Glycolysis-Mediated Activation of v-ATPase by Nicotinamide Mononucleotide Ameliorates Lipid-Induced Cardiomyopathy by Repressing the CD36-TLR4 Axis

作者全名："Wang, Shujin; Han, Yinying; Liu, Ruimin; Hou, Mengqian; Neumann, Dietbert; Zhang, Jun; Wang, Fang; Li, Yumeng; Zhao, Xueya; Schianchi, Francesco; Dai, Chao; Liu, Lizhong; Nabben, Miranda; Glatz, Jan F. C.; Wu, Xin; Lu, Xifeng; Li, Xi; Luiken, Joost J. F. P."

作者地址："[Wang, Shujin; Han, Yinying; Liu, Ruimin; Hou, Mengqian; Zhang, Jun; Zhao, Xueya; Li, Xi] Chongqing Med Univ, Sch Basic Med, Inst Life Sci, Chongqing 400016, Peoples R China; [Wang, Shujin; Wang, Fang; Schianchi, Francesco; Nabben, Miranda; Glatz, Jan F. C.; Luiken, Joost J. F. P.] Maastricht Univ, Fac Hlth Med & Life Sci, Dept Genet & Cell Biol, Maastricht, Netherlands; [Liu, Ruimin] Capital Med Univ, Anzhen Hosp, Dept Ultrasound, Beijing, Peoples R China; [Neumann, Dietbert] Maastricht Univ Med Ctr, Dept Pathol, Maastricht, Netherlands; [Nabben, Miranda; Glatz, Jan F. C.; Luiken, Joost J. F. P.] Maastricht Univ Med Ctr, Dept Clin Genet, Maastricht, Netherlands; [Li, Yumeng; Zhao, Xueya] Chinese Acad Sci, Tianjin Inst Ind Biotechnol, Tianjin, Peoples R China; [Dai, Chao; Wu, Xin] Inst Subtrop Agr, Chinese Acad Sci CAS, CAS Key Lab Agroecol Proc Subtrop Reg, Changsha, Peoples R China; [Liu, Lizhong] Shenzhen Univ, Dept Physiol, Med Sch, Shenzhen, Peoples R China; [Nabben, Miranda] Maastricht Sch Cardiovasc Dis, Cardiovasc Res Inst, Maastricht, Netherlands; [Lu, Xifeng] Shantou Univ, Affiliated Hosp 1, Med Coll, Clin Res Ctr, Shantou, Peoples R China; [Han, Yinying] Anhui Med Univ, Affiliated Hosp 1, Dept Infect Dis, Hefei, Peoples R China"

通信作者："Wang, SJ; Li, X (通讯作者)，Chongqing Med Univ, Sch Basic Med, Inst Life Sci, Chongqing 400016, Peoples R China.; Lu, XF (通讯作者)，Shantou Univ, Affiliated Hosp 1, Med Coll, Clin Res Ctr, Shantou, Peoples R China."

来源：CIRCULATION RESEARCH

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001178435400012

JCR分区：Q1

影响因子：16.5

年份：2024

卷号：134

期号：5

开始页：505

结束页：525

文献类型：Article

关键词：diabetic cardiomyopathies; endosomes; fibrosis; insulin resistance; lipid metabolism; toll-like receptor 4

摘要："BACKGROUND:Chronic overconsumption of lipids followed by their excessive accumulation in the heart leads to cardiomyopathy. The cause of lipid-induced cardiomyopathy involves a pivotal role for the proton-pump vacuolar-type H+-ATPase (v-ATPase), which acidifies endosomes, and for lipid-transporter CD36, which is stored in acidified endosomes. During lipid overexposure, an increased influx of lipids into cardiomyocytes is sensed by v-ATPase, which then disassembles, causing endosomal de-acidification and expulsion of stored CD36 from the endosomes toward the sarcolemma. Once at the sarcolemma, CD36 not only increases lipid uptake but also interacts with inflammatory receptor TLR4 (Toll-like receptor 4), together resulting in lipid-induced insulin resistance, inflammation, fibrosis, and cardiac dysfunction. Strategies inducing v-ATPase reassembly, that is, to achieve CD36 reinternalization, may correct these maladaptive alterations. For this, we used NAD+ (nicotinamide adenine dinucleotide)-precursor nicotinamide mononucleotide (NMN), inducing v-ATPase reassembly by stimulating glycolytic enzymes to bind to v-ATPase.METHODS:Rats/mice on cardiomyopathy-inducing high-fat diets were supplemented with NMN and for comparison with a cocktail of lysine/leucine/arginine (mTORC1 [mechanistic target of rapamycin complex 1]-mediated v-ATPase reassembly). We used the following methods: RNA sequencing, mRNA/protein expression analysis, immunofluorescence microscopy, (co)immunoprecipitation/proximity ligation assay (v-ATPase assembly), myocellular uptake of [3H]chloroquine (endosomal pH), and [14C]palmitate, targeted lipidomics, and echocardiography. To confirm the involvement of v-ATPase in the beneficial effects of both supplementations, mTORC1/v-ATPase inhibitors (rapamycin/bafilomycin A1) were administered. Additionally, 2 heart-specific v-ATPase-knockout mouse models (subunits V1G1/V0d2) were subjected to these measurements. Mechanisms were confirmed in pharmacologically/genetically manipulated cardiomyocyte models of lipid overload.RESULTS:NMN successfully preserved endosomal acidification during myocardial lipid overload by maintaining v-ATPase activity and subsequently prevented CD36-mediated lipid accumulation, CD36-TLR4 interaction toward inflammation, fibrosis, cardiac dysfunction, and whole-body insulin resistance. Lipidomics revealed C18:1-enriched diacylglycerols as lipid class prominently increased by high-fat diet and subsequently reversed/preserved by lysine/leucine/arginine/NMN treatment. Studies with mTORC1/v-ATPase inhibitors and heart-specific v-ATPase-knockout mice further confirmed the pivotal roles of v-ATPase in these beneficial actions.CONCLUSION:NMN preserves heart function during lipid overload by preventing v-ATPase disassembly."

基金机构：Stichting Fulbright Commission The Netherlands (NL)100021070

基金资助正文：No Statement Available