Molecular Metabolism最新文献

{"title":"Imatinib therapy of chronic myeloid leukemia significantly reduces carnitine cell intake, resulting in adverse events","authors":"Pavel Burda ,&nbsp;Alzbeta Hlavackova ,&nbsp;Vendula Polivkova ,&nbsp;Nikola Curik ,&nbsp;Adam Laznicka ,&nbsp;Jitka Krizkova ,&nbsp;Jiri Suttnar ,&nbsp;Pavel Klener ,&nbsp;Katerina Machova Polakova","doi":"10.1016/j.molmet.2024.102016","DOIUrl":"10.1016/j.molmet.2024.102016","url":null,"abstract":"<div><h3>Objective</h3><p>A prominent, safe and efficient therapy for patients with chronic myeloid leukemia (CML) is inhibiting oncogenic protein BCR::ABL1 in a targeted manner with imatinib, a tyrosine kinase inhibitor. A substantial part of patients treated with imatinib report skeletomuscular adverse events affecting their quality of life. OCTN2 membrane transporter is involved in imatinib transportation into the cells. At the same time, the crucial physiological role of OCTN2 is cellular uptake of carnitine which is an essential co-factor for the mitochondrial β-oxidation pathway. This work investigates the impact of imatinib treatment on carnitine intake and energy metabolism of muscle cells.</p></div><div><h3>Methods</h3><p>HTB-153 (human rhabdomyosarcoma) cell line and KCL-22 (CML cell line) were used to study the impact of imatinib treatment on intracellular levels of carnitine and vice versa. The energy metabolism changes in cells treated by imatinib were quantified and compared to changes in cells exposed to highly specific OCTN2 inhibitor vinorelbine. Mouse models were used to test whether <em>in vitro</em> observations are also achieved <em>in vivo</em> in thigh muscle tissue. The analytes of interest were quantified using a Prominence HPLC system coupled with a tandem mass spectrometer.</p></div><div><h3>Results</h3><p>This work showed that through the carnitine-specific transporter OCTN2, imatinib and carnitine intake competed unequally and intracellular carnitine concentrations were significantly reduced. In contrast, carnitine preincubation did not influence imatinib cell intake or interfere with leukemia cell targeting. Blocking the intracellular supply of carnitine with imatinib significantly reduced the production of most Krebs cycle metabolites and ATP. However, subsequent carnitine supplementation rescued mitochondrial energy production. Due to specific inhibition of OCTN2 activity, the influx of carnitine was blocked and mitochondrial energy metabolism was impaired in muscle cells <em>in vitro</em> and in thigh muscle tissue in a mouse model.</p></div><div><h3>Conclusions</h3><p>This preclinical experimental study revealed detrimental effect of imatinib on carnitine-mediated energy metabolism of muscle cells providing a possible molecular background of the frequently occurred side effects during imatinib therapy such as fatigue, muscle pain and cramps.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102016"},"PeriodicalIF":7.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001479/pdfft?md5=5d06e3c1393685b044f76a4004fd6375&pid=1-s2.0-S2212877824001479-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel lncRNA GM47544 modulates triglyceride metabolism by inducing ubiquitination-dependent protein degradation of APOC3","authors":"Qianqian Xiao ,&nbsp;Luyun Wang ,&nbsp;Jing Wang ,&nbsp;Man Wang ,&nbsp;Dao Wen Wang ,&nbsp;Hu Ding","doi":"10.1016/j.molmet.2024.102011","DOIUrl":"10.1016/j.molmet.2024.102011","url":null,"abstract":"<div><h3>Objective</h3><p>Emerging evidence highlights the pivotal roles of long non-coding RNAs (lncRNAs) in lipid metabolism. Apoprotein C3 (ApoC3) is a well-established therapeutic target for hypertriglyceridemia and exhibits a strong association with cardiovascular disease. However, the exact mechanisms via which the lncRNAs control ApoC3 expression remain unclear.</p></div><div><h3>Methods</h3><p>We identified a novel long noncoding RNA (lncRNA), <em>GM47544</em>, within the ApoA1/C3/A4/A5 gene cluster. Subsequently, the effect of <em>GM47544</em> on intracellular triglyceride metabolism was analyzed. The diet-induced mouse models of hyperlipidemia and atherosclerosis were established to explore the effect of <em>GM47544</em> on dyslipidemia and plaque formation <em>in vivo</em>. The molecular mechanism was explored through RNA sequencing, immunoprecipitation, RNA pull-down assay, and RNA immunoprecipitation.