Molecular Metabolism最新文献

{"title":"FITM2 deficiency results in ER lipid accumulation, ER stress, and reduced apolipoprotein B lipidation and VLDL triglyceride secretion in vitro and in mouse liver","authors":"Haizhen Wang ,&nbsp;Cyrus Nikain ,&nbsp;Konstantinos I. Fortounas ,&nbsp;Jaume Amengual ,&nbsp;Ozlem Tufanli ,&nbsp;Maxwell La Forest ,&nbsp;Yong Yu ,&nbsp;Meng C. Wang ,&nbsp;Russell Watts ,&nbsp;Richard Lehner ,&nbsp;Yunping Qiu ,&nbsp;Min Cai ,&nbsp;Irwin J. Kurland ,&nbsp;Ira J. Goldberg ,&nbsp;Sujith Rajan ,&nbsp;M. Mahmood Hussain ,&nbsp;Jeffrey L. Brodsky ,&nbsp;Edward A. Fisher","doi":"10.1016/j.molmet.2024.102048","DOIUrl":"10.1016/j.molmet.2024.102048","url":null,"abstract":"<div><h3>Objective</h3><div>Triglycerides (TGs) associate with apolipoprotein B100 (apoB100) to form very low density lipoproteins (VLDLs) in the liver. The repertoire of factors that facilitate this association is incompletely understood. FITM2, an integral endoplasmic reticulum (ER) protein, was originally discovered as a factor participating in cytosolic lipid droplet (LD) biogenesis in tissues that do not form VLDL. We hypothesized that in the liver, in addition to promoting cytosolic LD formation, FITM2 would also transfer TG from its site of synthesis in the ER membrane to nascent VLDL particles within the ER lumen.</div></div><div><h3>Methods</h3><div>Experiments were conducted using a rat hepatic cell line (McArdle-RH7777, or McA cells), an established model of mammalian lipoprotein metabolism, and mice. FITM2 expression was reduced using siRNA in cells and by liver specific cre-recombinase mediated deletion of the <em>Fitm2</em> gene in mice. Effects of FITM2 deficiency on VLDL assembly and secretion <em>in vitro</em> and <em>in vivo</em> were measured by multiple methods, including density gradient ultracentrifugation, chromatography, mass spectrometry, stimulated Raman scattering (SRS) microscopy, sub-cellular fractionation, immunoprecipitation, immunofluorescence, and electron microscopy.</div></div><div><h3>Main findings</h3><div>1) FITM2-deficient hepatic cells <em>in vitro</em> and <em>in vivo</em> secrete TG-depleted VLDL particles, but the number of particles is unchanged compared to controls; 2) FITM2 deficiency in mice on a high fat diet (HFD) results in decreased plasma TG levels. The number of apoB100-containing lipoproteins remains similar, but shift from VLDL to low density lipoprotein (LDL) density; 3) Both <em>in vitro</em> and <em>in vivo</em>, when TG synthesis is stimulated and FITM2 is deficient, TG accumulates in the ER, and despite its availability this pool is unable to fully lipidate apoB100 particles; 4) FITM2 deficiency disrupts ER morphology and results in ER stress.</div></div><div><h3>Conclusion</h3><div>The results suggest that FITM2 contributes to VLDL lipidation, especially when newly synthesized hepatic TG is in abundance. In addition to its fundamental importance in VLDL assembly, the results also suggest that under dysmetabolic conditions, FITM2 may be an important factor in the partitioning of TG between cytosolic LDs and VLDL particles.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102048"},"PeriodicalIF":7.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470174","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":"Distinct genetic signals at the FGF21 locus complicate studies of FGF21's role in diet regulation using human cohort data","authors":"Stina Ramne ,&nbsp;Mario García-Ureña ,&nbsp;Matthew P. Gillum ,&nbsp;Lars Ängquist ,&nbsp;Torben Hansen ,&nbsp;Jordi Merino ,&nbsp;Niels Grarup","doi":"10.1016/j.molmet.2024.102049","DOIUrl":"10.1016/j.molmet.2024.102049","url":null,"abstract":"<div><h3>Objectives</h3><div>Experimental and genetic studies suggest that fibroblast growth factor 21 (FGF21) modulates macronutrient and alcohol preferences, but evidence of such regulation in humans remains scarce. To address this gap in translation, we aimed to map the relationships between plasma FGF21 levels, <em>FGF21</em> genetic variation and habitual macronutrient intake in a large human population.</div></div><div><h3>Methods</h3><div>We fine-mapped and performed colocalization of the <em>FGF21</em> genetic region in GWAS summary statistics of plasma FGF21 levels and macronutrient intake. UK Biobank data were used to investigate the associations between <em>FGF21</em> genetic variants, plasma FGF21 protein levels, and macronutrient intake (including alcohol) assessed with repeated 24-hour recalls. One- and two-sample mendelian randomization were performed to estimate the effects of plasma FGF21 on macronutrient intake.