Genome-wide and candidate gene association studies have identified several variants that predispose indi- viduals to developing nonalcoholic fatty liver disease （NAFLD）. However, the gene that has been consis- tentl...Genome-wide and candidate gene association studies have identified several variants that predispose indi- viduals to developing nonalcoholic fatty liver disease （NAFLD）. However, the gene that has been consis- tently involved in the genetic susceptibility of NAFLD in humans is patatin-like phospholipase domain contain- ing 3 （PNPLA3, also known as adiponutrin）. A nonsyn- onymous single nucleotide polymorphism in PNPLA3 （rs738409 C/G, a coding variant that encodes an amino acid substitution I148M） is significantly associated with fatty liver and histological disease severity, not only in adults but also in children. Nevertheless, how PNPLA3 influences the biology of fatty liver disease is still an open question. A recent article describes new aspects about PNPLA3 gene/protein function and suggests that the I148M variant promotes hepatic lipid synthesis due to a gain of function. We revise here the published data about the role of the I148M variant in lipogen- esis/lipolysis, and suggest putative areas of future research. For instance we explored in silico whether the rs738409 C or G alleles have the ability to modify miRNA binding sites and miRNA gene regulation, and we found that prediction of PNPLA3 target miRNAs shows two miRNAs potentially interacting in the 3＇ UTR region （hsa-miR-769-3p and hsa-miR-516a-3p）. In addition, interesting unanswered questions remain to be explored. For example, PNPLA3 lies between two CCCTC-binding factor-bound sites that could be tested for insulator activity, and an intronic histone 3 lysine 4 trimethylation peak predicts an enhancer element, cor- roborated by the DNase I hypersensitivity site peak. Finally, an interaction between PNPLA3 and glycerol- 3-phosphate acyltransferase 2 is suggested by data miming.展开更多
BACKGROUND Patatin like phospholipase domain containing 8(PNPLA8)has been shown to play a significant role in various cancer entities.Previous studies have focused on its roles as an antioxidant and in lipid peroxidat...BACKGROUND Patatin like phospholipase domain containing 8(PNPLA8)has been shown to play a significant role in various cancer entities.Previous studies have focused on its roles as an antioxidant and in lipid peroxidation.However,the role of PNPLA8 in colorectal cancer(CRC)progression is unclear.AIM To explore the prognostic effects of PNPLA8 expression in CRC.METHODS A retrospective cohort containing 751 consecutive CRC patients was enrolled.PNPLA8 expression in tumor samples was evaluated by immunohistochemistry staining and semi-quantitated with immunoreactive scores.CRC patients were divided into high and low PNPLA8 expression groups based on the cut-off va-lues,which were calculated by X-tile software.The prognostic value of PNPLA8 was identified using univariate and multivariate Cox regression analysis.The over-all survival(OS)rates of CRC patients in the study cohort were compared with Kaplan-Meier analysis and Log-rank test.RESULTS PNPLA8 expression was significantly associated with distant metastases in our cohort(P=0.048).CRC patients with high PNPLA8 expression indicated poor OS(median OS=35.3,P=0.005).CRC patients with a higher PNPLA8 expression at either stage I and II or stage III and IV had statistically significant shorter OS.For patients with left-sided colon and rectal cancer,the survival curves of two PN-PLA8-expression groups showed statistically significant differences.Multivariate analysis also confirmed that high PNPLA8 expression was an independent prog-nostic factor for overall survival(hazard ratio HR=1.328,95%CI:1.016-1.734,P=0.038).展开更多