</p></div><div><h3>Results</h3><p><em>GM47544</em> was overexpressed under high-fat stimulation. <em>GM47544</em> effectively improved hepatic steatosis, reduced blood lipid levels, and alleviated atherosclerosis <em>in vitro</em> and <em>in vivo</em>. Mechanistically, <em>GM47544</em> directly bound to ApoC3 and facilitated the ubiquitination at lysine 79 in ApoC3, thereby facilitating ApoC3 degradation via the ubiquitin-proteasome pathway. Moreover, we identified <em>AP006216.5</em> as the human <em>GM47544</em> transcript, which fulfills a comparable function in human hepatocytes.</p></div><div><h3>Conclusions</h3><p>The identification of <em>GM47544</em> as a lncRNA modulator of ApoC3 reveals a novel mechanism of post-translational modification, with significant clinical implications for the treatment of hypertriglyceridemia and atherosclerosis.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102011"},"PeriodicalIF":7.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221287782400142X/pdfft?md5=34d4578f7f8fb6bc314ccce52f0a393a&pid=1-s2.0-S221287782400142X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conditional deletion of CEACAM1 in hepatic stellate cells causes their activation","authors":"Harrison T. Muturi ,&nbsp;Hilda E. Ghadieh ,&nbsp;Suman Asalla ,&nbsp;Sumona G. Lester ,&nbsp;Getachew D. Belew ,&nbsp;Sobia Zaidi ,&nbsp;Raziyeh Abdolahipour ,&nbsp;Abhishek P. Shrestha ,&nbsp;Agnes O. Portuphy ,&nbsp;Hannah L. Stankus ,&nbsp;Raghd Abu Helal ,&nbsp;Stefaan Verhulst ,&nbsp;Sergio Duarte ,&nbsp;Ali Zarrinpar ,&nbsp;Leo A. van Grunsven ,&nbsp;Scott L. Friedman ,&nbsp;Robert F. Schwabe ,&nbsp;Terry D. Hinds Jr. ,&nbsp;Sivarajan Kumarasamy ,&nbsp;Sonia M. Najjar","doi":"10.1016/j.molmet.2024.102010","DOIUrl":"10.1016/j.molmet.2024.102010","url":null,"abstract":"<div><h3>Objectives</h3><p>Hepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with metabolic dysfunction-associated steatohepatitis (MASH). Global and hepatocyte-specific deletions of <em>Ceacam1</em> impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPARγ on CEACAM1 transcription and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation.</p></div><div><h3>Methods</h3><p>We examined whether lentiviral shRNA-mediated CEACAM1 donwregulation (KD-LX2) activates cultured human LX2 stellate cells. We also generated <em>LratCre + Cc1</em>^{<em>fl/fl</em>} mutants with conditional <em>Ceacam1</em> deletion in HSCs and characterized their MASH phenotype. Media transfer experiments were employed to examine whether media from mutant human and murine HSCs activate their wild-type counterparts.</p></div><div><h3>Results</h3><p><em>LratCre + Cc1</em>^{<em>fl/fl</em>} mutants displayed hepatic inflammation and fibrosis but without insulin resistance or hepatic steatosis. Their HSCs, like KD-LX2 cells, underwent myofibroblastic transformation and their media activated wild-type HSCs. This was inhibited by nicotinic acid treatment which blunted the release of IL-6 and fatty acids, both of which activate the epidermal growth factor receptor (EGFR) tyrosine kinase. Gefitinib inhibition of EGFR and its downstream NF-κB/IL-6/STAT3 inflammatory and MAPK-proliferation pathways also blunted HSCs activation in the absence of CEACAM1.</p></div><div><h3>Conclusions</h3><p>Loss of CEACAM1 in HSCs provoked their myofibroblastic transformation in the absence of insulin resistance and hepatic steatosis. This response is mediated by autocrine HSCs activation of the EGFR pathway that amplifies inflammation and proliferation.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102010"},"PeriodicalIF":7.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001418/pdfft?md5=b57c6ee008b0431ca555967aad756b37&pid=1-s2.0-S2212877824001418-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial protein deacetylation by SIRT3 in osteoclasts promotes bone resorption with aging in female mice","authors":"Kimberly K. Richardson ,&nbsp;Gareeballah Osman Adam ,&nbsp;Wen Ling ,&nbsp;Aaron Warren ,&nbsp;Adriana Marques-Carvalho ,&nbsp;Jeff D. Thostenson ,&nbsp;Kimberly Krager ,&nbsp;Nukhet Aykin-Burns ,&nbsp;Stephanie D. Byrum ,&nbsp;Maria Almeida ,&nbsp;Ha-Neui Kim","doi":"10.1016/j.molmet.2024.102012","DOIUrl":"10.1016/j.molmet.2024.102012","url":null,"abstract":"<div><h3>Objectives</h3><p>The mitochondrial deacetylase sirtuin-3 (SIRT3) is necessary for the increased bone resorption and enhanced function of mitochondria in osteoclasts that occur with advancing age; how SIRT3 drives bone resorption remains elusive.