BACKGROUND Multiple acyl-CoA dehydrogenase deficiency(MADD)is a disease of rare autosomal recessive disorder.There are three types of MADD.Type I is a neonatalonset form with congenital anomalies.Type II is a neonatal...BACKGROUND Multiple acyl-CoA dehydrogenase deficiency(MADD)is a disease of rare autosomal recessive disorder.There are three types of MADD.Type I is a neonatalonset form with congenital anomalies.Type II is a neonatal-onset form without congenital anomalies.Type III is considered to a milder form and usually responds to riboflavin.However,late-onset form could also be fatal and not responsive to treatments.CASE SUMMARY We report a severe case of a young man with onset type III MADD induced by drugs and strenuous exercise characterized by rhabdomyolysis and liver dysfunction.Urine analysis indicated 12 out of 70 kinds of organic acids like glutaric acid-2 were detected.Serum analysis in genetic metabolic diseases revealed 24 out of 43 tested items were abnormal,revealing the elevation of several acylcarnitines and the reduction of carnitine in the patient.By next generation sequencing technology for gene sequencing related to fatty acid oxidation and carnitine cycle defects,a rare ETFDH gene variant was identified:NM_004453:4:C.1448C>T(p.Pro483 Leu).The patient was diagnosed with lateonset GAII.He was not responsive to riboflavin and progressively worsened into multiple organ failure that finally led to death.CONCLUSION Type III MADD can also be fatal and not responsive to treatments.展开更多
The intestinal mucosa is characterized by a high complexity in terms of structure and functions and allows for a controlled demarcation towards the gut lumen.On the one hand it is responsible for pulping and selective...The intestinal mucosa is characterized by a high complexity in terms of structure and functions and allows for a controlled demarcation towards the gut lumen.On the one hand it is responsible for pulping and selective absorption of alimentary substances ensuring the immunological tolerance,on the other hand it prevents the penetration of micro-organisms as well as bacterial outgrowth.The continuous regeneration of surface epithelia along the crypt-villus-axis in the small intestine is crucial to assuring these various functions.The core phenomena of intestinal epithelia regeneration comprise cell proliferation,migration,differentiation,and apoptosis.These partly contrarily oriented processes are molecularly balanced through numerous interacting signaling pathways like Wnt/β-catenin,Notch and Hedgehog,and regulated by various modifying factors.One of these modifiers is acyl-CoA synthetase 5(ACSL5).It plays a key role in de novo lipid synthesis,fatty acid degradation and membrane modifications,and regulates several intestinal processes,primarily through different variants of protein lipidation,e.g.,palmitoylation.ACSL5 was shown to interact with proapoptotic molecules,and besides seems to inhibit proliferation along the crypt-villus-axis.Because of its proapoptotic and antiproliferative characteristics it could be of significant relevance for intestinal homeostasis,cellular disorder and tumor development.展开更多
BACKGROUND Multiple acyl-CoA dehydrogenase deficiency(MADD)is an uncommon autosomal recessive disorder of mitochondrial fatty acid beta-oxidation.Syncope is a transient loss of consciousness due to acute global cerebr...BACKGROUND Multiple acyl-CoA dehydrogenase deficiency(MADD)is an uncommon autosomal recessive disorder of mitochondrial fatty acid beta-oxidation.Syncope is a transient loss of consciousness due to acute global cerebral hypoperfusion.Late-onset MADD with syncope has not been reported previously.CASE SUMMARY We report a 17-year-old girl with exercise intolerance and muscle weakness.She felt palpitation and shortness of breath after short bouts of exercise.She also suffered from a transient loss of consciousness many times.Muscle biopsy showed lipid storage.Genetic mutation analysis indicated a compound heterozygous mutation c.250G>A(p.A84T)and c.872T>G(p.V291G)in the ETFDH gene.The results of Holter electrocardiogram monitoring showed supraventricular tachycardia when the patient experienced a loss of consciousness.After treatment with riboflavin and carnitine,muscle weakness and palpitation symptoms improved rapidly.No loss of consciousness occurred,and the Holter electrocardiogram monitoring was normal.CONCLUSION Late-onset MADD with supraventricular tachycardia can cause cardiac syncope.Carnitine and riboflavin supplement were beneficial for treating the late-onset MADD with cardiac syncope.Attention should be paid to the prevention of cardiac syncope when diagnosing late-onset MADD.展开更多