</div></div><div><h3>Results</h3><div>We show that the main macronutrient-associated variant rs838133 and the FGF21 cis-pQTL rs838131, both in the <em>FGF21</em> gene, are distinct genetic signals. Effect directions also suggest that the influence of <em>FGF21</em> variation on macronutrient intake appear more complex than by direct mediation through plasma FGF21. Only when considering this complexity at <em>FGF21,</em> is plasma FGF21 estimated to reduce alcohol and increase protein and fat intake using mendelian randomization. Importantly, plasma FGF21 levels also appear markedly elevated by primarily high alcohol and low protein intake.</div></div><div><h3>Conclusions</h3><div>These findings support the feedback diet-regulatory mechanism of FGF21 in humans, but highlights the need for mechanistic characterization of the complex <em>FGF21</em> genetic region.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102049"},"PeriodicalIF":7.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470172","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":"Distinct roles for the domains of the mitochondrial aspartate/glutamate carrier citrin in organellar localization and substrate transport","authors":"Sotiria Tavoulari ,&nbsp;Denis Lacabanne ,&nbsp;Gonçalo C. Pereira ,&nbsp;Chancievan Thangaratnarajah,&nbsp;Martin S. King,&nbsp;Jiuya He,&nbsp;Suvagata R. Chowdhury,&nbsp;Lisa Tilokani,&nbsp;Shane M. Palmer,&nbsp;Julien Prudent,&nbsp;John E. Walker,&nbsp;Edmund R.S. Kunji","doi":"10.1016/j.molmet.2024.102047","DOIUrl":"10.1016/j.molmet.2024.102047","url":null,"abstract":"<div><h3>Objective</h3><div>Citrin, the mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), is structurally and mechanistically the most complex SLC25 family member, because it consists of three domains and forms a homo-dimer. Each protomer has an N-terminal calcium-binding domain with EF-hands, followed by a substrate-transporting carrier domain and a C-terminal domain with an amphipathic helix. The absence or dysfunction of citrin leads to citrin deficiency, a highly prevalent pan-ethnic mitochondrial disease. Here, we aim to understand the role of different citrin domains and how they contribute to pathogenic mechanisms in citrin deficiency.</div></div><div><h3>Methods</h3><div>We have employed structural modeling and functional reconstitution of purified proteins in proteoliposomes to assess the transport activity and calcium regulation of wild-type citrin and pathogenic variants associated with citrin deficiency. We have also developed a double knockout of citrin and aralar (AGC1), the two paralogs of the mitochondrial aspartate/glutamate carrier, in HAP1 cells to perform mitochondrial imaging and to investigate mitochondrial localisation.</div></div><div><h3>Results</h3><div>Using 33 pathogenic variants of citrin we clarify determinants of subcellular localization and transport mechanism. We identify crucial elements of the carrier domain that are required for transport, including those involved in substrate binding, network formation and dynamics. We show that the N-terminal domain is not involved in calcium regulation of transport, as previously thought, but when mutated causes a mitochondrial import defect.</div></div><div><h3>Conclusions</h3><div>Our work introduces a new role for the N-terminal domain of citrin and demonstrates that dysfunction of the different domains contributes to distinct pathogenic mechanisms in citrin deficiency.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102047"},"PeriodicalIF":7.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470173","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":"Hypothalamic tanycytes internalize ghrelin from the cerebrospinal fluid: Molecular mechanisms and functional implications","authors":"Ivana M. Gomez ,&nbsp;Maia Uriarte ,&nbsp;Gimena Fernandez ,&nbsp;Franco Barrile ,&nbsp;Daniel Castrogiovanni ,&nbsp;Sonia Cantel ,&nbsp;Jean-Alain Fehrentz ,&nbsp;Pablo N. De Francesco ,&nbsp;Mario Perello","doi":"10.1016/j.molmet.2024.102046","DOIUrl":"10.1016/j.molmet.2024.102046","url":null,"abstract":"<div><h3>Objective</h3><div>The peptide hormone ghrelin exerts potent effects in the brain, where its receptor is highly expressed. Here, we investigated the role of hypothalamic tanycytes in transporting ghrelin across the blood-cerebrospinal fluid (CSF) interface.