</p></div><div><h3>Methods</h3><p>To determine the role of SIRT3 in osteoclast mitochondria, we used mice with conditional loss of <em>Sirt3</em> in osteoclast lineage and mice with germline deletion of either <em>Sirt3</em> or its known target <em>Pink</em>1.</p></div><div><h3>Results</h3><p>SIRT3 stimulates mitochondrial quality in osteoclasts in a PINK1-independent manner, promoting mitochondrial activity and osteoclast maturation and function, thereby contributing to bone loss in female but not male mice. Quantitative analyses of global proteomes and acetylomes revealed that deletion of <em>Sirt3</em> dramatically increased acetylation of osteoclast mitochondrial proteins, particularly ATPase inhibitory factor 1 (ATPIF1), an essential protein for mitophagy. Inhibition of mitophagy via mdivi-1 recapitulated the effect of deletion of <em>Sirt3</em> or <em>Atpif1</em> in osteoclast formation and mitochondrial function.</p></div><div><h3>Conclusions</h3><p>Decreasing mitophagic flux in osteoclasts may be a promising pharmacotherapeutic approach to treat osteoporosis in older adults.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102012"},"PeriodicalIF":7.0,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001431/pdfft?md5=a9155d0d1cfd89d98d7d2140e9f088ca&pid=1-s2.0-S2212877824001431-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HSP60 chaperone deficiency disrupts the mitochondrial matrix proteome and dysregulates cholesterol synthesis","authors":"Cagla Cömert ,&nbsp;Kasper Kjær-Sørensen ,&nbsp;Jakob Hansen ,&nbsp;Jasper Carlsen ,&nbsp;Jesper Just ,&nbsp;Brandon F. Meaney ,&nbsp;Elsebet Østergaard ,&nbsp;Yonglun Luo ,&nbsp;Claus Oxvig ,&nbsp;Lisbeth Schmidt-Laursen ,&nbsp;Johan Palmfeldt ,&nbsp;Paula Fernandez-Guerra ,&nbsp;Peter Bross","doi":"10.1016/j.molmet.2024.102009","DOIUrl":"10.1016/j.molmet.2024.102009","url":null,"abstract":"<div><h3>Objective</h3><p>Mitochondrial proteostasis is critical for cellular function. The molecular chaperone HSP60 is essential for cell function and dysregulation of HSP60 expression has been implicated in cancer and diabetes. The few reported patients carrying HSP60 gene variants show neurodevelopmental delay and brain hypomyelination. Hsp60 interacts with more than 260 mitochondrial proteins but the mitochondrial proteins and functions affected by HSP60 deficiency are poorly characterized.</p></div><div><h3>Methods</h3><p>We studied two model systems for HSP60 deficiency: (1) engineered HEK cells carrying an inducible dominant negative HSP60 mutant protein, (2) zebrafish HSP60 knockout larvae. Both systems were analyzed by RNASeq, proteomics, and targeted metabolomics, and several functional assays relevant for the respective model. In addition, skin fibroblasts from patients with disease-associated HSP60 variants were analyzed by proteomics.</p></div><div><h3>Results</h3><p>We show that HSP60 deficiency leads to a differentially downregulated mitochondrial matrix proteome, transcriptional activation of stress responses, and dysregulated cholesterol biosynthesis. This leads to lipid accumulation in zebrafish knockout larvae.</p></div><div><h3>Conclusions</h3><p>Our data provide a compendium of the effects of HSP60 deficiency on the mitochondrial matrix proteome. We show that HSP60 is a master regulator and modulator of mitochondrial functions and metabolic pathways. HSP60 dysfunction also affects cellular metabolism and disrupts the integrated stress response. The effect on cholesterol synthesis explains the effect of HSP60 dysfunction on myelination observed in patients carrying genetic variants of HSP60.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102009"},"PeriodicalIF":7.