Background The association of rs1044925 polymorphism in the acyl- CoA:cholesterol acyltransferase-1(ACAT-1) gene and serum lipid profiles is not well known in different ethnic groups.Bai Ku Yao is a special subgroup o...Background The association of rs1044925 polymorphism in the acyl- CoA:cholesterol acyltransferase-1(ACAT-1) gene and serum lipid profiles is not well known in different ethnic groups.Bai Ku Yao is a special subgroup of the Yao minority in China.The present study was carried out to clarify the association of rs1044925 polymorphism in the ACAT-1 gene and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Methods A total of 626 subjects of Bai Ku Yao and 624 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples.Genotyping of rs 1044925 polymorphism in the ACAT-1 gene was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis,and then confirmed by direct sequencing.Results The levels of serum total cholesterol(TC),high-density lipoprotein cholesterol (HDL-C),apolipoprotein(Apo) AI and ApoB were lower in Bai Ku Yao than in Han(P【0.01 for all).The frequency of A and C alleles was 79.0%and 21.0%in Bai Ku Yao,and 87.3%and 12.7%in Han(P【0.001);respectively.The frequency of AA,AC and CC genotypes was 63.2%,31.4% and 5.2%in Bai Ku Yao,and 75.6%,23.2%and 1.1%in Han(P【0.001);respectively.The levels of TC,LDL-C and ApoB in Bai Ku Yao but not in Han were different between the AA and AC/CC genotypes in females but not in males (P【0.05 for all).The C allele carriers had lower serum TC, LDL-C and ApoB levels as compared with the C allele non-carriers. The levels of TC,LDL-C and ApoB in Bai Ku Yao but not in Han were correlated with genotypes in females but not in males(P【0.05 for all).Serum lipid parameters were also correlated with sex,age,body massindex,alcohol consumption, cigarette smoking,and blood pressure in both ethnic groups(P【0.05-0.001).Conclusions These results suggest that the polymorphism of rs1044925 associated with female serum TC,LDL-C and ApoB levels in the Bai Ku Yao population.The C allele carriers had more favorable serum TC,LDL-C and ApoB levels than the C allele noncarriers. in the ACAT-1 gene is展开更多
Fatty acids are energy substrates and cell components which participate in regulating signal transduction,transcription factor activity and secretion of bioactive lipid mediators.The acyl-CoA synthetases(ACSs)family c...Fatty acids are energy substrates and cell components which participate in regulating signal transduction,transcription factor activity and secretion of bioactive lipid mediators.The acyl-CoA synthetases(ACSs)family containing 26 family members exhibits tissue-specific distribution,distinct fatty acid substrate preferences and diverse biological functions.Increasing evidence indicates that dysregulation of fatty acid metabolism in the liver-gut axis,designated as the bidirectional relationship between the gut,microbiome and liver,is closely associated with a range of human diseases including metabolic disorders,inflammatory disease and carcinoma in the gastrointestinal tract and liver.In this review,we depict the role of ACSs in fatty acid metabolism,possible molecular mechanisms through which they exert functions,and their involvement in hepatocellular and colorectal carcinoma,with particular attention paid to long-chain fatty acids and small-chain fatty acids.Additionally,the liver-gut communication and the liver and gut intersection with the microbiome as well as diseases related to microbiota imbalance in the liver-gut axis are addressed.Moreover,the development of potentially therapeutic small molecules,proteins and compounds targeting ACSs in cancer treatment is summarized.展开更多
AIM:To investigate whether human acyl-CoA synthetase 5(ACSL5) is sensitive to the ACSL inhibitor triacsin C.METHODS:The ACSL isoforms ACSL1 and ACSL5 from rat as well as human ACSL5 were cloned and recombinantly expre...AIM:To investigate whether human acyl-CoA synthetase 5(ACSL5) is sensitive to the ACSL inhibitor triacsin C.METHODS:The ACSL isoforms ACSL1 and ACSL5 from rat as well as human ACSL5 were cloned and recombinantly expressed as 6xHis-tagged enzymes.Ni 2+-affinity purified recombinant enzymes were assayed at pH 7.5 or pH 9.5 in the presence or absence of triacsin C.In addition,ACSL5 transfected CaCo2 cells and intestinal human mucosa were monitored.ACSL5 expression in cellular systems was verified using Western blot and immunofluorescence.The ACSL assay mix included TrisHCl(pH 7.4),ATP,CoA,EDTA,DTT,MgCl 2,[9,103 H] palmitic acid,and triton X-100.The 200 μL reaction was initiated with the addition of solubilized,purified recombinant proteins or cellular lysates.Reactions were terminated after 10,30 or 60 min of incubation with Doles medium.RESULTS:Expression of soluble recombinant ACSL proteins was found after incubation with isopropyl betaD-1-thiogalactopyranoside