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1.
Cell ; 178(5): 1231-1244.e11, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31402172

RESUMO

Growth and differentiation factor 15 (GDF15) is an inflammation-associated hormone with poorly defined biology. Here, we investigated the role of GDF15 in bacterial and viral infections. We found that inflammation induced GDF15, and that GDF15 was necessary for surviving both bacterial and viral infections, as well as sepsis. The protective effects of GDF15 were largely independent of pathogen control or the magnitude of inflammatory response, suggesting a role in disease tolerance. Indeed, we found that GDF15 was required for hepatic sympathetic outflow and triglyceride metabolism. Failure to defend the lower limit of plasma triglyceride levels was associated with impaired cardiac function and maintenance of body temperature, effects that could be rescued by exogenous administration of lipids. Together, we show that GDF15 coordinates tolerance to inflammatory damage through regulation of triglyceride metabolism.


Assuntos
Fator 15 de Diferenciação de Crescimento/metabolismo , Fígado/metabolismo , Sepse/patologia , Animais , Anticorpos/farmacologia , Modelos Animais de Doenças , Fator 15 de Diferenciação de Crescimento/sangue , Fator 15 de Diferenciação de Crescimento/genética , Fator 15 de Diferenciação de Crescimento/imunologia , Coração/efeitos dos fármacos , Coração/virologia , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Orthomyxoviridae/patogenicidade , Poli I-C/toxicidade , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologia , Sepse/sangue , Sepse/mortalidade , Taxa de Sobrevida , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Troponina I/sangue , Fator de Necrose Tumoral alfa/sangue
2.
Cell ; 177(4): 881-895.e17, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31051106

RESUMO

Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease.


Assuntos
GTP Fosfo-Hidrolases/metabolismo , Proteínas Mitocondriais/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosfatidilserinas/metabolismo , Animais , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Inflamação/metabolismo , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Cultura Primária de Células , Transporte Proteico/fisiologia , Transdução de Sinais , Triglicerídeos/metabolismo
3.
Cell ; 179(6): 1276-1288.e14, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31778654

RESUMO

Although human genetic studies have implicated many susceptible genes associated with plasma lipid levels, their physiological and molecular functions are not fully characterized. Here we demonstrate that orphan G protein-coupled receptor 146 (GPR146) promotes activity of hepatic sterol regulatory element binding protein 2 (SREBP2) through activation of the extracellular signal-regulated kinase (ERK) signaling pathway, thereby regulating hepatic very low-density lipoprotein (VLDL) secretion, and subsequently circulating low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels. Remarkably, GPR146 deficiency reduces plasma cholesterol levels substantially in both wild-type and LDL receptor (LDLR)-deficient mice. Finally, aortic atherosclerotic lesions are reduced by 90% and 70%, respectively, in male and female LDLR-deficient mice upon GPR146 depletion. Taken together, these findings outline a regulatory role for the GPR146/ERK axis in systemic cholesterol metabolism and suggest that GPR146 inhibition could be an effective strategy to reduce plasma cholesterol levels and atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Hipercolesterolemia/metabolismo , Receptores Acoplados a Proteínas G/deficiência , Animais , Aterosclerose/sangue , Sequência de Bases , Colesterol/sangue , Dependovirus/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Jejum , Feminino , Hepatócitos/metabolismo , Humanos , Hipercolesterolemia/sangue , Lipoproteínas VLDL/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de LDL/metabolismo , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Triglicerídeos/sangue , Regulação para Cima
4.
Cell ; 175(1): 133-145.e15, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30220454

RESUMO

Nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis (NASH) in response to elevated endoplasmic reticulum (ER) stress. Whereas the onset of simple steatosis requires elevated de novo lipogenesis, progression to NASH is triggered by accumulation of hepatocyte-free cholesterol. We now show that caspase-2, whose expression is ER-stress inducible and elevated in human and mouse NASH, controls the buildup of hepatic-free cholesterol and triglycerides by activating sterol regulatory element-binding proteins (SREBP) in a manner refractory to feedback inhibition. Caspase-2 colocalizes with site 1 protease (S1P) and cleaves it to generate a soluble active fragment that initiates SCAP-independent SREBP1/2 activation in the ER. Caspase-2 ablation or pharmacological inhibition prevents diet-induced steatosis and NASH progression in ER-stress-prone mice. Caspase-2 inhibition offers a specific and effective strategy for preventing or treating stress-driven fatty liver diseases, whereas caspase-2-generated S1P proteolytic fragments, which enter the secretory pathway, are potential NASH biomarkers.


