Biochemical Journal最新文献_第10页

AMP-activated protein kinase activation suppresses leptin expression independently of adipogenesis in primary murine adipocytes. AMPK 激活可抑制原代小鼠脂肪细胞中瘦素的表达，而与脂肪生成无关。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-03-06 DOI: 10.1042/BCJ20240003

Sophia Bustraan, Jane Bennett, Chad Whilding, Betheney R Pennycook, David Smith, Alexis R Barr, Jon Read, David Carling, Alice Pollard

{"title":"AMP-activated protein kinase activation suppresses leptin expression independently of adipogenesis in primary murine adipocytes.","authors":"Sophia Bustraan, Jane Bennett, Chad Whilding, Betheney R Pennycook, David Smith, Alexis R Barr, Jon Read, David Carling, Alice Pollard","doi":"10.1042/BCJ20240003","DOIUrl":"10.1042/BCJ20240003","url":null,"abstract":"Adipogenesis, defined as the development of mature adipocytes from stem cell precursors, is vital for the expansion, turnover and health of adipose tissue. Loss of adipogenic potential in adipose stem cells, or impairment of adipogenesis is now recognised as an underlying cause of adipose tissue dysfunction and is associated with metabolic disease. In this study, we sought to determine the role of AMP-activated protein kinase (AMPK), an evolutionarily conserved master regulator of energy homeostasis, in adipogenesis. Primary murine adipose-derived stem cells were treated with a small molecule AMPK activator (BI-9774) during key phases of adipogenesis, to determine the effect of AMPK activation on adipocyte commitment, maturation and function. To determine the contribution of the repression of lipogenesis by AMPK in these processes, we compared the effect of pharmacological inhibition of acetyl-CoA carboxylase (ACC). We show that AMPK activation inhibits adipogenesis in a time- and concentration-dependent manner. Transient AMPK activation during adipogenic commitment leads to a significant, ACC-independent, repression of adipogenic transcription factor expression. Furthermore, we identify a striking, previously unexplored inhibition of leptin gene expression in response to both short-term and chronic AMPK activation irrespective of adipogenesis. These findings reveal that in addition to its effect on adipogenesis, AMPK activation switches off leptin gene expression in primary mouse adipocytes independently of adipogenesis. Our results identify leptin expression as a novel target of AMPK through mechanisms yet to be identified.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"345-362"},"PeriodicalIF":4.1,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11088909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139680691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Role of the leucine-rich repeat protein kinase 2 C-terminal tail in domain cross-talk. LRRK2 C 端尾部在结构域串扰中的作用

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230477

Pallavi Kaila Sharma, Jui-Hung Weng, Jascha T Manschwetus, Jian Wu, Wen Ma, Friedrich W Herberg, Susan S Taylor

{"title":"Role of the leucine-rich repeat protein kinase 2 C-terminal tail in domain cross-talk.","authors":"Pallavi Kaila Sharma, Jui-Hung Weng, Jascha T Manschwetus, Jian Wu, Wen Ma, Friedrich W Herberg, Susan S Taylor","doi":"10.1042/BCJ20230477","DOIUrl":"10.1042/BCJ20230477","url":null,"abstract":"Leucine-rich repeat protein kinase 2 (LRRK2) is a multi-domain protein encompassing two of biology's most critical molecular switches, a kinase and a GTPase, and mutations in LRRK2 are key players in the pathogenesis of Parkinson's disease (PD). The availability of multiple structures (full-length and truncated) has opened doors to explore intra-domain cross-talk in LRRK2. A helix extending from the WD40 domain and stably docking onto the kinase domain is common in all available structures. This C-terminal (Ct) helix is a hub of phosphorylation and organelle-localization motifs and thus serves as a multi-functional protein : protein interaction module. To examine its intra-domain interactions, we have recombinantly expressed a stable Ct motif (residues 2480-2527) and used peptide arrays to identify specific binding sites. We have identified a potential interaction site between the Ct helix and a loop in the CORB domain (CORB loop) using a combination of Gaussian accelerated molecular dynamics simulations and peptide arrays. This Ct-Motif contains two auto-phosphorylation sites (T2483 and T2524), and T2524 is a 14-3-3 binding site. The Ct helix, CORB loop, and the CORB-kinase linker together form a part of a dynamic 'CAP' that regulates the N-lobe of the kinase domain. We hypothesize that in inactive, full-length LRRK2, the Ct-helix will also mediate interactions with the N-terminal armadillo, ankyrin, and LRR domains (NTDs) and that binding of Rab substrates, PD mutations, or kinase inhibitors will unleash the NTDs.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"313-327"},"PeriodicalIF":4.4,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139671223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IL-4 activates the futile triacylglyceride cycle for glucose utilization in white adipocytes. IL-4 激活白色脂肪细胞中葡萄糖利用的三酰甘油循环。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230486

