lean percentage(P<0.01)compared to the control group.Moreover,in comparison with the control group,betaine significantly improved the redness(a*)and tenderness(shear force)of the longissimus dorsi(LD)muscle(P<0.05),whereas glycine only raised the value of a*of the LD muscle(P<0.05).These results showed that diet supplemented with 0.25%betaine and equimolar amounts of glycine could regulate cascass trait and meat quality of finishing Huan Jiang mini-pigs,and the effect of betaine was superior to that of glycine.
基金supported by grants from Ministry of Science and Technology of China (Grant Nos.2008ZX09401-05 and 2010ZX09401-403)the National Natural Science Foundation of China (Grant No. 31100074)Chinese Academy of Sciences (Grant No. XBXA-2011-009)
文摘L-Serine plays a critical role as a building block for cell growth, and thus it is difficult to achieve the direct fermentation of L-serine from glucose. In this study, Corynebacterium glutamicum ATCC 13032 was engineered de novo by blocking and attenuating the conversion of L-serine to pyruvate and glycine, releasing the feedback inhibition by L-serine to 3-phosphoglycerate dehydrogenase (PGDH), in combination with the co-expression of 3-phosphoglycerate kinase (PGK) and feedback-resistant PGDH (PGDHr). The resulting strain, SER-8, exhibited a lower specific growth rate and significant differences in L-serine levels from Phase I to Phase V as determined for fed-batch fermentation. The intracellular L-serine pool reached (14.22±1.41) μmol gCDM 1, which was higher than glycine pool, contrary to fermentation with the wild-type strain. Furthermore, metabolic flux analysis demonstrated that the over-expression of PGK directed the flux of the pentose phosphate pathway (PPP) towards the glycolysis pathway (EMP), and the expression of PGDHr improved the L-serine biosynthesis pathway. In addition, the flux from L-serine to glycine dropped by 24%, indicating that the deletion of the activator GlyR resulted in down-regulation of serine hydroxymethyltransferase (SHMT) expression. Taken together, our findings imply that L-serine pool management is fundamental for sustaining the viability of C. glutamicum, and improvement of C1 units generation by introducing the glycine cleavage system (GCV) to degrade the excessive glycine is a promising target for L-serine production in C. glutamicum.
文摘鞘脂(sphingolipids)是生物细胞中最主要的膜脂之一,同时也作为信号分子介导细胞生长、增殖、迁移及死亡等重要的生理反应,异常鞘脂代谢经常与心血管疾病、糖尿病、癌症、神经变性病以及自身免疫性疾病等相关。丝氨酸棕榈酰转移酶(serine palmitoyltransferase,SPT)及其复合物是鞘脂从头合成途径的起始酶和关键酶,催化L-丝氨酸与棕榈酰辅酶A缩合形成3-酮二氢鞘氨醇,之后再经过一系列反应生成神经酰胺和其它重要的鞘脂,在鞘脂代谢和稳态调节方面发挥重要作用。本文基于国内外对SPT的研究,综述了SPT的构型、活性位点、底物结合位点等关键的结构信息,尤其近2年的研究发现,SPT是一种组成极其复杂的酶,各个亚基之间存在错综复杂的相互作用和高度调控。SPT具有重要的生物学功能,包括参与胚胎发育、调节内环境稳态、诱导细胞凋亡和参与机体免疫调节等。SPT还可以通过调节酶活性影响鞘脂代谢,进而影响血管疾病和肿瘤的发生发展,并有潜力成为肿瘤诊断和治疗的关键分子。此外,SPT突变体与神经变性病密切相关,本文着重介绍了遗传性感觉与自主神经病变1型(hereditary sensory and autonomic neuropathy type 1,HSAN1)和早发性肌萎缩侧索硬化症(amyotrophic lateral sclerosis,ALS)的病变机制及最新的治疗手段,为深入了解该酶及其参与的鞘脂代谢提供理论参考,同时也为今后的功能研究和药物研发奠定基础。