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001406/pdfft?md5=d1b8b84d08e9a5261b1d124f08fd7658&pid=1-s2.0-S2212877824001406-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucose intolerance as a consequence of hematopoietic stem cell dysfunction in offspring of obese mice","authors":"Merve Denizli ,&nbsp;James Ropa ,&nbsp;Lindsay Beasley ,&nbsp;Joydeep Ghosh ,&nbsp;Kelli DeVanna ,&nbsp;Taylor Spice ,&nbsp;Laura S. Haneline ,&nbsp;Maegan Capitano ,&nbsp;Kok Lim Kua","doi":"10.1016/j.molmet.2024.102008","DOIUrl":"10.1016/j.molmet.2024.102008","url":null,"abstract":"<div><h3>Objective</h3><p>Maternal obesity is increasingly common and negatively impacts offspring health. Children of mothers with obesity are at higher risk of developing diseases linked to hematopoietic system abnormalities and metabolism such as type 2 diabetes. Interestingly, disease risks are often dependent on the offspring's sex, suggesting sex-specific reprogramming effect of maternal obesity on offspring hematopoietic stem and progenitor cell (HSPC) function. However, the impact of maternal obesity exposure on offspring HSPC function, and the capability of HSPC to regulate offspring metabolic health is largely understudied. This study aims to test the hypothesis that offspring of obese mice exhibit sex-differences in HSPC function that affect offspring's metabolic health.</p></div><div><h3>Methods</h3><p>We first assessed bone marrow hematopoietic stem and progenitor cell phenotype using postnatal day 21 (P21) and 8-week-old C57BL/6J mice born to control and diet-induced obese dams. We also sorted HSPC (Lineage-, Sca1+, cKit + cells) from P21 mice for competitive primary and secondary transplant, as well as transcriptomic analysis. Body weight, adiposity, insulin tolerance test and glucose tolerance tests were performed in primary and secondary transplant recipient animals.</p></div><div><h3>Results</h3><p>We discovered sex-differences in offspring HSPC function in response to maternal obesity exposure, where male offspring of obese dams (MatOb) showed decreased HSPC numbers and engraftment, while female MatOb offspring remained largely unaffected. RNA-seq revealed immune stimulatory pathways in female MatOb offspring. Finally, only recipients of male MatOb offspring HSPC exhibited glucose intolerance.</p></div><div><h3>Conclusions</h3><p>This study demonstrated the lasting effect of maternal obesity exposure on offspring HSPC function and implicates HSPC in metabolic regulation.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102008"},"PeriodicalIF":7.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221287782400139X/pdfft?md5=f13eb9522ff2b72d9db1a4356fbf8a32&pid=1-s2.0-S221287782400139X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mitochondrial pyruvate carrier regulates adipose glucose partitioning in female mice","authors":"Christopher E. Shannon ,&nbsp;Terry Bakewell ,&nbsp;Marcel J. Fourcaudot ,&nbsp;Iriscilla Ayala ,&nbsp;Annie A. Smelter ,&nbsp;Edgar A. Hinostroza ,&nbsp;Giovanna Romero ,&nbsp;Mara Asmis ,&nbsp;Leandro C. Freitas Lima ,&nbsp;Martina Wallace ,&nbsp;Luke Norton","doi":"10.1016/j.molmet.2024.102005","DOIUrl":"10.1016/j.molmet.2024.102005","url":null,"abstract":"<div><h3>Objective</h3><p>The mitochondrial pyruvate carrier (MPC) occupies a critical node in intermediary metabolism, prompting interest in its utility as a therapeutic target for the treatment of obesity and cardiometabolic disease. Dysregulated nutrient metabolism in adipose tissue is a prominent feature of obesity pathophysiology, yet the functional role of adipose MPC has not been explored. We investigated whether the MPC shapes the adaptation of adipose tissue to dietary stress in female and male mice.</p></div><div><h3>Methods</h3><p>The impact of pharmacological and genetic disruption of the MPC on mitochondrial pathways of triglyceride assembly (lipogenesis and glyceroneogenesis) was assessed in 3T3L1 adipocytes and murine adipose explants, combined with analyses of adipose MPC expression in metabolically compromised humans. Whole-body and adipose-specific glucose metabolism were subsequently investigated in male and female mice lacking adipocyte MPC1 (<em>Mpc1</em>^AD−/−) and fed either standard chow, high-fat western style, or high-sucrose lipid restricted diets for 24 weeks, using a combination of radiolabeled tracers and GC/MS metabolomics.