Glucose and fatty acids are the major sources of energy for human body. Cholesterol, the most abundant sterol in mammals, is a key component of cell membranes although it does not generate ATP. The metabolisms of gluc...Glucose and fatty acids are the major sources of energy for human body. Cholesterol, the most abundant sterol in mammals, is a key component of cell membranes although it does not generate ATP. The metabolisms of glucose, fatty acids and cholesterol are often intertwined and regulated. For example, glucose can be converted to fatty acids and cholesterol through de novo lipid biosynthesis pathways. Excessive lipids are secreted in lipoproteins or stored in lipid droplets. The metabolites of glucose and lipids are dynamically transported intercellularly and intracellularly, and then converted to other molecules in specific compartments. The disorders of glucose and lipid metabolism result in severe diseases including cardiovascular disease, diabetes and fatty liver. This review summarizes the major metabolic aspects of glucose and lipid, and their regulations in the context of physiology and diseases.展开更多
Most mammalian cells take up cholesterol from low-density lipoproteins(LDLs) via receptor-mediated endocytosis.After reaching lysosomes,LDL-derived cholesterol continues to transport to downstream organelles including...Most mammalian cells take up cholesterol from low-density lipoproteins(LDLs) via receptor-mediated endocytosis.After reaching lysosomes,LDL-derived cholesterol continues to transport to downstream organelles including the ER for specific structural and functional needs.Peroxisomes are recently found to receive cholesterol from lysosomes through lysosomeperoxisome membrane contacts.However,whether and how cholesterol is conveyed from peroxisomes to the ER remain unknown.Here,by combining high-resolution microscopic analyses and in vitro reconstitution of highly purified organelles or artificial liposomes,we demonstrate that peroxisomes form membrane contacts with the ER through the interaction between peroxisomal PI(4,5)P2 and ER-resident extended synaptotagmin-1,2 and 3(E-Syts).Depletion of peroxisomal PI(4,5)P2 or ESyts markedly decreases peroxisome-ER membrane contacts and induces cholesterol accumulation in lysosomes.Furthermore,we show that cholesterol is delivered from 3H-labeled peroxisomes or PI(4,5)P2-containing liposomes to the ER in vitro,and that the presence of peroxisomes augments cholesterol transfer from lysosomes to the ER.Together,our study reveals a new cholesterol transport pathway along the lysosome-peroxisome-ER membrane contacts in the cell.展开更多
We have previously reported that the human ACAT1 gene produces a chimeric mRNA through the interchromosomal processing of two discontinuous RNAs transcribed from chromosomes 1 and 7. The chimeric mRNA uses AUG1397-139...We have previously reported that the human ACAT1 gene produces a chimeric mRNA through the interchromosomal processing of two discontinuous RNAs transcribed from chromosomes 1 and 7. The chimeric mRNA uses AUG1397-1399 and GGC1274-1276 as translation initiation codons to produce normal 50-kDa ACAT1 and a novel enzymatically active 56-kDa isoform, respectively, with the latter being authentically present in human cells, including human monocyte- derived macrophages. In this work, we report that RNA secondary structures located in the vicinity of the GGC1274-1276 codon are required for production of the 56-kDa isoform. The effects of the three predicted stem-loops （nt 1255-1268, 1286-1342 and 1355-1384） were tested individually by transfecting expression plasmids into cells that contained the wild-type, deleted or mutant stem-loop sequences linked to a partial ACAT1 AUG open reading frame （ORF） or to the ORFs of other genes. The expression patterns were monitored by western blot analyses. We found that the upstream stem-loop1255-1268 from chromosome 7 and downstream stem-loop1286-1342 from chromosome 1 were needed for production of the 56-kDa isoform, whereas the last stem-loop135s-1384 from chromosome 1 was dispensable. The results of experi- ments using both monocistronic and bicistronic vectors with a stable hairpin showed that translation initiation from the GGC1274-1276 codon was mediated by an internal ribosome entry site （IRES）. Further experiments revealed that translation initiation from the GGC1274-1276 codon requires the upstream AU-constituted RNA secondary structure and the downstream GC-rich structure. This mechanistic work provides further support for the biological significance of the chimeric nature of the human ACAT1 transcript.展开更多