马铃薯淀粉汁水经分离与纯化后得到马铃薯糖蛋白Patatin。通过对Patatin纯度、结构的测定与分析表明:Patatin纯度在90%以上,分子量为40.6 k Da。Patatin是糖和蛋白质的复合物。单糖组成为:鼠李糖、甘露糖、葡萄糖和半乳糖。Patatin中含...马铃薯淀粉汁水经分离与纯化后得到马铃薯糖蛋白Patatin。通过对Patatin纯度、结构的测定与分析表明:Patatin纯度在90%以上,分子量为40.6 k Da。Patatin是糖和蛋白质的复合物。单糖组成为:鼠李糖、甘露糖、葡萄糖和半乳糖。Patatin中含有α-糖苷键,糖苷类型为吡喃型;糖链和肽链之间由O-型糖肽键连接。Patatin的热变性温度为75℃。展开更多
Non-alcoholic fatty liver disease (NAFLD) comprehends a wide range of conditions, encompassing from fatty liver or steatohepatitis with or without fibrosis, to cirrhosis and its complications. NAFLD has become the mos...Non-alcoholic fatty liver disease (NAFLD) comprehends a wide range of conditions, encompassing from fatty liver or steatohepatitis with or without fibrosis, to cirrhosis and its complications. NAFLD has become the most common form of liver disease in childhood as its prevalence has more than doubled over the past 20 years, paralleling the increased prevalence of childhood obesity. It currently affects between 3% and 11% of the pediatric population reaching the rate of 46% among overweight and obese children and adolescents. The prevalence of hepatic steatosis varies among different ethnic groups. The ethnic group with the highest prevalence is the Hispanic one followed by the Caucasian and the African-American. This evidence suggests that there is a strong genetic background in the predisposition to fatty liver. In fact, since 2008 several common gene variants have been implicated in the pathogenesis of fatty liver disease. The most important is probably the patatin like phospholipase containing domain 3 gene (PNPLA3) discovered by the Hobbs’ group in 2008. This article reviews the current knowledge regarding the role of ethnicity and genetics in pathogenesis of pediatric fatty liver.展开更多
The 10 ku zein gene of maize was under control of patatin class I promoter of potato and transferred into potato genome by the leaf-disc method. The expression of 10 ku zein was determined in the tuber of transgenic p...The 10 ku zein gene of maize was under control of patatin class I promoter of potato and transferred into potato genome by the leaf-disc method. The expression of 10 ku zein was determined in the tuber of transgenic plants by RT-PCR. Furthermore, the sulphur-containing amino acids in transgenic tuber increase remarkably.展开更多
Plants can respond to traumatism by synthesis and secretion of defence molecules. Wound-healing and desiccation stress of pieces of potato tuber parenchyma (Solanum tuberosum) promoted the secretion of a patatin-like ...Plants can respond to traumatism by synthesis and secretion of defence molecules. Wound-healing and desiccation stress of pieces of potato tuber parenchyma (Solanum tuberosum) promoted the secretion of a patatin-like phospholipase A2, PLA2 (EC.3.1.1.4.) that displayed cytotoxic activity against tumour cells. The potato secretion product, an oligomeric form of patatin-like protein, was shown to contain several isoforms of PLA2 polypeptides and to be associated with other proteins, including Kunitz-type protease inhibitors. Patatin-like protein secretion was inhibited by vanadate. Secreted patatin-like proteins displayed specific features, such as extracellular function and low molecular weights, mainly 36 to 40 kDa. The 36-kDa polypeptide sequence was related to iPLA2α. Polypeptide spots of secreted patatin-like protein exhibited a