Svetlana Michurina, Margarita Agareva, Ekaterina Zubkova, Mikhail Menshikov, Iurii Stafeev, Yelena Parfyonova

{"title":"IL-4 activates the futile triacylglyceride cycle for glucose utilization in white adipocytes.","authors":"Svetlana Michurina, Margarita Agareva, Ekaterina Zubkova, Mikhail Menshikov, Iurii Stafeev, Yelena Parfyonova","doi":"10.1042/BCJ20230486","DOIUrl":"10.1042/BCJ20230486","url":null,"abstract":"The development of cardiometabolic complications during obesity is strongly associated with chronic latent inflammation in hypertrophied adipose tissue (AT). IL-4 is an anti-inflammatory cytokine, playing a protective role against insulin resistance, glucose intolerance and weight gain. The positive effects of IL-4 are associated not only with the activation of anti-inflammatory immune cells in AT, but also with the modulation of adipocyte metabolism. IL-4 is known to activate lipolysis and glucose uptake in adipocytes, but the precise regulatory mechanisms and physiological significance of these processes remain unclear. In this study, we detail IL-4 effects on glucose and triacylglycerides (TAGs) metabolism and propose mechanisms of IL-4 metabolic action in adipocytes. We have shown that IL-4 activates glucose oxidation, lipid droplet (LD) fragmentation, lipolysis and thermogenesis in mature 3T3-L1 adipocytes. We found that lipolysis was not accompanied by fatty acids (FAs) release from adipocytes, suggesting FA re-esterification. Moreover, glucose oxidation and thermogenesis stimulation depended on adipocyte triglyceride lipase (ATGL) activity, but not the uncoupling protein (UCP1) expression. Based on these data, IL-4 may activate the futile TAG-FA cycle in adipocytes, which enhances the oxidative activity of cells and heat production. Thus, the positive effect of IL-4 on systemic metabolism can be the result of the activation of non-canonical thermogenic mechanism in AT, increasing TAG turnover and utilization of excessive glucose.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"329-344"},"PeriodicalIF":4.1,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139696873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of a 10-mer peptide from the death domain of MyD88 which attenuates inflammation and insulin resistance and improves glucose metabolism. 从 MyD88 的死亡域中鉴定出一种 10-mer 肽，它能减轻炎症和胰岛素抵抗，改善葡萄糖代谢。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230369

Mehmood Ali, Tripti Kumari, Arvind Gupta, Sariyah Akhtar, Rahul Dev Verma, Jimut Kanti Ghosh

{"title":"Identification of a 10-mer peptide from the death domain of MyD88 which attenuates inflammation and insulin resistance and improves glucose metabolism.","authors":"Mehmood Ali, Tripti Kumari, Arvind Gupta, Sariyah Akhtar, Rahul Dev Verma, Jimut Kanti Ghosh","doi":"10.1042/BCJ20230369","DOIUrl":"10.1042/BCJ20230369","url":null,"abstract":"Insulin resistance (IR) is the key pathophysiological cause of type 2 diabetes, and inflammation has been implicated in it. The death domain (DD) of the adaptor protein, MyD88 plays a crucial role in the transduction of TLR4-associated inflammatory signal. Herein, we have identified a 10-residue peptide (M10), from the DD of MyD88 which seems to be involved in Myddosome formation. We hypothesized that M10 could inhibit MyD88-dependent TLR4-signaling and might have effects on inflammation-associated IR. Intriguingly, 10-mer M10 showed oligomeric nature and reversible self-assembly property indicating the peptide's ability to recognize its own amino acid sequence. M10 inhibited LPS-induced nuclear translocation of NF-κB in L6 myotubes and also reduced LPS-induced IL-6 and TNF-α production in peritoneal macrophages of BALB/c mice. Remarkably, M10 inhibited IL-6 and TNF-α secretion in diabetic, db/db mice. Notably, M10 abrogated IR in insulin-resistant L6 myotubes, which was associated with an increase in glucose uptake and a decrease in Ser307-phosphorylation of IRS1, TNF-α-induced JNK activation and nuclear translocation of NF-κB in these cells. Alternate day dosing with M10 (10 and 20 mg/kg) for 30 days in db/db mice significantly lowered blood glucose and improved glucose intolerance after loading, 3.0 g/kg glucose orally. Furthermore, M10 increased insulin and adiponectin secretion in db/db mice. M10-induced glucose uptake in L6 myotubes involved the activation of PI3K/AKT/GLUT4 pathways. A scrambled M10-analog was mostly inactive. Overall, the results show the identification of a 10-mer peptide from the DD of MyD88 with anti-inflammatory and anti-diabetic properties, suggesting that targeting of TLR4-inflammatory pathway, could lead to the discovery of molecules against IR and diabetes.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"191-218"},"PeriodicalIF":4.1,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139471830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of filamentous matrix molecules in shaping the architecture and emergent properties of bacterial biofilms. 丝状基质分子在塑造细菌生物膜的结构和新兴特性中的作用。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-02-21 DOI: 10.1042/BCJ20210301