and after ultracentrifugation these were further purified to near homogeneity with Ni 2+-affinity chromatography.Triacsin C selectively and strongly inhibited recombinant human ACSL5 protein at pH 7.5 and pH 9.5,as well as recombinant rat ACSL1(sensitive control),but not recombinant rat ACSL5(insensitive control).The IC50 for human ACSL5 was about 10 μmol/L.The inhibitory triacsin C effect was similar for different incubation times(10,30 and 60 min) and was not modified by the N-or C-terminal location of the 6xHis-tag.In order to evaluate ACSL5 sensitivity to triacsin C in a cellular environment,stable human ACSL5 CaCo2 transfectants and mechanically dissected normal human intestinal mucosa with high physiological expression of ACSL5 were analyzed.In both models,ACSL5 peak activity was found at pH 7.5 and pH 9.5,corresponding to the properties of recombinant human ACSL5 protein.In the presence of triacsin C(25 μmol/L),total ACSL activity was dramatically diminished in human ACSL5 transfectants as well as in ACSL5-rich human intestinal mucosa.CONCLUSION:The data strongly indicate that human ACSL5 is sensitive to triacsin C and does not compensate for other triacsin C-sensitive ACSL isoforms.展开更多
Pseudo-neonatal adrenoleukodystrophy (P-NALD) is a neurodegenerative disorder caused by acyl-CoA oxidase 1 (ACOX1) deficiency with subsequent impairment of peroxisomal fatty acid β-oxidation, accumulation of very lon...Pseudo-neonatal adrenoleukodystrophy (P-NALD) is a neurodegenerative disorder caused by acyl-CoA oxidase 1 (ACOX1) deficiency with subsequent impairment of peroxisomal fatty acid β-oxidation, accumulation of very long chain fatty acids (VLCFAs) and strong reduction in peroxisome abundance. Increase in peroxisome number has been previously suggested to improve peroxisomal disorders, and in this perspective, the present work was aimed at exploring whether modulation of peroxisomes abundance could be achieved in P-NALD fibroblasts. Here we showed that treatment with the natural Argan oil induced peroxisome proliferation in P-NALD fibroblasts. This induction was independent on activations of both nuclear receptor PPARα and its coactivator PGC-1α. Lipopolysaccharides (LPS) treatment, which caused inflammation, induced also a peroxisome proliferation that, in contrast, was dependent on activations of PPARα and PGC-1α. By its ability to induce peroxisome proliferation, Argan oil is suggested to be of potential therapeutic use in patients with P-NALD.展开更多
Previous studies have reported upregulation of heme oxygenase-1 in different central nervous system injury models.Heme oxygenase-1 plays a critical anti-inflammatory role and is essential for regulating cellular redox...Previous studies have reported upregulation of heme oxygenase-1 in different central nervous system injury models.Heme oxygenase-1 plays a critical anti-inflammatory role and is essential for regulating cellular redox homeostasis.Metformin is a classic drug used to treat type 2 diabetes that can inhibit ferroptosis.Previous studies have shown that,when used to treat cardiovascular and digestive system diseases,metformin can also upregulate heme oxygenase-1 expression.Therefore,we hypothesized that heme oxygenase-1 plays a significant role in mediating the beneficial effects of metformin on neuronal ferroptosis after spinal cord injury.To test this,we first performed a bioinformatics analysis based on the GEO database and found that heme oxygenase-1 was upregulated in the lesion of rats with spinal cord injury.Next,we confirmed this finding in a rat model of T9 spinal cord compression injury that exhibited spinal cord nerve cell ferroptosis.Continuous intraperitoneal injection of metformin for 14 days was found to both upregulate heme oxygenase-1 expression and reduce neuronal ferroptosis in rats with spinal cord injury.Subsequently,we used a lentivirus vector to knock down heme oxygenase-1 expression in the spinal cord,and found that this significantly reduced the effect of metformin on ferroptosis after spinal cord injury.Taken together,these findings suggest that metformin inhibits neuronal ferroptosis after spinal cord injury,and that this effect is partially dependent on upregulation of heme oxygenase-1.展开更多