</p></div><div><h3>Results</h3><p>Treatment with UK5099 or siMPC1 impaired the synthesis of lipids and glycerol-3-phosphate from pyruvate and blunted triglyceride accumulation in 3T3L1 adipocytes, whilst MPC expression in human adipose tissue was negatively correlated with indices of whole-body and adipose tissue metabolic dysfunction. Mature adipose explants from <em>Mpc1</em>^AD−/− mice were intrinsically incapable of incorporating pyruvate into triglycerides. <em>In vivo</em>, MPC deletion restricted the incorporation of circulating glucose into adipose triglycerides, but only in female mice fed a zero fat diet, and this associated with sex-specific reductions in tricarboxylic acid cycle pool sizes and compensatory transcriptional changes in lipogenic and glycerol metabolism pathways. However, whole-body adiposity and metabolic health were preserved in <em>Mpc1</em>^AD−/− mice regardless of sex, even under conditions of zero dietary fat.</p></div><div><h3>Conclusions</h3><p>These findings highlight the greater capacity for mitochondrially driven triglyceride assembly in adipose from female versus male mice and expose a reliance upon MPC-gated metabolism for glucose partitioning in female adipose under conditions of dietary lipid restriction.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102005"},"PeriodicalIF":7.0,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001364/pdfft?md5=538729392c0d283f3f722866d7ac9094&pid=1-s2.0-S2212877824001364-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The low-density lipoprotein receptor contributes to carotenoid homeostasis by regulating tissue uptake and fecal elimination","authors":"Anthony P. Miller ,&nbsp;Walter C. Monroy ,&nbsp;Gema Soria ,&nbsp;Jaume Amengual","doi":"10.1016/j.molmet.2024.102007","DOIUrl":"10.1016/j.molmet.2024.102007","url":null,"abstract":"<div><h3>Objective</h3><p>Carotenoids are lipophilic plant molecules with antioxidant properties. Some carotenoids such as β-carotene also serve as vitamin A precursors, playing a key role in human health. Carotenoids are transported in lipoproteins with other lipids such as cholesterol, however, the mechanisms responsible for carotenoid storage in tissues and their non-enzymatic elimination remain relatively unexplored. The goal of this study was to examine the contribution of the low-density lipoprotein receptor (LDLR) in the bodily distribution and disposal of carotenoids.</p></div><div><h3>Methods</h3><p>We employed mice lacking one or both carotenoid-cleaving enzymes as suitable models for carotenoid accumulation. We examined the contribution of LDLR in carotenoid distribution by crossbreeding these mice with Ldlr-/- mice or overexpressing LDLR in the liver.</p></div><div><h3>Results</h3><p>Our results show that LDLR plays a dual role in carotenoid homeostasis by simultaneously favoring carotenoid storage in the liver and adipose tissue while facilitating their fecal elimination.</p></div><div><h3>Conclusions</h3><p>Our results highlight a novel role of the LDLR in carotenoid homeostasis, and unveil a previously unrecognized disposal pathway for these important bioactive molecules.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102007"},"PeriodicalIF":7.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001388/pdfft?md5=c24f61a7aa1444b2b5cd60e3dc7d0f59&pid=1-s2.0-S2212877824001388-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AT-7687, a novel GIPR peptide antagonist, combined with a GLP-1 agonist, leads to enhanced weight loss and metabolic improvements in cynomolgus monkeys","authors":"Mette H. Jensen ,&nbsp;Samra J. Sanni ,&nbsp;Ditte Riber ,&nbsp;Jens J. Holst ,&nbsp;Mette M. Rosenkilde ,&nbsp;Alexander H. Sparre-Ulrich","doi":"10.1016/j.molmet.2024.102006","DOIUrl":"10.1016/j.molmet.2024.102006","url":null,"abstract":"<div><h3>Objectives</h3><p>Obesity represents a global health crisis with significant patient burdens and healthcare costs. Despite the advances with glucagon-like peptide-1 (GLP-1) receptor agonists in treating obesity, unmet needs remain. This study characterizes a novel glucose-dependent insulinotropic polypeptide receptor (GIPR) peptide antagonist, AT-7687, evaluating its potential to enhance obesity treatment.