nucleotide-binding consensus motif, GGGIKG that has been described in iPLA2 gene family. The cytotoxic agent caused cell death of plant crown-gall induced by Agrobacterium tumefaciens, and inhibited B16 cell proliferation, but at the same concentration did not display any toxicity against non-transformed cells. PLA2 enzyme activity was required for cytotoxicity against B16 melanoma cells. A model for such a specific activity against tumour cells is discussed in connection with asymmetric phospholipid patterns of cell membranes. In conclusion, secreted patatin-like PLA2 (e-patatin) may represent a novel therapeutic target for the development of new agents against cancer.展开更多
Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoh...Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease(NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148 M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.展开更多
目的探讨PNPLA3、TM6SF2基因多态性及其与吸烟、饮酒交互作用对HBV相关肝癌(hepatitis B virus—associated hepatocellular carcinoma,HBV-HCC)的影响。方法收集2010年1月至2014年3月HBV-HCC患者、慢性乙型肝炎(乙肝)患者(CHB)、肝硬...目的探讨PNPLA3、TM6SF2基因多态性及其与吸烟、饮酒交互作用对HBV相关肝癌(hepatitis B virus—associated hepatocellular carcinoma,HBV-HCC)的影响。方法收集2010年1月至2014年3月HBV-HCC患者、慢性乙型肝炎(乙肝)患者(CHB)、肝硬化患者(LC)以及健康体检者的血液标本,应用飞行质谱技术检测patatin样磷脂酶域3(PNPLA3)基因位点rs738409和6号跨膜超家族成员2(TM6sF2)基因位点rs58542926的单核苷酸多态性(SNP)。利用在线SNP stats寻找基因多态性的最优赋值方法;检验SNP是否符合哈一温(H-W)遗传平衡定律;采用多分类logistic回归分析PNPLA3和TM6SF2多态性及吸烟、饮酒因素对HBV-HCC的影响,采用叉生分析和二分类logistic回归分析探讨基因一基因、基因一吸烟、饮酒交互作用对HBV-HCC的影响。结果H—W遗传平衡检验结果显示,CHB组rs738409位点的基因型频率分布不符合H—W遗传平衡定律(Χ^2=11.980,P<0.005),CHB组rs58542926位点、HBV-HCC组和LC组rs738409和rs58542926位点均符合H-W遗传平衡定律;调整年龄、性别的影响后,与健康体检者相比,HBV-HCC组rs58542926突变的OR=1.659,95%CI:1.026~2.684,P=0.039。与CHB组相比,HBV-HCC组饮酒的OR=1.680,95%CI:1.121~2.519,P=0.012。与LC组相比,HBV-HCC组饮酒与吸烟的OR值(95%CI)分别为1.539(1.071~2.213)和1.453(1.005~2.099)。交互作用分析显示,HBV-HCC组与CHB+LC组相比,rs738409与rs58542926交互作用的叉生分析相加模型OR=1.548(u=1.885,P=0.029),logistic回归相乘模型OR=1.658(P=0.024);饮酒与rs738409的交互作用叉生分析,饮酒且rs738409突变相加模型OR=1.811(U=1.965,P=0.024),相乘模型无统计学意义;logistic回归相乘模型吸烟与饮酒的交互作用OR=1.756(P<0.001)。结论TM6SF2基因突变、吸烟、饮酒是HBV-HCC的危险因素,PNPLA3与TM6SF2基因都突变、饮酒并且吸烟是HBV-HCC的危险因素。PNPLA3的单基因突变可以减弱饮酒对HBV-HCC的危害。展开更多
The 148 Isoleucine to Methionine protein variant(I148M)of patatin-like phospholipase domain-containing 3(PNPLA3),a protein is expressed in the liver and is involved in lipid metabolism,has recently been identified as ...The 148 Isoleucine to Methionine protein variant(I148M)of patatin-like phospholipase domain-containing 3(PNPLA3),a protein is expressed in the liver and is involved in lipid metabolism,has recently been identified as a major determinant of liver fat content.Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver:from simple steatosis to steatohepatitis and progressive fibrosis.Furthermore,the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis,and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis,and possibly chronic hepatitis B virus hepatitis,hereditary hemochromatosis and primary sclerosing cholangitis.All in all,studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases.Remarkably,the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation,suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes,directly promoting fibrogenesis.Therefore,PNPLA3 is a key player in liver disease progression.Assessment of the I148M polymorphism will possibly inform clinical practice in the future,whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis.展开更多
基金Supported by Grants PICT 2008-1521 and PICT 2010 0441,from National Agency for Science and TechnologyUBACYT CM04,from Universidad de Buenos AiresSookoian S and Pirola CJ belong to National Council of Scientific and Technical Research
