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Hitching a ride to the top:peroxisomes fuel cilium with cholesterol

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Science China(Life Sciences) 2021年第3期64卷 478-481页

作者： Jie Luo Yuan-Bin Liu bao-liang song Hubei Key Laboratory of Cell Homeostasis College of Life SciencesWuhan UniversityWuhan 430072China

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 *** 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 *** Hh binding,however,Ptch is suppressed and displaced from the ciliary *** 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.

关键词： ilium carcinogenesis specialized

The non-canonical NF-κB pathway promotes NPC2 expression and regulates intracellular cholesterol trafficking

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Science China(Life Sciences) 2018年第10期61卷 1222-1232页

作者： Yacheng Liao Jian Wei Juqiong Wang Xiongjie Shi Jie Luo bao-liang song Hubei Key Laboratory of Cell Homeostasis College of Life Sciences the Institute for Advanced StudiesWuhan University

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.

关键词： cholesterol transport NF-KB2 NPC2 transcriptional regulation

Regulation of glucose and lipid metabolism in health and disease

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Science China(Life Sciences) 2019年第11期62卷 1420-1458页

作者： Ligong Chen Xiao-Wei Chen Xun Huang bao-liang song Yan Wang Yiguo Wang School of Pharmaceutical Sciences Beijing Advanced Innovation Center for Structural BiologyKey Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology(Ministry of Education)Tsinghua UniversityBeijing 100084China State Key Laboratory of Membrane Biology Institute of Molecular MedicinePeking-Tsinghua Center for Life SciencesPeking UniversityBeijing 100871China State Key Laboratory of Molecular Developmental Biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China Hubei Key Laboratory of Cell Homeostasis College of Life SciencesWuhan UniversityWuhan 430072China MOE Key Laboratory of Bioinformatics Tsinghua-Peking Joint Center for Life SciencesSchool of Life SciencesTsinghua UniversityBeijing 100084China

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.

关键词： cholesterol fatty acid glucose lysosome endoplasmic reticulum lipid droplet metabolic disease

Lowering low-density lipoprotein cholesterol: from mechanisms to therapies

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Life Metabolism 2022年第1期1卷 25-38页

作者： Jie Luo Jin-Kai Wang bao-liang song College of Life Sciences Hubei Key Laboratory of Cell HomeostasisTaiKang Center for Life and Medical SciencesTaiKang Medical SchoolWuhan UniversityWuhanChina

Low-density lipoprotein(LDL)is the main carrier of cholesterol and cholesteryl ester in *** 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 ***,ezetimibe,and proprotein convertase subtilisin/kexin type 9 inhibitors are the mainstay of LDL-C-lowering *** therapies are also emerging for patients who are intolerant to statins or respond poorly to standard ***,we review the most recent advances on LDL-C-lowering drugs,focusing on the mechanisms by which they act to reduce LDL-C *** article starts with the cornerstone therapies applicable to most patients at risk for *** treatments for those with little or no LDL receptor function then *** 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 *** 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.

关键词： cholesterol low-density lipoprotein statin ezetimibe proprotein convertase subtilisin/kexin type 9 atherosclerotic cardiovascular disease

Lysosomal cholesterol accumulation is commonly found in most peroxisomal disorders and reversed by 2-hydroxypropyl-β-cyclodextrin

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Science China(Life Sciences) 2023年第8期66卷 1786-1799页

作者： Lewei Dong Jian Xiao Shuai Liu Gang Deng Yacheng Liao Beibei Chu Xiaolu Zhao bao-liang song Jie Luo College of Life Sciences Taikang Center for Life and Medical SciencesHubei Key Laboratory of Cell HomeostasisWuhan UniversityWuhan 430072China College of Veterinary Medicine Henan Agricultural UniversityZhengzhou 450046China

Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or *** 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 ***,we investigated whether cholesterol accumulation in the lysosomes is a biochemical feature shared by a broad spectrum of *** 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 *** ABCD1 knockdown cells,HPCD treatment lowered reactive oxygen species and VLCFA to normal *** Abcd1 knockout mice,HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal *** plasma levels of adrenocortical hormones were increased and the behavioral abnormalities were greatly ameliorated upon HPCD ***,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.