</div></div><div><h3>Methods</h3><div>We investigated the internalization and transport of fluorescent ghrelin (Fr-ghrelin) in primary cultures of rat hypothalamic tanycytes, mouse hypothalamic explants, and mice. We also tested the impact of inhibiting clathrin-mediated endocytosis of ghrelin in the brain ventricular system on the orexigenic and locomotor effects of the hormone.</div></div><div><h3>Results</h3><div><em>In vitro</em>, we found that Fr-ghrelin is selectively and rapidly internalized at the soma of tanycytes, via a GHSR-independent and clathrin-dependent mechanism, and then transported to the endfoot. In hypothalamic explants, we also found that Fr-ghrelin is internalized at the apical pole of tanycytes. In mice, Fr-ghrelin present in the CSF was rapidly internalized by hypothalamic β-type tanycytes in a clathrin-dependent manner, and pharmacological inhibition of clathrin-mediated endocytosis in the brain ventricular system prolonged the ghrelin-induced locomotor effects.</div></div><div><h3>Conclusions</h3><div>We propose that tanycyte-mediated transport of ghrelin is functionally relevant, as it may contribute to reduce the concentration of this peptide hormone in the CSF and consequently shortens the duration of its central effects.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102046"},"PeriodicalIF":7.0,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470175","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":"Protein kinase D2 modulates hepatic insulin sensitivity in male mice","authors":"Patricia Rada ,&nbsp;Elena Carceller-López ,&nbsp;Ana B. Hitos ,&nbsp;Beatriz Gómez-Santos ,&nbsp;Constanza Fernández-Hernández ,&nbsp;Esther Rey ,&nbsp;Julia Pose-Utrilla ,&nbsp;Carmelo García-Monzón ,&nbsp;Águeda González-Rodríguez ,&nbsp;Guadalupe Sabio ,&nbsp;Antonia García ,&nbsp;Patricia Aspichueta ,&nbsp;Teresa Iglesias ,&nbsp;Ángela M. Valverde","doi":"10.1016/j.molmet.2024.102045","DOIUrl":"10.1016/j.molmet.2024.102045","url":null,"abstract":"<div><h3>Objectives</h3><div>Protein kinase D (PKD) family is emerging as relevant regulator of metabolic homeostasis. However, the precise role of PKD2 in modulating hepatic insulin signaling has not been fully elucidated and it is the aim of this study.</div></div><div><h3>Methods</h3><div>PKD inhibition was analyzed for insulin signaling in mouse and human hepatocytes. PKD2 was overexpressed in Huh7 hepatocytes and mouse liver, and insulin responses were evaluated. Mice with hepatocyte-specific PKD2 depletion (PKD2^ΔHep) and PKD2^fl/fl mice were fed a chow (CHD) or high fat diet (HFD) and glucose homeostasis and lipid metabolism were investigated.</div></div><div><h3>Results</h3><div>PKD2 silencing enhanced insulin signaling in hepatocytes, an effect also found in primary hepatocytes from PKD2^ΔHep mice. Conversely, a constitutively active PKD2 mutant reduced insulin-stimulated AKT phosphorylation. A more in-depth analysis revealed reduced IRS1 serine phosphorylation under basal conditions and increased IRS1 tyrosine phosphorylation in PKD2^ΔHep primary hepatocytes upon insulin stimulation and, importantly PKD co-immunoprecipitates with IRS1. <em>In vivo</em> constitutively active PKD2 overexpression resulted in a moderate impairment of glucose homeostasis and reduced insulin signaling in the liver. On the contrary, HFD-fed PKD2^ΔHep male mice displayed improved glucose and pyruvate tolerance, as well as higher peripheral insulin tolerance and enhanced hepatic insulin signaling compared to control PKD2^fl/fl mice. Despite of a remodeling of hepatic lipid metabolism in HFD-fed PKD2^ΔHep mice, similar steatosis grade was found in both genotypes.</div></div><div><h3>Conclusions</h3><div>Results herein have unveiled an unknown role of PKD2 in the control of insulin signaling in the liver at the level of IRS1 and point PKD2 as a therapeutic target for hepatic insulin resistance.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102045"},"PeriodicalIF":7.0,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470189","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":"Peroxisomes and PPARs: Emerging role as master regulators of cancer metabolism","authors":"Anggi Muhtar Pratama ,&nbsp;Mansi Sharma ,&nbsp;Srivatsava Naidu ,&nbsp;Heike Bömmel ,&nbsp;Samudyata C. Prabhuswamimath ,&nbsp;Thati Madhusudhan ,&nbsp;Hevi Wihadmadyatami ,&nbsp;Akash Bachhuka ,&nbsp;Srikanth Karnati","doi":"10.1016/j.molmet.2024.102044","DOIUrl":"10.1016/j.molmet.2024.102044","url":null,"abstract":"<div><div>Cancer is a disease characterized by the acquisition of a multitude of unique traits. It has long been understood that cancer cells divert significantly from normal cell metabolism. The most obvious of metabolic changes is that cancer cells strongly rely on glucose conversion by aerobic glycolysis. In addition, they also regularly develop mechanisms to use lipids and fatty acids for their energy needs. Peroxisomes lie central to these adaptive changes of lipid metabolism.