Carboxyl ester lipase(CEL),a pivotal enzyme involved in lipid metabolism,is recurrently mutated in obese mice.Here,we aimed to elucidate the functional significance,molecular mechanism,and therapeutic potential of CEL...Carboxyl ester lipase(CEL),a pivotal enzyme involved in lipid metabolism,is recurrently mutated in obese mice.Here,we aimed to elucidate the functional significance,molecular mechanism,and therapeutic potential of CEL in metabolic dysfunction-associated steatohepatitis(MASH).Hepatocyte-specific carboxyl ester lipase gene(Cel)knockout(Cel^(DHEP))and wildtype(WT)littermates were fed with cholinedeficient high-fat diet(CD-HFD)for 16 weeks,or methionine-and choline-deficient diet(MCD)for three weeks to induce MASH.Liquid chromatography–mass spectrometry and co-immunoprecipitation were employed to identify the downstream targets of CEL.CD-HFD/MCD-fed WT mice received intravenous injections of CEL-adeno-associated viral,serotype 8(AAV8)to induce specific overexpression of CEL in the liver.We observed a decrease in CEL protein levels in MASH induced by CD-HFD or MCD in mice.Cel^(DHEP) mice fed with CD-HFD or MCD exhibited pronounced hepatic steatosis,inflammation,lipid peroxidation,and liver injury compared to WT littermates,accompanied by increased hepatic nuclear factor kappa-light-chain-enhancer of activated B cell(NF-jB)activation.Consistently,Cel knockdown in mouse primary hepatocytes and AML12 cells aggravated lipid accumulation and inflammation,whereas CEL overexpression exerted the opposite effect.Mechanistically,CEL directly bound to fatty acid synthase(FASN),resulting in reduced FASN SUMOylation,which in turn promoted FASN degradation through the proteasome pathway.Furthermore,inhibition of FASN ameliorated hepatocyte lipid accumulation and inflammation induced by Cel knockdown in vivo and in vitro.Hepatocyte-specific CEL overexpression using AAV8-Cel significantly mitigated steatohepatitis in mice fed with CD-HFD or MCD.CEL protects against steatohepatitis development by directly interacting with FASN and suppressing its expression for de novo lipogenesis.CEL overexpression confers a therapeutic benefit in steatohepatitis.展开更多
The conventional saponification method could result in lower recoveries and artificial changes of longchain fatty acids. The main reason is the error judgment of the intermediate layer suspended between the aqueous an...The conventional saponification method could result in lower recoveries and artificial changes of longchain fatty acids. The main reason is the error judgment of the intermediate layer suspended between the aqueous and organic layer during the liquid–liquid extraction process.This study shows that the intermediate layer consists of lots of medium- to long-chain carboxylic salts for their special physical and chemical properties. An improved saponification extraction method is also developed and the results show that the carboxylic salts distributed in the intermediate layer could be obtained completely, which greatly enhances the authenticity and accuracy of fatty acid analysis. Additionally, the possible reasons of formation of the intermediate layer are also discussed.展开更多
为研制新型清洁压裂液,采用脂肪酸甲酯磺酸钠与芥酸酰胺丙基甜菜碱复配得到了一种增稠剂MC-1,研究了MC-1及无机盐加量对压裂液黏度的影响,考察了压裂液(3%MC-1+5%KCl)的耐温性、耐剪切性、悬砂性和破胶性能。结果表明,MC-1与多种无机盐...为研制新型清洁压裂液,采用脂肪酸甲酯磺酸钠与芥酸酰胺丙基甜菜碱复配得到了一种增稠剂MC-1,研究了MC-1及无机盐加量对压裂液黏度的影响,考察了压裂液(3%MC-1+5%KCl)的耐温性、耐剪切性、悬砂性和破胶性能。结果表明,MC-1与多种无机盐KCl、NH4Cl和Na Cl均有较好的协同性,其中与KCl的协同性最好,压裂液黏度随MC-1和KCl加量增大而增加;该压裂液具有较好的耐温耐剪切性和悬砂性,在80℃、砂比40%的条件下,砂子的沉降速度为1.18 mm/s;与煤油混合后在80℃下2 h内完全破胶,破胶液黏度为4.5 m Pa·s,表面张力为24 m N/m,界面张力为0.8764 m N/m。该压裂液可适用于小于90℃的地层使用。展开更多
基金supported by the National Natural Science Foundation of China(82222901,82103355,and 82272619)the Innovation and Technology Fund—Guangdong–Hong Kong Technology Cooperation Funding Scheme(GHP/086/21GD)+4 种基金the Research Grants Council(RGC)Theme-based Research Scheme(T12-703/19-R)the Research Grants Council-General Research Fund(14117422 and 14117123)the Health and Medical Research Fund,Hong Kong(08191336 and 07210097)the CUHK Research Startup Fund(FPU/2023/149)the Natural Science Foundation of Fujian Province(2020J01122587).