Transposable elements(TEs)account for a large proportion of eukaryotic genomes and contribute to the evolution of novel genic sequences as well as regulatory elements(Long et al.,2003;Wang et al.,2019;Wang et al.,2016...Transposable elements(TEs)account for a large proportion of eukaryotic genomes and contribute to the evolution of novel genic sequences as well as regulatory elements(Long et al.,2003;Wang et al.,2019;Wang et al.,2016b).The questions of how and to what extent transposable elements may contribute to new functional genes remain largely unknown.In the current issue,Yang et al.展开更多
Niemann-Pick type C2(NPC2) is a lysosome luminal protein that functions in concert with NPC1 to mediate egress of lowdensity lipoprotein-derived cholesterol from lysosome. The nuclear factor kappa B subunit 2(NF-κB2)...Niemann-Pick type C2(NPC2) is a lysosome luminal protein that functions in concert with NPC1 to mediate egress of lowdensity lipoprotein-derived cholesterol from lysosome. The nuclear factor kappa B subunit 2(NF-κB2) protein is a component of NF-κB transcription factor complex critically implicated in immune and inflammatory responses. Here, we report that NF-κB2 regulates intracellular cholesterol transport by controlling NPC2 expression. RNAi-mediated disruption of NF-κB2, as well as other signaling members of the non-canonical NF-κB pathway, caused intracellular cholesterol accumulation. Blockage of the non-canonical NF-κB pathway suppressed NPC2 expression, whereas Lymphotoxin β receptor(LTβR) activation or Baff receptor(BaffR) stimulation up-regulated the mRNA abundance and protein level of NPC2. Further, NF-κB2 activated NPC2 transcription through direct binding to its promoter region. We also observed cholesterol accumulation in NF-κB2-deficient zebrafish embryo and NF-κB2 mutant mice. Collectively, these data identify a regulatory role for the non-canonical NF-κB pathway in intracellular cholesterol trafficking and suggest a link between cholesterol transport and immune system.展开更多
Sterol-regulatory element binding proteins(SREBPs)are the key transcriptional regulators of lipid metabolism.The activation of SREBP requires translocation of the SREBP precursor from the endoplasmic reticulum to the ...Sterol-regulatory element binding proteins(SREBPs)are the key transcriptional regulators of lipid metabolism.The activation of SREBP requires translocation of the SREBP precursor from the endoplasmic reticulum to the Golgi,where it is sequentially cleaved by site-1 protease(S1P)and site-2 protease and releases a nuclear form to modulate gene expression.To search for new genes regulating cholesterol metabolism,we perform a genome-wide CRISPR/Cas9 knockout screen and find that partner of site-1 protease(POSH),encoded by C120RF49,is critically involved in the SREBP signaling.Ablation of POSH decreases the generation of nuclear SREBP and reduces the expression of SREBP target genes.POSH binds S1P,which is synthesized as an inactive protease(form A)and becomes fully mature via a two-step autocatalytic process involving forms B/B and C/C.POSH promotes the generation of the functional S1P-C/C from S1P-B/B(canonical cleavage)and,notably,from S1P-A directly(non-canonical cleavage)as well.This POSH-mediated S1P activation is also essential for the cleavages of other S1P substrates including ATF6,CREB3 family members and the a/p-subunit precursor of N-acetylglucosamine-1-phospho-transferase.Together,we demonstrate that POSH is a cofactor controlling S1P maturation and plays important roles in lipid homeostasis,unfolded protein response,lipoprotein metabolism and lysosome biogenesis.展开更多
Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions.Xlinked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the A...Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions.Xlinked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the ABCD1 gene,which encodes a transporter mediating the uptake of very long-chain fatty acids(VLCFAs).The curative approaches for PDs are very limited.Here,we investigated whether cholesterol accumulation in the lysosomes is a biochemical feature shared by a broad spectrum of PDs.We individually knocked down fifteen PD-associated genes in cultured cells and found ten induced cholesterol accumulation in the lysosome.2-Hydroxypropyl-β-cyclodextrin(HPCD)effectively alleviated the cholesterol accumulation phenotype in PD-mimicking cells through reducing intracellular cholesterol content as well as promoting cholesterol redistribution to other cellular membranes.In ABCD1 knockdown cells,HPCD treatment lowered reactive oxygen species and VLCFA to normal levels.In Abcd1 knockout mice,HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal cortex.The plasma levels of adrenocortical hormones were increased and the behavioral abnormalities were greatly ameliorated upon HPCD administration.Together,our results suggest that defective cholesterol transport underlies most,if not all,PDs,and that HPCD can serve as a novel and effective strategy for the treatment of PDs.展开更多