Background:Late-onset multiple acyl-coA dehydrogenase deficiency (MADD) is an autosomal recessive inherited metabolic disorder. It is still unclear about the muscle magnetic resonance image (MRI) pattern of the distal...Background:Late-onset multiple acyl-coA dehydrogenase deficiency (MADD) is an autosomal recessive inherited metabolic disorder. It is still unclear about the muscle magnetic resonance image (MRI) pattern of the distal lower limb pre- and post-treatment in patients with late-onset MADD. This study described the clinical and genetic findings in a cohort of patients with late-onset MADD, and aimed to characterize the MRI pattern of the lower limbs.Methods:Clinical data were retrospectively collected from clinic centers of Peking University People's Hospital between February 2014 and February 2018. Muscle biopsy, blood acylcarnitines, and urine organic acids profiles, and genetic analysis were conducted to establish the diagnosis of MADD in 25 patients. Muscle MRI of the thigh and leg were performed in all patients before treatment. Eight patients received MRI re-examinations after treatment.Results:All patients presented with muscle weakness or exercise intolerance associated with variants in the electron transfer flavoprotein dehydrogenase gene. Muscle MRI showed a sign of both edema-like change and fat infiltration selectively involving in the soleus (SO) but sparing of the gastrocnemius (GA) in the leg. Similar sign of selective involvement of the biceps femoris longus (BFL) but sparing of the semitendinosus (ST) was observed in the thigh. The sensitivity and specificity of the combination of either "SO+/GA-" sign or "BFL+/ST-" sign for the diagnosis of late-onset MADD were 80.0% and 83.5%, respectively. Logistic regression model supported the findings. The edema-like change in the SO and BFL muscles were quickly recovered at 1 month after treatment, and the clinical symptom was also relieved.Conclusions:This study expands the clinical and genetic spectrums of late-onset MADD. Muscle MRI shows a distinct pattern in the lower limb of patients with late-onset MADD. The dynamic change of edema-like change in the affected muscles might be a potential biomarker of treatment response.展开更多
Background:Very long chain acyl-CoA dehydrogenase deficiency(VLCADD)is an inherited metabolic disease caused by deleterious mutations in the ACADVL gene that encodes very long chain acyl-CoA dehydrogenase(VLCAD),and w...Background:Very long chain acyl-CoA dehydrogenase deficiency(VLCADD)is an inherited metabolic disease caused by deleterious mutations in the ACADVL gene that encodes very long chain acyl-CoA dehydrogenase(VLCAD),and which can present as cardiomyopathy in neonates,as hypoketotic hypoglycemia in infancy,and as myopathy in late-onset patients.Although many ACADVL mutations have been described,no prevalent mutations in the ACADVL gene have been associated with VLCADD.Herein,we report the clinical course of the disease and explore the genetic mutation spectrum in seven Chinese patients with VLCADD.Methods:Seven Chinese patients,from newborn to 17 years old,were included in this study.Tandem mass spectrometry was performed to screen for VLCAD defi ciency.All exons and fl anking introns of the ACADVL gene were analyzed using polymerase chain reaction and direct sequencing.Online analysis tools were used to predict the impact of novel mutations.Results:All cases had elevated serum levels of tetradecanoylcarnitine(C14:1)which is the characteristic biomarker for VLCADD.The phenotype of VLCADD is heterogeneous.Two patients were hospitalized for hypoactivity and hypoglycemia shortly after birth.Three patients showed hepatomegaly and hypoglycemia in infancy.The other two adolescent patients showed initial manifestations of exercise intolerance or rhabdomyolysis.Three of the patients died at the age of 6-8 months.Eleven different mutations in the ACADVL gene in the 7 patients were identified,including seven reported mutations(p.S22X,p.W427X,p.A213T,p.G222R,p.R450H,c.296-297delCA,c.1605+1G>T)and four novel mutations(p.S72F,p.Q100X,p.M437T,p.D466Y).The p.R450H and p.D466Y(14.28%,2/14 alleles)mutations were identifi ed in two alleles respectively.Conclusions:The clinical manifestations were heterogeneous and ACADVL gene mutations were heterozygous in the seven VLCADD Chinese patients.R450H may be a relatively common mutation in Asian populations.The genotype and phenotype had a certain correlation in our patients.展开更多
The pathogenesis of very-long-chain acyl-CoA dehydrogenase(VLCAD)deficiency is highly heterogeneous and still unclear.Additional novel variants have been recently detected in the population.The molecular and cellular ...The pathogenesis of very-long-chain acyl-CoA dehydrogenase(VLCAD)deficiency is highly heterogeneous and still unclear.Additional novel variants have been recently detected in the population.The molecular and cellular effects of these previously unreported variants are still poorly understood and require further characterization.To address this problem,we have evaluated the various functions and biochemical consequences of six novel missense variants that lead to mild VLCAD deficiency.Marked deficiencies in fatty acid oxidation(FAO)and other mitochondrial defects were observed in cells carrying one of these six