文摘Carboxyl ester lipase(CEL),a pivotal enzyme involved in lipid metabolism,is recurrently mutated in obese mice.Here,we aimed to elucidate the functional significance,molecular mechanism,and therapeutic potential of CEL in metabolic dysfunction-associated steatohepatitis(MASH).Hepatocyte-specific carboxyl ester lipase gene(Cel)knockout(Cel^(DHEP))and wildtype(WT)littermates were fed with cholinedeficient high-fat diet(CD-HFD)for 16 weeks,or methionine-and choline-deficient diet(MCD)for three weeks to induce MASH.Liquid chromatography–mass spectrometry and co-immunoprecipitation were employed to identify the downstream targets of CEL.CD-HFD/MCD-fed WT mice received intravenous injections of CEL-adeno-associated viral,serotype 8(AAV8)to induce specific overexpression of CEL in the liver.We observed a decrease in CEL protein levels in MASH induced by CD-HFD or MCD in mice.Cel^(DHEP) mice fed with CD-HFD or MCD exhibited pronounced hepatic steatosis,inflammation,lipid peroxidation,and liver injury compared to WT littermates,accompanied by increased hepatic nuclear factor kappa-light-chain-enhancer of activated B cell(NF-jB)activation.Consistently,Cel knockdown in mouse primary hepatocytes and AML12 cells aggravated lipid accumulation and inflammation,whereas CEL overexpression exerted the opposite effect.Mechanistically,CEL directly bound to fatty acid synthase(FASN),resulting in reduced FASN SUMOylation,which in turn promoted FASN degradation through the proteasome pathway.Furthermore,inhibition of FASN ameliorated hepatocyte lipid accumulation and inflammation induced by Cel knockdown in vivo and in vitro.Hepatocyte-specific CEL overexpression using AAV8-Cel significantly mitigated steatohepatitis in mice fed with CD-HFD or MCD.CEL protects against steatohepatitis development by directly interacting with FASN and suppressing its expression for de novo lipogenesis.CEL overexpression confers a therapeutic benefit in steatohepatitis.
基金supports by the National Natural Science Foundation of China (No.41003021)the Key Laboratory Project of Gansu Province (Grant No.1309RTSA041)
文摘The conventional saponification method could result in lower recoveries and artificial changes of longchain fatty acids. The main reason is the error judgment of the intermediate layer suspended between the aqueous and organic layer during the liquid–liquid extraction process.This study shows that the intermediate layer consists of lots of medium- to long-chain carboxylic salts for their special physical and chemical properties. An improved saponification extraction method is also developed and the results show that the carboxylic salts distributed in the intermediate layer could be obtained completely, which greatly enhances the authenticity and accuracy of fatty acid analysis. Additionally, the possible reasons of formation of the intermediate layer are also discussed.
文摘为研制新型清洁压裂液,采用脂肪酸甲酯磺酸钠与芥酸酰胺丙基甜菜碱复配得到了一种增稠剂MC-1,研究了MC-1及无机盐加量对压裂液黏度的影响,考察了压裂液(3%MC-1+5%KCl)的耐温性、耐剪切性、悬砂性和破胶性能。结果表明,MC-1与多种无机盐KCl、NH4Cl和Na Cl均有较好的协同性,其中与KCl的协同性最好,压裂液黏度随MC-1和KCl加量增大而增加;该压裂液具有较好的耐温耐剪切性和悬砂性,在80℃、砂比40%的条件下,砂子的沉降速度为1.18 mm/s;与煤油混合后在80℃下2 h内完全破胶,破胶液黏度为4.5 m Pa·s,表面张力为24 m N/m,界面张力为0.8764 m N/m。该压裂液可适用于小于90℃的地层使用。