Low-density lipoprotein(LDL)is the main carrier of cholesterol and cholesteryl ester in circulation.High plasma levels of LDL cholesterol(LDL-C)are a major risk factor of atherosclerotic cardiovascular disease(ASCVD)....Low-density lipoprotein(LDL)is the main carrier of cholesterol and cholesteryl ester in circulation.High plasma levels of LDL cholesterol(LDL-C)are a major risk factor of atherosclerotic cardiovascular disease(ASCVD).LDL-C lowering is recommended by many guidelines for the prevention and treatment of ASCVD.Statins,ezetimibe,and proprotein convertase subtilisin/kexin type 9 inhibitors are the mainstay of LDL-C-lowering therapy.Novel therapies are also emerging for patients who are intolerant to statins or respond poorly to standard treatments.Here,we review the most recent advances on LDL-C-lowering drugs,focusing on the mechanisms by which they act to reduce LDL-C levels.The article starts with the cornerstone therapies applicable to most patients at risk for ASCVD.Special treatments for those with little or no LDL receptor function then follow.The inhibitors of ATP-citrate lyase and cholesteryl ester transfer protein,which are recently approved and still under investigation for LDL-C lowering,respectively,are also included.Strategies targeting the stability of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol catabolism can be novel regimens to reduce LDL-C levels and cardiovascular risk.展开更多
Primary cilium,which protrudes from the cell,is a microtubule-based structure ensheathed by a highly specialized plasma membrane(PM).It serves as a signaling hub for sensing and transducing various external stimuli in...Primary cilium,which protrudes from the cell,is a microtubule-based structure ensheathed by a highly specialized plasma membrane(PM).It serves as a signaling hub for sensing and transducing various external stimuli including fluids,light,odorants as well as extracellular molecules.Of various signal transduction pathways that act through the primary cilium,the Hedgehog(Hh)pathway draws the most attention owing to its essential role in vertebrate development and its intimate link to carcinogenesis(Bangs and Anderson,2017).The major components of the Hh pathway include the secreted ligand Hh,two transmembrane proteins Patched(Ptch)and Smoothened(Smo),and the transcription factor glioma-associated oncogene(Gli).Ptch is the receptor for Hh which,in the absence of Hh,resides at the primary cilium and prevents ciliary localization and activation of Smo.Upon Hh binding,however,Ptch is suppressed and displaced from the ciliary membrane.This permits Smo to enter the primary cilium and initiate a cascade of events that lead to the activation of Gli transcription factors and transcription of downstream target genes.展开更多
基金supported by grants from the National Natural Science Foundation of China(31521062,31570807,31571213,31625014,31621063,31630019,31830040,91857000 and 91857108)the Ministry of Science and Technology of China(2016YFA0500100,2016YFC1304803,2017YFA0503404 and 2018YFA0506900)
文摘Glucose and fatty acids are the major sources of energy for human body. Cholesterol, the most abundant sterol in mammals, is a key component of cell membranes although it does not generate ATP. The metabolisms of glucose, fatty acids and cholesterol are often intertwined and regulated. For example, glucose can be converted to fatty acids and cholesterol through de novo lipid biosynthesis pathways. Excessive lipids are secreted in lipoproteins or stored in lipid droplets. The metabolites of glucose and lipids are dynamically transported intercellularly and intracellularly, and then converted to other molecules in specific compartments. The disorders of glucose and lipid metabolism result in severe diseases including cardiovascular disease, diabetes and fatty liver. This review summarizes the major metabolic aspects of glucose and lipid, and their regulations in the context of physiology and diseases.