variants(c.541 C>T,c.863 T>G,c.895 A>G,c.1238 T>C,c.1276 G>A,and c.1505 T>A),including reductions in mitochondrial respiratory-chain function and adenosine teriphosphate(ATP)production,and increased levels of mitochondrial reactive oxygen species(ROS).Intriguingly,higher apoptosis levels were found in cells carrying the mutant VLCAD under glucose-limited stress.Moreover,the stability of the mutant homodimer was disturbed,and major conformational changes in each mutant VLCAD structure were predicted by molecular dynamics(MD)simulation.The data presented here may provide valuable information for improving management of diagnosis and treatment of VLCAD deficiency and for a better understanding of the general molecular bases of disease variability.展开更多
文摘BACKGROUND Multiple acyl-CoA dehydrogenase deficiency(MADD)is a disease of rare autosomal recessive disorder.There are three types of MADD.Type I is a neonatalonset form with congenital anomalies.Type II is a neonatal-onset form without congenital anomalies.Type III is considered to a milder form and usually responds to riboflavin.However,late-onset form could also be fatal and not responsive to treatments.CASE SUMMARY We report a severe case of a young man with onset type III MADD induced by drugs and strenuous exercise characterized by rhabdomyolysis and liver dysfunction.Urine analysis indicated 12 out of 70 kinds of organic acids like glutaric acid-2 were detected.Serum analysis in genetic metabolic diseases revealed 24 out of 43 tested items were abnormal,revealing the elevation of several acylcarnitines and the reduction of carnitine in the patient.By next generation sequencing technology for gene sequencing related to fatty acid oxidation and carnitine cycle defects,a rare ETFDH gene variant was identified:NM_004453:4:C.1448C>T(p.Pro483 Leu).The patient was diagnosed with lateonset GAII.He was not responsive to riboflavin and progressively worsened into multiple organ failure that finally led to death.CONCLUSION Type III MADD can also be fatal and not responsive to treatments.
文摘The intestinal mucosa is characterized by a high complexity in terms of structure and functions and allows for a controlled demarcation towards the gut lumen.On the one hand it is responsible for pulping and selective absorption of alimentary substances ensuring the immunological tolerance,on the other hand it prevents the penetration of micro-organisms as well as bacterial outgrowth.The continuous regeneration of surface epithelia along the crypt-villus-axis in the small intestine is crucial to assuring these various functions.The core phenomena of intestinal epithelia regeneration comprise cell proliferation,migration,differentiation,and apoptosis.These partly contrarily oriented processes are molecularly balanced through numerous interacting signaling pathways like Wnt/β-catenin,Notch and Hedgehog,and regulated by various modifying factors.One of these modifiers is acyl-CoA synthetase 5(ACSL5).It plays a key role in de novo lipid synthesis,fatty acid degradation and membrane modifications,and regulates several intestinal processes,primarily through different variants of protein lipidation,e.g.,palmitoylation.ACSL5 was shown to interact with proapoptotic molecules,and besides seems to inhibit proliferation along the crypt-villus-axis.Because of its proapoptotic and antiproliferative characteristics it could be of significant relevance for intestinal homeostasis,cellular disorder and tumor development.
文摘BACKGROUND Multiple acyl-CoA dehydrogenase deficiency(MADD)is an uncommon autosomal recessive disorder of mitochondrial fatty acid beta-oxidation.Syncope is a transient loss of consciousness due to acute global cerebral hypoperfusion.Late-onset MADD with syncope has not been reported previously.CASE SUMMARY We report a 17-year-old girl with exercise intolerance and muscle weakness.She felt palpitation and shortness of breath after short bouts of exercise.She also suffered from a transient loss of consciousness many times.Muscle biopsy showed lipid storage.Genetic mutation analysis indicated a compound heterozygous mutation c.250G>A(p.A84T)and c.872T>G(p.V291G)in the ETFDH gene.The results of Holter electrocardiogram monitoring showed supraventricular tachycardia when the patient experienced a loss of consciousness.After treatment with riboflavin and carnitine,muscle weakness and palpitation symptoms improved rapidly.No loss of consciousness occurred,and the Holter electrocardiogram monitoring was normal.CONCLUSION Late-onset MADD with supraventricular tachycardia can cause cardiac syncope.Carnitine and riboflavin supplement were beneficial for treating the late-onset MADD with cardiac syncope.Attention should be paid to the prevention of cardiac syncope when diagnosing late-onset MADD.