Jan Böhning, Abul K Tarafder, Tanmay A M Bharat

引用次数: 0

Colonic ketogenesis, a microbiota-regulated process, contributes to blood ketones and protects against colitis in mice. 结肠酮体生成是一个受微生物群调控的过程，它有助于血液中酮体的生成并防止小鼠患结肠炎。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230403

Kevin Bass, Sathish Sivaprakasam, Gunadharini Dharmalingam-Nandagopal, Muthusamy Thangaraju, Vadivel Ganapathy

{"title":"Colonic ketogenesis, a microbiota-regulated process, contributes to blood ketones and protects against colitis in mice.","authors":"Kevin Bass, Sathish Sivaprakasam, Gunadharini Dharmalingam-Nandagopal, Muthusamy Thangaraju, Vadivel Ganapathy","doi":"10.1042/BCJ20230403","DOIUrl":"10.1042/BCJ20230403","url":null,"abstract":"Ketogenesis is considered to occur primarily in liver to generate ketones as an alternative energy source for non-hepatic tissues when glucose availability/utilization is impaired. 3-Hydroxy-3-methylglutaryl-CoA synthase-2 (HMGCS2) mediates the rate-limiting step in this mitochondrial pathway. Publicly available databases show marked down-regulation of HMGCS2 in colonic tissues in Crohn's disease and ulcerative colitis. This led us to investigate the expression and function of this pathway in colon and its relevance to colonic inflammation in mice. Hmgcs2 is expressed in cecum and colon. As global deletion of Hmgcs2 showed significant postnatal mortality, we used a conditional knockout mouse with enzyme deletion restricted to intestinal tract. These mice had no postnatal mortality. Fasting blood ketones were lower in these mice, indicating contribution of colonic ketogenesis to circulating ketones. There was also evidence of gut barrier breakdown and increased susceptibility to experimental colitis with associated elevated levels of IL-6, IL-1β, and TNF-α in circulation. Interestingly, many of these phenomena were mostly evident in male mice. Hmgcs2 expression in colon is controlled by colonic microbiota as evidenced from decreased expression in germ-free mice and antibiotic-treated conventional mice and from increased expression in a human colonic epithelial cell line upon treatment with aqueous extracts of cecal contents. Transcriptomic analysis of colonic epithelia from control mice and Hmgcs2-null mice indicated an essential role for colonic ketogenesis in the maintenance of optimal mitochondrial function, cholesterol homeostasis, and cell-cell tight-junction organization. These findings demonstrate a sex-dependent obligatory role for ketogenesis in protection against colonic inflammation in mice.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"481 4","pages":"295-312"},"PeriodicalIF":4.1,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Parkinson's disease related mutant VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress. 与帕金森病相关的突变体 VPS35 (D620N) 会放大 LRRK2 对溶酶体内压力的反应。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230492

Katy R McCarron, Hannah Elcocks, Heather Mortiboys, Sylvie Urbé, Michael J Clague