基金supported by the National Natural Science Foundation of China (91754102, 31771568, 31690102, 31600651, 31701030)National Key Research and Development Project of the Ministry of Science and Technology of China (2016YFA0500100)+2 种基金Shenzhen City Technology Basic Research Program (JCYJ20170818144026198)Science and Technology Department of Hubei Province (2017CFB617)the 111 Project of Ministry of Education of China (B16036)
文摘Most mammalian cells take up cholesterol from low-density lipoproteins(LDLs) via receptor-mediated endocytosis.After reaching lysosomes,LDL-derived cholesterol continues to transport to downstream organelles including the ER for specific structural and functional needs.Peroxisomes are recently found to receive cholesterol from lysosomes through lysosomeperoxisome membrane contacts.However,whether and how cholesterol is conveyed from peroxisomes to the ER remain unknown.Here,by combining high-resolution microscopic analyses and in vitro reconstitution of highly purified organelles or artificial liposomes,we demonstrate that peroxisomes form membrane contacts with the ER through the interaction between peroxisomal PI(4,5)P2 and ER-resident extended synaptotagmin-1,2 and 3(E-Syts).Depletion of peroxisomal PI(4,5)P2 or ESyts markedly decreases peroxisome-ER membrane contacts and induces cholesterol accumulation in lysosomes.Furthermore,we show that cholesterol is delivered from 3H-labeled peroxisomes or PI(4,5)P2-containing liposomes to the ER in vitro,and that the presence of peroxisomes augments cholesterol transfer from lysosomes to the ER.Together,our study reveals a new cholesterol transport pathway along the lysosome-peroxisome-ER membrane contacts in the cell.
文摘We have previously reported that the human ACAT1 gene produces a chimeric mRNA through the interchromosomal processing of two discontinuous RNAs transcribed from chromosomes 1 and 7. The chimeric mRNA uses AUG1397-1399 and GGC1274-1276 as translation initiation codons to produce normal 50-kDa ACAT1 and a novel enzymatically active 56-kDa isoform, respectively, with the latter being authentically present in human cells, including human monocyte- derived macrophages. In this work, we report that RNA secondary structures located in the vicinity of the GGC1274-1276 codon are required for production of the 56-kDa isoform. The effects of the three predicted stem-loops （nt 1255-1268, 1286-1342 and 1355-1384） were tested individually by transfecting expression plasmids into cells that contained the wild-type, deleted or mutant stem-loop sequences linked to a partial ACAT1 AUG open reading frame （ORF） or to the ORFs of other genes. The expression patterns were monitored by western blot analyses. We found that the upstream stem-loop1255-1268 from chromosome 7 and downstream stem-loop1286-1342 from chromosome 1 were needed for production of the 56-kDa isoform, whereas the last stem-loop135s-1384 from chromosome 1 was dispensable. The results of experi- ments using both monocistronic and bicistronic vectors with a stable hairpin showed that translation initiation from the GGC1274-1276 codon was mediated by an internal ribosome entry site （IRES）. Further experiments revealed that translation initiation from the GGC1274-1276 codon requires the upstream AU-constituted RNA secondary structure and the downstream GC-rich structure. This mechanistic work provides further support for the biological significance of the chimeric nature of the human ACAT1 transcript.