文摘Background The association of rs1044925 polymorphism in the acyl- CoA:cholesterol acyltransferase-1(ACAT-1) gene and serum lipid profiles is not well known in different ethnic groups.Bai Ku Yao is a special subgroup of the Yao minority in China.The present study was carried out to clarify the association of rs1044925 polymorphism in the ACAT-1 gene and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Methods A total of 626 subjects of Bai Ku Yao and 624 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples.Genotyping of rs 1044925 polymorphism in the ACAT-1 gene was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis,and then confirmed by direct sequencing.Results The levels of serum total cholesterol(TC),high-density lipoprotein cholesterol (HDL-C),apolipoprotein(Apo) AI and ApoB were lower in Bai Ku Yao than in Han(P【0.01 for all).The frequency of A and C alleles was 79.0%and 21.0%in Bai Ku Yao,and 87.3%and 12.7%in Han(P【0.001);respectively.The frequency of AA,AC and CC genotypes was 63.2%,31.4% and 5.2%in Bai Ku Yao,and 75.6%,23.2%and 1.1%in Han(P【0.001);respectively.The levels of TC,LDL-C and ApoB in Bai Ku Yao but not in Han were different between the AA and AC/CC genotypes in females but not in males (P【0.05 for all).The C allele carriers had lower serum TC, LDL-C and ApoB levels as compared with the C allele non-carriers. The levels of TC,LDL-C and ApoB in Bai Ku Yao but not in Han were correlated with genotypes in females but not in males(P【0.05 for all).Serum lipid parameters were also correlated with sex,age,body massindex,alcohol consumption, cigarette smoking,and blood pressure in both ethnic groups(P【0.05-0.001).Conclusions These results suggest that the polymorphism of rs1044925 associated with female serum TC,LDL-C and ApoB levels in the Bai Ku Yao population.The C allele carriers had more favorable serum TC,LDL-C and ApoB levels than the C allele noncarriers. in the ACAT-1 gene is
基金Supported by the Interdisziplinäres Zentrum für Klinische Forschung(IZKF-MSP-06)of University Hospital Jena.
文摘Fatty acids are energy substrates and cell components which participate in regulating signal transduction,transcription factor activity and secretion of bioactive lipid mediators.The acyl-CoA synthetases(ACSs)family containing 26 family members exhibits tissue-specific distribution,distinct fatty acid substrate preferences and diverse biological functions.Increasing evidence indicates that dysregulation of fatty acid metabolism in the liver-gut axis,designated as the bidirectional relationship between the gut,microbiome and liver,is closely associated with a range of human diseases including metabolic disorders,inflammatory disease and carcinoma in the gastrointestinal tract and liver.In this review,we depict the role of ACSs in fatty acid metabolism,possible molecular mechanisms through which they exert functions,and their involvement in hepatocellular and colorectal carcinoma,with particular attention paid to long-chain fatty acids and small-chain fatty acids.Additionally,the liver-gut communication and the liver and gut intersection with the microbiome as well as diseases related to microbiota imbalance in the liver-gut axis are addressed.Moreover,the development of potentially therapeutic small molecules,proteins and compounds targeting ACSs in cancer treatment is summarized.
基金Supported by Deutsche Forschungsgemeinschaft, No. GA785/6-1Deutsche Krebshilfe, No. 109313the Rotationsprogramm of the Medical Faculty RWTH Aachen University (to Kaemmerer E)
文摘AIM:To investigate whether human acyl-CoA synthetase 5(ACSL5) is sensitive to the ACSL inhibitor triacsin C.METHODS:The ACSL isoforms ACSL1 and ACSL5 from rat as well as human ACSL5 were cloned and recombinantly expressed as 6xHis-tagged enzymes.Ni 2+-affinity purified recombinant enzymes were assayed at pH 7.5 or pH 9.5 in the presence or absence of triacsin C.In addition,ACSL5 transfected CaCo2 cells and intestinal human mucosa were monitored.ACSL5 expression in cellular systems was verified using Western blot and immunofluorescence.The ACSL assay mix included TrisHCl(pH 7.4),ATP,CoA,EDTA,DTT,MgCl 2,[9,103 H] palmitic acid,and triton X-100.The 200 μL reaction was initiated with the addition of solubilized,purified recombinant proteins or cellular lysates.Reactions were terminated after 10,30 or 60 min of incubation with Doles medium.RESULTS:Expression of soluble recombinant ACSL proteins was found after incubation with isopropyl betaD-1-thiogalactopyranoside and after ultracentrifugation these were further purified to near homogeneity with Ni 2+-affinity chromatography.Triacsin C selectively and strongly inhibited recombinant human ACSL5 protein at pH 7.5 and pH 9.5,as well as recombinant rat ACSL1(sensitive control),but not recombinant rat ACSL5(insensitive control).The IC50 for human ACSL5 was about 10 μmol/L.The inhibitory triacsin C effect was similar for different incubation times(10,30 and 60 min) and was not modified by the N-or C-terminal location of the 6xHis-tag.In order to evaluate ACSL5 sensitivity to triacsin C in a cellular environment,stable human ACSL5 CaCo2 transfectants and mechanically dissected normal human intestinal mucosa with high physiological expression of ACSL5 were analyzed.In both models,ACSL5 peak activity was found at pH 7.5 and pH 9.5,corresponding to the properties of recombinant human ACSL5 protein.In the presence of triacsin C(25 μmol/L),total ACSL activity was dramatically diminished in human ACSL5 transfectants as well as in ACSL5-rich human intestinal mucosa.CONCLUSION:The data strongly indicate that human ACSL5 is sensitive to triacsin C and does not compensate for other triacsin C-sensitive ACSL isoforms.