关键词： cholesterol peroxisome lysosome peroxisomal disorders X-ALD cyclodextrin ABCD1 VLCFA

Metal-Organic Framework Enabling Poly(Vinylidene Fluoride)-Based Polymer Electrolyte for Dendrite-Free and Long-Lifespan Sodium Metal Batteries

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Energy & Environmental Materials 2024年第1期7卷 68-76页

作者： Yusi Lei liang Yue Yuruo Qi Yubin Niu Shujuan bao Jie song Maowen Xu Faculty of Materials and Energy Institute for Clean Energy&Advanced MaterialsSouthwest UniversityChongqing 400715China Shandong Zero-One-Four Advanced Materials Co. Ltd.Feicheng 271099China

Sodium dentrite formed by uneven plating/stripping can reduce the utilization of active sodium with poor cyclic stability and,more importantly,cause internal short circuit and lead to thermal runaway and ***,sodium dendrites and their related problems seriously hinder the practical application of sodium metal batteries(SMBs).Herein,a design concept for the incorporation of metal-organic framework(MOF)in polymer matrix(polyvinylidene fluoride-hexafluoropropylene)is practiced to prepare a novel gel polymer electrolyte(PH@MOF polymer-based electrolyte[GPE])and thus to achieve high-performance *** addition of the MOF particles can not only reduce the movement hindrance of polymer chains to promote the transfer of Na^(+)but also anchor anions by virtue of their negative charge to reduce polarization during electrochemical reaction.A stable cycling performance with tiny overpotential for over 800 h at a current density of 5 mA cm^(-2)with areal capacity of 5 mA h cm^(-2)is achieved by symmetric cells based on the resulted GPE while the Na_(3)V_(2)O_(2)(PO_(4))_(2)F@rGO(NVOPF)|PH@MOF|Nacell also displays impressive specific cycling capacity(113.3 mA h g^(-1)at 1 C)and rate capability with considerable capacity retention.

关键词： dendrite-free gel polymer electrolyte metal organic framework sodium batteries

Functions of cholesterol in development and atherosclerotic cardiovascular disease

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Functions of cholesterol in development and atherosclerotic ...

POST1/C12ORF49 regulates the SREBP pathway by promoting site-1 protease maturation

第四届中国生物物理学会代谢生物学分会学术研讨会

作者： bao-liang song College of Life Sciences Wuhan University

＜正＞Cholesterol plays a critical role in regulating embryonic development and membrane functions. But high level of circulating cholesterol causes cardiovascular *** （Hh） has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of Smoothened （SMO）. We performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 （D95） residue through an ester bond. This modification was inhibited by Patched-1 （Ptch1） but enhanced by Hh. The SMO（D95N） mutation,

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来源： cnki会议评论

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Protein & Cell 2021年第4期12卷 279-296页

作者： Jian Xiao Yanni Xiong Liu-Ting Yang Ju-Qiong Wang Zi-Mu Zhou Le-Wei Dong Xiong-Jie Shi Xiaolu Zhao Jie Luo bao-liang song Hubei Key Laboratory of Cell Homeostasis College of Life SciencesFrontier Science Center for Immunology and MetabolismWuhan UniversityWuhan 430072China

Sterol-regulatory element binding proteins(SREBPs)are the key transcriptional regulators of lipid *** 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 *** 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 *** of POSH decreases the generation of nuclear SREBP and reduces the expression of SREBP target *** 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/*** 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 *** 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 ***,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.

关键词： SREBP site-1 protease proteolytic activation unfolded protein response activating transcription factor 6 mannose-6-phosphate

The liver-adipose tissue crosstalk in lipid biosynthesis

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The liver-adipose tissue crosstalk in lipid biosynthesis