文摘Transposable elements(TEs)account for a large proportion of eukaryotic genomes and contribute to the evolution of novel genic sequences as well as regulatory elements(Long et al.,2003;Wang et al.,2019;Wang et al.,2016b).The questions of how and to what extent transposable elements may contribute to new functional genes remain largely unknown.In the current issue,Yang et al.
基金supported by National Natural Science Foundation of China (91754102, 31771568, 31701030, 31601147, 31600651)111 Project of Ministry of Education of China (B16036)Natural Science Foundation of Hubei Province (2016CFA012)
文摘Niemann-Pick type C2(NPC2) is a lysosome luminal protein that functions in concert with NPC1 to mediate egress of lowdensity lipoprotein-derived cholesterol from lysosome. The nuclear factor kappa B subunit 2(NF-κB2) protein is a component of NF-κB transcription factor complex critically implicated in immune and inflammatory responses. Here, we report that NF-κB2 regulates intracellular cholesterol transport by controlling NPC2 expression. RNAi-mediated disruption of NF-κB2, as well as other signaling members of the non-canonical NF-κB pathway, caused intracellular cholesterol accumulation. Blockage of the non-canonical NF-κB pathway suppressed NPC2 expression, whereas Lymphotoxin β receptor(LTβR) activation or Baff receptor(BaffR) stimulation up-regulated the mRNA abundance and protein level of NPC2. Further, NF-κB2 activated NPC2 transcription through direct binding to its promoter region. We also observed cholesterol accumulation in NF-κB2-deficient zebrafish embryo and NF-κB2 mutant mice. Collectively, these data identify a regulatory role for the non-canonical NF-κB pathway in intracellular cholesterol trafficking and suggest a link between cholesterol transport and immune system.
文摘Sterol-regulatory element binding proteins(SREBPs)are the key transcriptional regulators of lipid metabolism.The activation of SREBP requires translocation of the SREBP precursor from the endoplasmic reticulum to the Golgi,where it is sequentially cleaved by site-1 protease(S1P)and site-2 protease and releases a nuclear form to modulate gene expression.To search for new genes regulating cholesterol metabolism,we perform a genome-wide CRISPR/Cas9 knockout screen and find that partner of site-1 protease(POSH),encoded by C120RF49,is critically involved in the SREBP signaling.Ablation of POSH decreases the generation of nuclear SREBP and reduces the expression of SREBP target genes.POSH binds S1P,which is synthesized as an inactive protease(form A)and becomes fully mature via a two-step autocatalytic process involving forms B/B and C/C.POSH promotes the generation of the functional S1P-C/C from S1P-B/B(canonical cleavage)and,notably,from S1P-A directly(non-canonical cleavage)as well.This POSH-mediated S1P activation is also essential for the cleavages of other S1P substrates including ATF6,CREB3 family members and the a/p-subunit precursor of N-acetylglucosamine-1-phospho-transferase.Together,we demonstrate that POSH is a cofactor controlling S1P maturation and plays important roles in lipid homeostasis,unfolded protein response,lipoprotein metabolism and lysosome biogenesis.
基金supported by the China Postdoctoral Science Foundation Grant(2021M692478)the Ministry of Science and Technology of China(2018YFA0800703)+2 种基金the National Natural Science Foundation of China(32293203,31771568)111 Project of Ministry of Education of China(B16036)the support from the Tencent Foundation through the XPLORER PRIZE。
文摘Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions.Xlinked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the ABCD1 gene,which encodes a transporter mediating the uptake of very long-chain fatty acids(VLCFAs).The curative approaches for PDs are very limited.Here,we investigated whether cholesterol accumulation in the lysosomes is a biochemical feature shared by a broad spectrum of PDs.We individually knocked down fifteen PD-associated genes in cultured cells and found ten induced cholesterol accumulation in the lysosome.2-Hydroxypropyl-β-cyclodextrin(HPCD)effectively alleviated the cholesterol accumulation phenotype in PD-mimicking cells through reducing intracellular cholesterol content as well as promoting cholesterol redistribution to other cellular membranes.In ABCD1 knockdown cells,HPCD treatment lowered reactive oxygen species and VLCFA to normal levels.In Abcd1 knockout mice,HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal cortex.The plasma levels of adrenocortical hormones were increased and the behavioral abnormalities were greatly ameliorated upon HPCD administration.Together,our results suggest that defective cholesterol transport underlies most,if not all,PDs,and that HPCD can serve as a novel and effective strategy for the treatment of PDs.