基金Integree of the Comite Mixte Inter-universitaire Franco-Maro- cain (CMIFM, AIMA/10/238, EGIDE)
文摘Pseudo-neonatal adrenoleukodystrophy (P-NALD) is a neurodegenerative disorder caused by acyl-CoA oxidase 1 (ACOX1) deficiency with subsequent impairment of peroxisomal fatty acid β-oxidation, accumulation of very long chain fatty acids (VLCFAs) and strong reduction in peroxisome abundance. Increase in peroxisome number has been previously suggested to improve peroxisomal disorders, and in this perspective, the present work was aimed at exploring whether modulation of peroxisomes abundance could be achieved in P-NALD fibroblasts. Here we showed that treatment with the natural Argan oil induced peroxisome proliferation in P-NALD fibroblasts. This induction was independent on activations of both nuclear receptor PPARα and its coactivator PGC-1α. Lipopolysaccharides (LPS) treatment, which caused inflammation, induced also a peroxisome proliferation that, in contrast, was dependent on activations of PPARα and PGC-1α. By its ability to induce peroxisome proliferation, Argan oil is suggested to be of potential therapeutic use in patients with P-NALD.
文摘Previous studies have reported upregulation of heme oxygenase-1 in different central nervous system injury models.Heme oxygenase-1 plays a critical anti-inflammatory role and is essential for regulating cellular redox homeostasis.Metformin is a classic drug used to treat type 2 diabetes that can inhibit ferroptosis.Previous studies have shown that,when used to treat cardiovascular and digestive system diseases,metformin can also upregulate heme oxygenase-1 expression.Therefore,we hypothesized that heme oxygenase-1 plays a significant role in mediating the beneficial effects of metformin on neuronal ferroptosis after spinal cord injury.To test this,we first performed a bioinformatics analysis based on the GEO database and found that heme oxygenase-1 was upregulated in the lesion of rats with spinal cord injury.Next,we confirmed this finding in a rat model of T9 spinal cord compression injury that exhibited spinal cord nerve cell ferroptosis.Continuous intraperitoneal injection of metformin for 14 days was found to both upregulate heme oxygenase-1 expression and reduce neuronal ferroptosis in rats with spinal cord injury.Subsequently,we used a lentivirus vector to knock down heme oxygenase-1 expression in the spinal cord,and found that this significantly reduced the effect of metformin on ferroptosis after spinal cord injury.Taken together,these findings suggest that metformin inhibits neuronal ferroptosis after spinal cord injury,and that this effect is partially dependent on upregulation of heme oxygenase-1.
基金a grant from the National Natural Science Foundation of China (No.81460199).
文摘Background:Late-onset multiple acyl-coA dehydrogenase deficiency (MADD) is an autosomal recessive inherited metabolic disorder. It is still unclear about the muscle magnetic resonance image (MRI) pattern of the distal lower limb pre- and post-treatment in patients with late-onset MADD. This study described the clinical and genetic findings in a cohort of patients with late-onset MADD, and aimed to characterize the MRI pattern of the lower limbs.Methods:Clinical data were retrospectively collected from clinic centers of Peking University People's Hospital between February 2014 and February 2018. Muscle biopsy, blood acylcarnitines, and urine organic acids profiles, and genetic analysis were conducted to establish the diagnosis of MADD in 25 patients. Muscle MRI of the thigh and leg were performed in all patients before treatment. Eight patients received MRI re-examinations after treatment.Results:All patients presented with muscle weakness or exercise intolerance associated with variants in the electron transfer flavoprotein dehydrogenase gene. Muscle MRI showed a sign of both edema-like change and fat infiltration selectively involving in the soleus (SO) but sparing of the gastrocnemius (GA) in the leg. Similar sign of selective involvement of the biceps femoris longus (BFL) but sparing of the semitendinosus (ST) was observed in the thigh. The sensitivity and specificity of the combination of either "SO+/GA-" sign or "BFL+/ST-" sign for the diagnosis of late-onset MADD were 80.0% and 83.5%, respectively. Logistic regression model supported the findings. The edema-like change in the SO and BFL muscles were quickly recovered at 1 month after treatment, and the clinical symptom was also relieved.Conclusions:This study expands the clinical and genetic spectrums of late-onset MADD. Muscle MRI shows a distinct pattern in the lower limb of patients with late-onset MADD. The dynamic change of edema-like change in the affected muscles might be a potential biomarker of treatment response.