</p></div><div><h3>Methods</h3><p>We assessed the in vitro potency and pharmacokinetics of AT-7687, alongside its therapeutic effects when administered subcutaneously (SC) alone and in combination with liraglutide to high-fat-diet-fed obese non-human primates (NHP). The study spanned a 42-day treatment period and a 15-day washout period.</p></div><div><h3>Results</h3><p>AT-7687 demonstrated a subnanomolar cAMP antagonistic potency (pKB of 9.5) in HEK-293 cells and a 27.4 h half-life in NHPs. It effectively maintained weight stability in obese monkeys, whereas placebo recipients had an 8.6% weight increase by day 42 (<em>P</em> = 0.01). Monotherapy with liraglutide resulted in a 12.4% weight reduction compared to placebo (<em>P</em> = 0.03) and combining AT-7687 with liraglutide led to a 16.3% weight reduction (<em>P</em> = 0.0002). The combination therapy significantly improved metabolic markers, reducing insulin levels by 52% (<em>P</em> = 0.008), glucose by 30% (<em>P</em> = 0.02), triglycerides by 39% (<em>P</em> = 0.05), total cholesterol by 29% (<em>P</em> = 0.03), and LDL cholesterol by 48% (<em>P</em> = 0.003) compared to placebo. AT-7687 treatment was well tolerated and not associated with any side effects.</p></div><div><h3>Conclusions</h3><p>This study underscores the potential of AT-7687 as a promising addition to current obesity treatments.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102006"},"PeriodicalIF":7.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001376/pdfft?md5=d4e3ed6d91b514b386ce580c9aecd09d&pid=1-s2.0-S2212877824001376-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141917128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal gut Bifidobacterium breve modifies fetal brain metabolism in germ-free mice","authors":"Jorge Lopez-Tello ,&nbsp;Raymond Kiu ,&nbsp;Zoe Schofield ,&nbsp;Cindy X.W. Zhang ,&nbsp;Douwe van Sinderen ,&nbsp;Gwénaëlle Le Gall ,&nbsp;Lindsay J. Hall ,&nbsp;Amanda N. Sferruzzi-Perri","doi":"10.1016/j.molmet.2024.102004","DOIUrl":"10.1016/j.molmet.2024.102004","url":null,"abstract":"<div><h3>Background</h3><p>Recent advances have significantly expanded our understanding of the gut microbiome's influence on host physiology and metabolism. However, the specific role of certain microorganisms in gestational health and fetal development remains underexplored.</p></div><div><h3>Objective</h3><p>This study investigates the impact of <em>Bifidobacterium breve</em> UCC2003 on fetal brain metabolism when colonized in the maternal gut during pregnancy.</p></div><div><h3>Methods</h3><p>Germ-free pregnant mice were colonized with or without <em>B. breve</em> UCC2003 during pregnancy. The metabolic profiles of fetal brains were analyzed, focusing on the presence of key metabolites and the expression of critical metabolic and cellular pathways.</p></div><div><h3>Results</h3><p>Maternal colonization with <em>B. breve</em> resulted in significant metabolic changes in the fetal brain. Specifically, ten metabolites, including citrate, 3-hydroxyisobutyrate, and carnitine, were reduced in the fetal brain. These alterations were accompanied by increased abundance of transporters involved in glucose and branched-chain amino acid uptake. Furthermore, supplementation with this bacterium was associated with elevated expression of critical metabolic pathways such as PI3K-AKT, AMPK, STAT5, and Wnt-β-catenin signaling, including its receptor Frizzled-7. Additionally, there was stabilization of HIF-2 protein and modifications in genes and proteins related to cellular growth, axogenesis, and mitochondrial function.</p></div><div><h3>Conclusions</h3><p>The presence of maternal <em>B. breve</em> during pregnancy plays a crucial role in modulating fetal brain metabolism and growth. These findings suggest that <em>Bifidobacterium</em> could modify fetal brain development, potentially offering new avenues for enhancing gestational health and fetal development through microbiota-targeted interventions.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102004"},"PeriodicalIF":7.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001352/pdfft?md5=3e90f92db17997955d5e68124ce516ef&pid=1-s2.0-S2212877824001352-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}