</div><div>Peroxisomes are metabolic organelles that take part in over 50 enzymatic reactions crucial for cellular functioning. Thus, they are essential for an effective and comprehensive use of lipids’ energy supplied to cells. Cancer cells display a substantial increase in the biogenesis of peroxisomes and an increased expression of proteins necessary for the enzymatic functions provided by peroxisomes. Moreover, the enzymatic conversion of FAs in peroxisomes is a significant source of reactive oxygen and nitrogen species (ROS/RNS) that strongly impact cancer malignancy. Important regulators in peroxisomal FA oxidation and ROS/RNS generation are the transcription factors of the peroxisome proliferator-activated receptor (PPAR) family. This review describes the metabolic changes in tumorigenesis and cancer progression influenced by peroxisomes. We will highlight the ambivalent role that peroxisomes and PPARs play in the different stages of tumor development and summarize our current understanding of how to capitalize on the comprehension of peroxisomal biology for cancer treatment.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102044"},"PeriodicalIF":7.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378104","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":"Mammalian D-Cysteine controls insulin secretion in the pancreas","authors":"Robin Roychaudhuri ,&nbsp;Timothy West ,&nbsp;Soumyaroop Bhattacharya ,&nbsp;Harry G. Saavedra ,&nbsp;Hangnoh Lee ,&nbsp;Lauren Albacarys ,&nbsp;Moataz M. Gadalla ,&nbsp;Mario Amzel ,&nbsp;Peixin Yang ,&nbsp;Solomon H. Snyder","doi":"10.1016/j.molmet.2024.102043","DOIUrl":"10.1016/j.molmet.2024.102043","url":null,"abstract":"<div><h3>Background</h3><div>D-amino acids are being recognized as important molecules in mammals with function. This is a first identification of endogenous D-cysteine in mammalian pancreas.</div></div><div><h3>Methods</h3><div>Using a novel stereospecific bioluminescent assay, chiral chromatography, enzyme kinetics and a transgenic mouse model we identify endogenous D-cysteine. We elucidate its function in two mice models of type 1 diabetes (STZ and NOD), and in tests of Glucose Stimulated Insulin Secretion in isolated mouse and human islets and INS-1 832/13 cell line.</div></div><div><h3>Results and Discussion</h3><div>D-cysteine is synthesized by serine racemase (SR) and SR^−/− mice produce 6–10 fold higher levels of insulin in the pancreas and plasma including higher glycogen and ketone bodies in the liver. The excess insulin is stored as amyloid in secretory vesicles and exosomes. In glucose stimulated insulin secretion in mouse and human islets, equimolar amount of D-cysteine showed higher inhibition of insulin secretion compared to D-serine, another closely related stereoisomer synthesized by SR. In mouse models of diabetes (Streptozotocin (STZ) and Non Obese Diabetes (NOD) and human pancreas, the diabetic state showed increased expression of D-cysteine compared to D-serine followed by increased expression of SR. SR^−/− mice show decreased cAMP in the pancreas, lower DNA methyltransferase enzymatic and promoter activities followed by reduced phosphorylation of CREB (S133), resulting in decreased methylation of the <em>Ins1</em> promoter. D-cysteine is efficiently metabolized by D-amino acid oxidase and transported by ASCT2 and Asc1. Dietary supplementation with methyl donors restored the high insulin levels and low DNMT enzymatic activity in SR^−/− mice.</div></div><div><h3>Conclusions</h3><div>Our data show that endogenous D-cysteine in the mammalian pancreas is a regulator of insulin secretion.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102043"},"PeriodicalIF":7.