文摘Genome-wide and candidate gene association studies have identified several variants that predispose indi- viduals to developing nonalcoholic fatty liver disease （NAFLD）. However, the gene that has been consis- tently involved in the genetic susceptibility of NAFLD in humans is patatin-like phospholipase domain contain- ing 3 （PNPLA3, also known as adiponutrin）. A nonsyn- onymous single nucleotide polymorphism in PNPLA3 （rs738409 C/G, a coding variant that encodes an amino acid substitution I148M） is significantly associated with fatty liver and histological disease severity, not only in adults but also in children. Nevertheless, how PNPLA3 influences the biology of fatty liver disease is still an open question. A recent article describes new aspects about PNPLA3 gene/protein function and suggests that the I148M variant promotes hepatic lipid synthesis due to a gain of function. We revise here the published data about the role of the I148M variant in lipogen- esis/lipolysis, and suggest putative areas of future research. For instance we explored in silico whether the rs738409 C or G alleles have the ability to modify miRNA binding sites and miRNA gene regulation, and we found that prediction of PNPLA3 target miRNAs shows two miRNAs potentially interacting in the 3＇ UTR region （hsa-miR-769-3p and hsa-miR-516a-3p）. In addition, interesting unanswered questions remain to be explored. For example, PNPLA3 lies between two CCCTC-binding factor-bound sites that could be tested for insulator activity, and an intronic histone 3 lysine 4 trimethylation peak predicts an enhancer element, cor- roborated by the DNase I hypersensitivity site peak. Finally, an interaction between PNPLA3 and glycerol- 3-phosphate acyltransferase 2 is suggested by data miming.
基金This study was approved by the Clinical Research Ethics Committee of Zhongshan Hospital,Fudan University.
文摘BACKGROUND Patatin like phospholipase domain containing 8(PNPLA8)has been shown to play a significant role in various cancer entities.Previous studies have focused on its roles as an antioxidant and in lipid peroxidation.However,the role of PNPLA8 in colorectal cancer(CRC)progression is unclear.AIM To explore the prognostic effects of PNPLA8 expression in CRC.METHODS A retrospective cohort containing 751 consecutive CRC patients was enrolled.PNPLA8 expression in tumor samples was evaluated by immunohistochemistry staining and semi-quantitated with immunoreactive scores.CRC patients were divided into high and low PNPLA8 expression groups based on the cut-off va-lues,which were calculated by X-tile software.The prognostic value of PNPLA8 was identified using univariate and multivariate Cox regression analysis.The over-all survival(OS)rates of CRC patients in the study cohort were compared with Kaplan-Meier analysis and Log-rank test.RESULTS PNPLA8 expression was significantly associated with distant metastases in our cohort(P=0.048).CRC patients with high PNPLA8 expression indicated poor OS(median OS=35.3,P=0.005).CRC patients with a higher PNPLA8 expression at either stage I and II or stage III and IV had statistically significant shorter OS.For patients with left-sided colon and rectal cancer,the survival curves of two PN-PLA8-expression groups showed statistically significant differences.Multivariate analysis also confirmed that high PNPLA8 expression was an independent prog-nostic factor for overall survival(hazard ratio HR=1.328,95%CI:1.016-1.734,P=0.038).