Assuntos
Caspase 2/fisiologia , Lipogênese/fisiologia , Pró-Proteína Convertases/fisiologia , Serina Endopeptidases/fisiologia , Animais , Colesterol/metabolismo , Retículo Endoplasmático/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Fígado Gorduroso/fisiopatologia , Células HEK293 , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pró-Proteína Convertases/metabolismo , Serina Endopeptidases/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
5.
Cell ; 165(2): 343-56, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-26997483

RESUMO

Control of plasma glucose level is essential to organismal survival. Sustained inflammation has been implicated in control of glucose homeostasis in cases of infection, obesity, and type 2 diabetes; however, the precise role of inflammation in these complex disease states remains poorly understood. Here, we find that sustained inflammation results in elevated plasma glucose due to increased hepatic glucose production. We find that sustained inflammation suppresses CYP7A1, leading to accumulation of intermediate metabolites at the branch point of the mevalonate pathway. This results in prenylation of RHOC, which is concomitantly induced by inflammatory cytokines. Subsequent activation of RHO-associated protein kinase results in elevated plasma glucose. These findings uncover an unexpected mechanism by which sustained inflammation alters glucose homeostasis.


Assuntos
Vias Biossintéticas , Hepatite/metabolismo , Hiperglicemia/metabolismo , Ácido Mevalônico/metabolismo , Animais , Glicemia/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Colesterol 7-alfa-Hidroxilase/metabolismo , Jejum/sangue , Lipopolissacarídeos , Camundongos , Camundongos Obesos , Prenilação de Proteína , Transcrição Gênica , Triglicerídeos/sangue , Proteínas ras/metabolismo , Quinases Associadas a rho/metabolismo , Proteína de Ligação a GTP rhoC
6.
Annu Rev Cell Dev Biol ; 33: 491-510, 2017 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-28793795

RESUMO

Lipid droplets (LDs) are ubiquitous organelles that store neutral lipids for energy or membrane synthesis and act as hubs for metabolic processes. Cells generate LDs de novo, converting cells to emulsions with LDs constituting the dispersed oil phase in the aqueous cytoplasm. Here we review our current view of LD biogenesis. We present a model of LD formation from the ER in distinct steps and highlight the biology of proteins that govern this biophysical process. Areas of incomplete knowledge are identified, as are connections with physiology and diseases linked to alterations in LD biology.


Assuntos
Gotículas Lipídicas/metabolismo , Animais , Fenômenos Biofísicos , Humanos , Modelos Biológicos , Proteínas/metabolismo , Triglicerídeos/metabolismo
7.
Cell ; 161(4): 750-61, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25957683

RESUMO

Memory T cells are critical for long-term immunity against reinfection and require interleukin-7 (IL-7), but the mechanisms by which IL-7 controls memory T cell survival, particularly metabolic fitness, remain elusive. We discover that IL-7 induces expression of the glycerol channel aquaporin 9 (AQP9) in virus-specific memory CD8+ T cells, but not naive cells, and that AQP9 is vitally required for their long-term survival. AQP9 deficiency impairs glycerol import into memory CD8+ T cells for fatty acid esterification and triglyceride (TAG) synthesis and storage. These defects can be rescued by ectopic expression of TAG synthases, which restores lipid stores and memory T cell survival. Finally, we find that TAG synthesis is a central component of IL-7-mediated survival of human and mouse memory CD8+T cells. This study uncovers the metabolic mechanisms by which IL-7 tailors the metabolism of memory T cells to promote their longevity and fast response to rechallenge.


Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Sobrevivência Celular , Memória Imunológica , Triglicerídeos/metabolismo , Animais , Aquaporinas/metabolismo , Infecções por Arenaviridae/imunologia , Linfócitos T CD8-Positivos/metabolismo , Glicerol/metabolismo , Humanos , Interleucina-7/metabolismo , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos , Transdução de Sinais
8.
Nature ; 628(8006): 154-161, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38480892

RESUMO

Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aß induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Gotículas Lipídicas , Microglia , Animais , Feminino , Humanos , Masculino , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Microglia/citologia , Microglia/metabolismo , Microglia/patologia , Triglicerídeos , Proteínas tau , Meios de Cultivo Condicionados , Fosforilação , Predisposição Genética para Doença
9.
Genes Dev ; 36(21-24): 1129-1144, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36522129

RESUMO

GATA4 is a transcription factor known for its crucial role in the development of many tissues, including the liver; however, its role in adult liver metabolism is unknown. Here, using high-throughput sequencing technologies, we identified GATA4 as a transcriptional regulator of metabolism in the liver. GATA4 expression is elevated in response to refeeding, and its occupancy is increased at enhancers of genes linked to fatty acid and lipoprotein metabolism. Knocking out GATA4 in the adult liver (Gata4LKO) decreased transcriptional activity at GATA4 binding sites, especially during feeding. Gata4LKO mice have reduced plasma HDL cholesterol and increased liver triglyceride levels. The expression of a panel of GATA4 binding genes involved in hepatic cholesterol export and triglyceride hydrolysis was down-regulated in Gata4LKO mice. We further demonstrate that GATA4 collaborates with LXR nuclear receptors in the liver. GATA4 and LXRs share a number of binding sites, and GATA4 was required for the full transcriptional response to LXR activation. Collectively, these results show that hepatic GATA4 contributes to the transcriptional control of hepatic and systemic lipid homeostasis.