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378103","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":"Hepatic retinol dehydrogenase 11 dampens stress associated with the maintenance of cellular cholesterol levels","authors":"Michael F. Keating ,&nbsp;Christine Yang ,&nbsp;Yingying Liu ,&nbsp;Eleanor AM. Gould ,&nbsp;Mitchell T. Hallam ,&nbsp;Darren C. Henstridge ,&nbsp;Natalie A. Mellett ,&nbsp;Peter J. Meikle ,&nbsp;Kevin I. Watt ,&nbsp;Paul Gregorevic ,&nbsp;Anna C. Calkin ,&nbsp;Brian G. Drew","doi":"10.1016/j.molmet.2024.102041","DOIUrl":"10.1016/j.molmet.2024.102041","url":null,"abstract":"<div><h3>Objective</h3><div>Dysregulation of hepatic cholesterol metabolism can contribute to elevated circulating cholesterol levels, which is a significant risk factor for cardiovascular disease. Cholesterol homeostasis in mammalian cells is tightly regulated by an integrated network of transcriptional and post-transcriptional signalling pathways. Whilst prior studies have identified many of the central regulators of these pathways, the extended supporting networks remain to be fully elucidated.</div></div><div><h3>Methods</h3><div>Here, we leveraged an integrated discovery platform, combining multi-omics data from 107 strains of mice to investigate these supporting networks. We identified retinol dehydrogenase 11 (RDH11; also known as SCALD) as a novel protein associated with cholesterol metabolism. Prior studies have suggested that RDH11 may be regulated by alterations in cellular cholesterol status, but its specific roles in this pathway are mostly unknown.</div></div><div><h3>Results</h3><div>Here, we show that mice fed a Western diet (high fat, high cholesterol) exhibited a significant reduction in hepatic <em>Rdh11</em> mRNA expression. Conversely, mice treated with a statin (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitor) exhibited a 2-fold increase in hepatic <em>Rdh11</em> mRNA expression. Studies in human and mouse hepatocytes demonstrated that <em>RDH11</em> expression was regulated by altered cellular cholesterol conditions in a manner consistent with SREBP2 target genes <em>HMGCR</em> and <em>LDLR</em>. Modulation of RDH11 <em>in vitro</em> and <em>in vivo</em> demonstrated modulation of pathways associated with cholesterol metabolism, inflammation and cellular stress. Finally, RDH11 silencing in mouse liver was associated with a reduction in hepatic cardiolipin abundance and a concomitant reduction in the abundance of proteins of the mitochondrial electron transport chain.</div></div><div><h3>Conclusion</h3><div>Taken together, these findings suggest that RDH11 likely plays a role in protecting cells against the cellular toxicity that can arise as a by-product of endogenous cellular cholesterol synthesis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102041"},"PeriodicalIF":7.0,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372253","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 metabolic sensor AMPK: Twelve enzymes in one","authors":"William J. Smiles ,&nbsp;Ashley J. Ovens ,&nbsp;Jonathan S. Oakhill ,&nbsp;Barbara Kofler","doi":"10.1016/j.molmet.2024.102042","DOIUrl":"10.1016/j.molmet.2024.102042","url":null,"abstract":"<div><h3>Background</h3><div>AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of energy metabolism. AMPK is sensitive to acute perturbations to cellular energy status and leverages fundamental bioenergetic pathways to maintain cellular homeostasis. AMPK is a heterotrimer comprised of αβγ-subunits that in humans are encoded by seven individual genes (isoforms α1, α2, β1, β2, γ1, γ2 and γ3), permitting formation of at least 12 different complexes with personalised biochemical fingerprints and tissue expression patterns. While the canonical activation mechanisms of AMPK are well-defined, delineation of subtle, as well as substantial, differences in the regulation of heterogenous AMPK complexes remain poorly defined.</div></div><div><h3>Scope of review</h3><div>Here, taking advantage of multidisciplinary findings, we dissect the many aspects of isoform-specific AMPK function and links to health and disease. These include, but are not limited to, allosteric activation by adenine nucleotides and small molecules, co-translational myristoylation and post-translational modifications (particularly phosphorylation), governance of subcellular localisation, and control of transcriptional networks. Finally, we delve into current debate over whether AMPK can form novel protein complexes (e.g., dimers lacking the α-subunit), altogether highlighting opportunities for future and impactful research.