文摘马铃薯淀粉汁水经分离与纯化后得到马铃薯糖蛋白Patatin。通过对Patatin纯度、结构的测定与分析表明:Patatin纯度在90%以上,分子量为40.6 k Da。Patatin是糖和蛋白质的复合物。单糖组成为:鼠李糖、甘露糖、葡萄糖和半乳糖。Patatin中含有α-糖苷键,糖苷类型为吡喃型;糖链和肽链之间由O-型糖肽键连接。Patatin的热变性温度为75℃。
基金Supported by The American Heart Association(13SDG14640038)2012 Yale Center for Clinical Investigation cholar award to Santoro NThis publication was also made possible by CTSA Grant Number UL1 RR024139 from the National Center for Advancing Translational Science,a component of the National Institutes of Health(NIH),and NIH roadmap for Medical Research,Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH
文摘Non-alcoholic fatty liver disease (NAFLD) comprehends a wide range of conditions, encompassing from fatty liver or steatohepatitis with or without fibrosis, to cirrhosis and its complications. NAFLD has become the most common form of liver disease in childhood as its prevalence has more than doubled over the past 20 years, paralleling the increased prevalence of childhood obesity. It currently affects between 3% and 11% of the pediatric population reaching the rate of 46% among overweight and obese children and adolescents. The prevalence of hepatic steatosis varies among different ethnic groups. The ethnic group with the highest prevalence is the Hispanic one followed by the Caucasian and the African-American. This evidence suggests that there is a strong genetic background in the predisposition to fatty liver. In fact, since 2008 several common gene variants have been implicated in the pathogenesis of fatty liver disease. The most important is probably the patatin like phospholipase containing domain 3 gene (PNPLA3) discovered by the Hobbs’ group in 2008. This article reviews the current knowledge regarding the role of ethnicity and genetics in pathogenesis of pediatric fatty liver.
基金the National High-Tech Project (Grant No. 010-04-03-01).
文摘The 10 ku zein gene of maize was under control of patatin class I promoter of potato and transferred into potato genome by the leaf-disc method. The expression of 10 ku zein was determined in the tuber of transgenic plants by RT-PCR. Furthermore, the sulphur-containing amino acids in transgenic tuber increase remarkably.
文摘Plants can respond to traumatism by synthesis and secretion of defence molecules. Wound-healing and desiccation stress of pieces of potato tuber parenchyma (Solanum tuberosum) promoted the secretion of a patatin-like phospholipase A2, PLA2 (EC.3.1.1.4.) that displayed cytotoxic activity against tumour cells. The potato secretion product, an oligomeric form of patatin-like protein, was shown to contain several isoforms of PLA2 polypeptides and to be associated with other proteins, including Kunitz-type protease inhibitors. Patatin-like protein secretion was inhibited by vanadate. Secreted patatin-like proteins displayed specific features, such as extracellular function and low molecular weights, mainly 36 to 40 kDa. The 36-kDa polypeptide sequence was related to iPLA2α. Polypeptide spots of secreted patatin-like protein exhibited a nucleotide-binding consensus motif, GGGIKG that has been described in iPLA2 gene family. The cytotoxic agent caused cell death of plant crown-gall induced by Agrobacterium tumefaciens, and inhibited B16 cell proliferation, but at the same concentration did not display any toxicity against non-transformed cells. PLA2 enzyme activity was required for cytotoxicity against B16 melanoma cells. A model for such a specific activity against tumour cells is discussed in connection with asymmetric phospholipid patterns of cell membranes. In conclusion, secreted patatin-like PLA2 (e-patatin) may represent a novel therapeutic target for the development of new agents against cancer.
文摘Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease(NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148 M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.
基金Supported by Associazione Malattie Metaboliche del Fegato ONLUS(Non-profit organization for the Study and Care of Metabolic Liver Diseases)Centro Studi Malattie Metaboliche del Fegato,Universitàdegli Studi di Milano
文摘The 148 Isoleucine to Methionine protein variant(I148M)of patatin-like phospholipase domain-containing 3(PNPLA3),a protein is expressed in the liver and is involved in lipid metabolism,has recently been identified as a major determinant of liver fat content.Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver:from simple steatosis to steatohepatitis and progressive fibrosis.Furthermore,the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis,and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis,and possibly chronic hepatitis B virus hepatitis,hereditary hemochromatosis and primary sclerosing cholangitis.All in all,studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases.Remarkably,the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation,suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes,directly promoting fibrogenesis.Therefore,PNPLA3 is a key player in liver disease progression.Assessment of the I148M polymorphism will possibly inform clinical practice in the future,whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis.