{"title":"The Parkinson's disease related mutant VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress.","authors":"Katy R McCarron, Hannah Elcocks, Heather Mortiboys, Sylvie Urbé, Michael J Clague","doi":"10.1042/BCJ20230492","DOIUrl":"10.1042/BCJ20230492","url":null,"abstract":"The identification of multiple genes linked to Parkinson's disease (PD) invites the question as to how they may co-operate. We have generated isogenic cell lines that inducibly express either wild-type or a mutant form of the retromer component VPS35 (D620N), which has been linked to PD. This has enabled us to test proposed effects of this mutation in a setting where the relative expression reflects the physiological occurrence. We confirm that this mutation compromises VPS35 association with the WASH complex, but find no defect in WASH recruitment to endosomes, nor in the distribution of lysosomal receptors, cation-independent mannose-6-phosphate receptor and Sortilin. We show VPS35 (D620N) enhances the activity of the Parkinson's associated kinase LRRK2 towards RAB12 under basal conditions. Furthermore, VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress resulting in enhanced phosphorylation of RABs 10 and 12. By comparing different types of endolysosomal stresses such as the ionophore nigericin and the membranolytic agent l-leucyl-l-leucine methyl ester, we are able to dissociate phospho-RAB accumulation from membrane rupture.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"265-278"},"PeriodicalIF":4.1,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Beyond the tail: the consequence of context in histone post-translational modification and chromatin research. 超越尾巴：组蛋白翻译后修饰和染色质研究中的背景影响。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230342

Ellen N Weinzapfel, Karlie N Fedder-Semmes, Zu-Wen Sun, Michael-Christopher Keogh

引用次数: 0

The role of mitochondrial RNA association for mitochondrial homeostasis in neurons 线粒体 RNA 关联对神经元线粒体平衡的作用

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-02-07 DOI: 10.1042/bcj20230110

Segura, Inmaculada, Harbauer, Angelika

引用次数: 0

A highly conserved ligand-binding site for AccA transporters of antibiotic and quorum-sensing regulator in Agrobacterium leads to a different specificity. 在农杆菌中，抗生素和群体感应调节剂的AccA转运体的高度保守的配体结合位点导致了不同的特异性。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-01-25 DOI: 10.1042/BCJ20230273

Solange Moréra, Armelle Vigouroux, Magali Aumont-Nicaise, Mohammed Ahmar, Thibault Meyer, Abbas El Sahili, Grégory Deicsics, Almudena González-Mula, Sizhe Li, Jeanne Doré, Serena Sirigu, Pierre Legrand, Camille Penot, François André, Denis Faure, Laurent Soulère, Yves Queneau, Ludovic Vial

{"title":"A highly conserved ligand-binding site for AccA transporters of antibiotic and quorum-sensing regulator in Agrobacterium leads to a different specificity.","authors":"Solange Moréra, Armelle Vigouroux, Magali Aumont-Nicaise, Mohammed Ahmar, Thibault Meyer, Abbas El Sahili, Grégory Deicsics, Almudena González-Mula, Sizhe Li, Jeanne Doré, Serena Sirigu, Pierre Legrand, Camille Penot, François André, Denis Faure, Laurent Soulère, Yves Queneau, Ludovic Vial","doi":"10.1042/BCJ20230273","DOIUrl":"10.1042/BCJ20230273","url":null,"abstract":"Plants genetically modified by the pathogenic Agrobacterium strain C58 synthesize agrocinopines A and B, whereas those modified by the pathogenic strain Bo542 produce agrocinopines C and D. The four agrocinopines (A, B, C and D) serve as nutrients by agrobacteria and signaling molecule for the dissemination of virulence genes. They share the uncommon pyranose-2-phosphate motif, represented by the l-arabinopyranose moiety in agrocinopines A/B and the d-glucopyranose moiety in agrocinopines C/D, also found in the antibiotic agrocin 84. They are imported into agrobacterial cytoplasm via the Acc transport system, including the solute-binding protein AccA coupled to an ABC transporter. We have previously shown that unexpectedly, AccA from strain C58 (AccAC58) recognizes the pyranose-2-phosphate motif present in all four agrocinopines and agrocin 84, meaning that strain C58 is able to import agrocinopines C/D, originating from the competitor strain Bo542. Here, using agrocinopine derivatives and combining crystallography, affinity and stability measurements, modeling, molecular dynamics, in vitro and vivo assays, we show that AccABo542 and AccAC58 behave differently despite 75% sequence identity and a nearly identical ligand binding site. Indeed, strain Bo542 imports only compounds containing the d-glucopyranose-2-phosphate moiety, and with a lower affinity compared with strain C58. This difference in import efficiency makes C58 more competitive than Bo542 in culture media. We can now explain why Agrobacterium/Allorhizobium vitis strain S4 is insensitive to agrocin 84, although its genome contains a conserved Acc transport system. Overall, our work highlights AccA proteins as a case study, for which stability and dynamics drive specificity.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"93-117"},"PeriodicalIF":4.1,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138497730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0