基金This work was supported by grants from the Ministry of Science and Technology(2018YFA0800703)the National Natural Science Foundation(91957103,31690102,32021003,and 91957208).B.-L.Song acknowledges the support from the Tencent Foundation through the XPLORER PRIZE.
文摘Low-density lipoprotein(LDL)is the main carrier of cholesterol and cholesteryl ester in circulation.High plasma levels of LDL cholesterol(LDL-C)are a major risk factor of atherosclerotic cardiovascular disease(ASCVD).LDL-C lowering is recommended by many guidelines for the prevention and treatment of ASCVD.Statins,ezetimibe,and proprotein convertase subtilisin/kexin type 9 inhibitors are the mainstay of LDL-C-lowering therapy.Novel therapies are also emerging for patients who are intolerant to statins or respond poorly to standard treatments.Here,we review the most recent advances on LDL-C-lowering drugs,focusing on the mechanisms by which they act to reduce LDL-C levels.The article starts with the cornerstone therapies applicable to most patients at risk for ASCVD.Special treatments for those with little or no LDL receptor function then follow.The inhibitors of ATP-citrate lyase and cholesteryl ester transfer protein,which are recently approved and still under investigation for LDL-C lowering,respectively,are also included.Strategies targeting the stability of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol catabolism can be novel regimens to reduce LDL-C levels and cardiovascular risk.
基金the National Natural Science Foundation of China(31771568,32021003 and 91954203)the Ministry of Science and Technology of China(2016YFA0500100).
文摘Primary cilium,which protrudes from the cell,is a microtubule-based structure ensheathed by a highly specialized plasma membrane(PM).It serves as a signaling hub for sensing and transducing various external stimuli including fluids,light,odorants as well as extracellular molecules.Of various signal transduction pathways that act through the primary cilium,the Hedgehog(Hh)pathway draws the most attention owing to its essential role in vertebrate development and its intimate link to carcinogenesis(Bangs and Anderson,2017).The major components of the Hh pathway include the secreted ligand Hh,two transmembrane proteins Patched(Ptch)and Smoothened(Smo),and the transcription factor glioma-associated oncogene(Gli).Ptch is the receptor for Hh which,in the absence of Hh,resides at the primary cilium and prevents ciliary localization and activation of Smo.Upon Hh binding,however,Ptch is suppressed and displaced from the ciliary membrane.This permits Smo to enter the primary cilium and initiate a cascade of events that lead to the activation of Gli transcription factors and transcription of downstream target genes.
文摘瞬变电磁一维反演方法对初始模型依赖大,对异常体边界反映不清晰,计算速度也难以达到实时化水平.为此,本文开展基于深度学习的瞬变电磁实时反演方法研究,提出在非观测时间段进行反演训练,而在观测时间段进行实时精细成像的瞬变电磁长短时记忆网络反演策略.以正演模拟获得的海量采样时间-视电阻率为输入数据,基于长短时记忆网络构造Seq2seq编码器-解码器模型,并针对瞬变电磁反演的问题特性,对decoder的结构进行适应性更改,同时加入Bahdanau Attention机制突出重点信息作用,获得深度-电阻率输出数据.将该反演网络应用于随机生成的数万组以上三层和五层地电模型,测试组三大衡量指标标准差均小于10%,验证了本文算法的可靠性,在此基础上,构建了接近实际的两组含局部异常体模型,将该反演网络进一步用于三维数值模拟数据,取得了对异常体边界反映清晰的成像结果,且计算速度均小于1 s.