</div></div><div><h3>Major conclusions</h3><div>Baseline activity of α1-AMPK is higher than its α2 counterpart and is more sensitive to synergistic allosteric activation by metabolites and small molecules. α2 complexes however, show a greater response to energy stress (i.e., AMP production) and appear to be better substrates for LKB1 and mTORC1 upstream. These differences may explain to some extent why in certain cancers α1 is a tumour promoter and α2 a suppressor. β1-AMPK activity is toggled by a ‘myristoyl-switch’ mechanism that likely precedes a series of signalling events culminating in phosphorylation by ULK1 and sensitisation to small molecules or endogenous ligands like fatty acids. β2-AMPK, not entirely beholden to this myristoyl-switch, has a greater propensity to infiltrate the nucleus, which we suspect contributes to its oncogenicity in some cancers. Last, the unique N-terminal extensions of the γ2 and γ3 isoforms are major regulatory domains of AMPK. mTORC1 may directly phosphorylate this region in γ2, although whether this is inhibitory, especially in disease states, is unclear. Conversely, γ3 complexes might be preferentially regulated by mTORC1 in response to physical exercise.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102042"},"PeriodicalIF":7.0,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372254","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 long non-coding RNA connects obesity to impaired adipocyte function","authors":"Aina Lluch ,&nbsp;Jèssica Latorre ,&nbsp;Núria Oliveras-Cañellas ,&nbsp;Ana Fernández-Sánchez ,&nbsp;José M. Moreno-Navarrete ,&nbsp;Anna Castells-Nobau ,&nbsp;Ferran Comas ,&nbsp;Maria Buxò ,&nbsp;José I. Rodríguez-Hermosa ,&nbsp;María Ballester ,&nbsp;Isabel Espadas ,&nbsp;Alejandro Martín-Montalvo ,&nbsp;Birong Zhang ,&nbsp;You Zhou ,&nbsp;Ralph Burkhardt ,&nbsp;Marcus Höring ,&nbsp;Gerhard Liebisch ,&nbsp;Ainara Castellanos-Rubio ,&nbsp;Izortze Santin ,&nbsp;Asha Kar ,&nbsp;Francisco J. Ortega","doi":"10.1016/j.molmet.2024.102040","DOIUrl":"10.1016/j.molmet.2024.102040","url":null,"abstract":"<div><h3>Background</h3><div>Long non-coding RNAs (lncRNAs) can perform tasks of key relevance in fat cells, contributing, when defective, to the burden of obesity and its sequelae. Here, scrutiny of adipose tissue transcriptomes before and after bariatric surgery (GSE53378) granted identification of 496 lncRNAs linked to the obese phenotype. Only expression of linc-GALNTL6-4 displayed an average recovery over 2-fold and FDR-adjusted p-value &lt;0.0001 after weight loss. The aim of the present study was to investigate the impact on adipocyte function and potential clinical value of impaired adipose linc-GALNTL6-4 in obese subjects.</div></div><div><h3>Methods</h3><div>We employed transcriptomic analysis of public dataset GSE199063, and cross validations in two large transversal cohorts to report evidence of a previously unknown association of adipose linc-GALNTL6-4 with obesity. We then performed functional analyses in human adipocyte cultures, genome-wide transcriptomics, and untargeted lipidomics in cell models of loss and gain of function to explore the molecular implications of its associations with obesity and weight loss.</div></div><div><h3>Results</h3><div>The expression of linc-GALNTL6-4 in human adipose tissue is adipocyte-specific and co-segregates with obesity, being normalized upon weight loss. This co-segregation is demonstrated in two longitudinal weight loss studies and two cross-sectional samples. While compromised expression of linc-GALNTL6-4 in obese subjects is primarily due to the inflammatory component in the context of obesity, adipogenesis requires the transcriptional upregulation of linc-GALNTL6-4, the expression of which reaches an apex in terminally differentiated adipocytes. Functionally, we demonstrated that the knockdown of linc-GALNTL6-4 impairs adipogenesis, induces alterations in the lipidome, and leads to the downregulation of genes related to cell cycle, while propelling in adipocytes inflammation, impaired fatty acid metabolism, and altered gene expression patterns, including that of apolipoprotein C1 (APOC1). Conversely, the genetic gain of linc-GALNTL6-4 ameliorated differentiation and adipocyte phenotype, putatively by constraining APOC1, also contributing to the metabolism of triglycerides in adipose.</div></div><div><h3>Conclusions</h3><div>Current data unveil the unforeseen connection of adipocyte-specific linc-GALNTL6-4 as a modulator of lipid homeostasis challenged by excessive body weight and meta-inflammation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102040"},"PeriodicalIF":7.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372252","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}