基金supported by grants from the National Natural Science Foundation of China(81170811,30973216)Shanghai School Board(12ZZ114)and Shanghai Health Bureau(20134005)+1 种基金supported by grants from the Major Program of Shanghai Committee of Science and Technology(11dz195030)the National Key Technology R&D Program(2012BAI09B04).
文摘Background:Very long chain acyl-CoA dehydrogenase deficiency(VLCADD)is an inherited metabolic disease caused by deleterious mutations in the ACADVL gene that encodes very long chain acyl-CoA dehydrogenase(VLCAD),and which can present as cardiomyopathy in neonates,as hypoketotic hypoglycemia in infancy,and as myopathy in late-onset patients.Although many ACADVL mutations have been described,no prevalent mutations in the ACADVL gene have been associated with VLCADD.Herein,we report the clinical course of the disease and explore the genetic mutation spectrum in seven Chinese patients with VLCADD.Methods:Seven Chinese patients,from newborn to 17 years old,were included in this study.Tandem mass spectrometry was performed to screen for VLCAD defi ciency.All exons and fl anking introns of the ACADVL gene were analyzed using polymerase chain reaction and direct sequencing.Online analysis tools were used to predict the impact of novel mutations.Results:All cases had elevated serum levels of tetradecanoylcarnitine(C14:1)which is the characteristic biomarker for VLCADD.The phenotype of VLCADD is heterogeneous.Two patients were hospitalized for hypoactivity and hypoglycemia shortly after birth.Three patients showed hepatomegaly and hypoglycemia in infancy.The other two adolescent patients showed initial manifestations of exercise intolerance or rhabdomyolysis.Three of the patients died at the age of 6-8 months.Eleven different mutations in the ACADVL gene in the 7 patients were identified,including seven reported mutations(p.S22X,p.W427X,p.A213T,p.G222R,p.R450H,c.296-297delCA,c.1605+1G>T)and four novel mutations(p.S72F,p.Q100X,p.M437T,p.D466Y).The p.R450H and p.D466Y(14.28%,2/14 alleles)mutations were identifi ed in two alleles respectively.Conclusions:The clinical manifestations were heterogeneous and ACADVL gene mutations were heterozygous in the seven VLCADD Chinese patients.R450H may be a relatively common mutation in Asian populations.The genotype and phenotype had a certain correlation in our patients.
基金the National Natural Science Foundation of China(No.81741090)the Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talentsthe National KePy R&D Program of China(Nos.2017YFC1001703 and 2018YFC1002700)。
文摘The pathogenesis of very-long-chain acyl-CoA dehydrogenase(VLCAD)deficiency is highly heterogeneous and still unclear.Additional novel variants have been recently detected in the population.The molecular and cellular effects of these previously unreported variants are still poorly understood and require further characterization.To address this problem,we have evaluated the various functions and biochemical consequences of six novel missense variants that lead to mild VLCAD deficiency.Marked deficiencies in fatty acid oxidation(FAO)and other mitochondrial defects were observed in cells carrying one of these six variants(c.541 C>T,c.863 T>G,c.895 A>G,c.1238 T>C,c.1276 G>A,and c.1505 T>A),including reductions in mitochondrial respiratory-chain function and adenosine teriphosphate(ATP)production,and increased levels of mitochondrial reactive oxygen species(ROS).Intriguingly,higher apoptosis levels were found in cells carrying the mutant VLCAD under glucose-limited stress.Moreover,the stability of the mutant homodimer was disturbed,and major conformational changes in each mutant VLCAD structure were predicted by molecular dynamics(MD)simulation.The data presented here may provide valuable information for improving management of diagnosis and treatment of VLCAD deficiency and for a better understanding of the general molecular bases of disease variability.