Assuntos
Fígado , Receptores Nucleares Órfãos , Camundongos , Animais , Receptores Nucleares Órfãos/metabolismo , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Fígado/metabolismo , Homeostase/genética , Colesterol , Triglicerídeos/metabolismo , Metabolismo dos Lipídeos , Camundongos Endogâmicos C57BL , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo
10.
Nat Rev Mol Cell Biol ; 18(11): 671-684, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28852221

RESUMO

Fatty acids are the most efficient substrates for energy production in vertebrates and are essential components of the lipids that form biological membranes. Synthesis of triacylglycerols from non-esterified free fatty acids (FFAs) combined with triacylglycerol storage represents a highly efficient strategy to stockpile FFAs in cells and prevent FFA-induced lipotoxicity. Although essentially all vertebrate cells have some capacity to store and utilize triacylglycerols, white adipose tissue is by far the largest triacylglycerol depot and is uniquely able to supply FFAs to other tissues. The release of FFAs from triacylglycerols requires their enzymatic hydrolysis by a process called lipolysis. Recent discoveries thoroughly altered and extended our understanding of lipolysis. This Review discusses how cytosolic 'neutral' lipolysis and lipophagy, which utilizes 'acid' lipolysis in lysosomes, degrade cellular triacylglycerols as well as how these pathways communicate, how they affect lipid metabolism and energy homeostasis and how their dysfunction affects the pathogenesis of metabolic diseases. Answers to these questions will likely uncover novel strategies for the treatment of prevalent metabolic diseases.


Assuntos
Tecido Adiposo Branco/metabolismo , Citosol/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Lipólise , Lisossomos/metabolismo , Triglicerídeos/metabolismo , Tecido Adiposo Branco/patologia , Animais , Citosol/patologia , Metabolismo Energético , Humanos , Lisossomos/patologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Doenças Metabólicas/terapia
11.
Cell ; 159(3): 691-6, 2014 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-25417115

RESUMO

Recently, it was reported that angiopoietin-like protein 8 (ANGPTL8) was the long-sought "betatrophin" that could control pancreatic beta cell proliferation. However, studies of Angptl8(?/?) mice revealed profound reduction of triglyceride levels, but no abnormalities in glucose homeostasis. We now report that Angptl8(?/?) mice undergo entirely normal beta cell expansion in response to insulin resistance resulting from either a high-fat diet or from the administration of the insulin receptor antagonist S961. Furthermore, overexpression of ANGPTL8 in livers of mice doubles plasma triglyceride levels, but does not alter beta cell expansion nor glucose metabolism. These data indicate that ANGPTL8 does not play a role in controlling beta cell growth, nor can it be given to induce such expansion. The findings that plasma triglyceride levels are reduced by Angptl8 deletion and increased following ANGPTL8 overexpression support the possibility that inhibition of ANGPTL8 represents a therapeutic strategy for hypertriglyceridemia.


Assuntos
Angiopoietinas/metabolismo , Células Secretoras de Insulina/citologia , Proteína 8 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina , Angiopoietinas/genética , Animais , Dieta Hiperlipídica , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Triglicerídeos/metabolismo
12.
Nature ; 622(7984): 775-783, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37821706

RESUMO

Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories and complex trait architectures remain hidden owing to insufficient data1. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural and urban localities across all 32 states in Mexico at a resolution of 1.8 million genome-wide markers with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. Here, using ancestry deconvolution and inference of identity-by-descent segments, we inferred ancestral population sizes across Mesoamerican regions over time, unravelling Indigenous, colonial and postcolonial demographic dynamics2-6. We observed variation in runs of homozygosity among genomic regions with different ancestries reflecting distinct demographic histories and, in turn, different distributions of rare deleterious variants. We conducted genome-wide association studies (GWAS) for 22 complex traits and found that several traits are better predicted using the Mexican Biobank GWAS compared to the UK Biobank GWAS7,8. We identified genetic and environmental factors associating with trait variation, such as the length of the genome in runs of homozygosity as a predictor for body mass index, triglycerides, glucose and height. This study provides insights into the genetic histories of individuals in Mexico and dissects their complex trait architectures, both crucial for making precision and preventive medicine initiatives accessible worldwide.


Assuntos
Bancos de Espécimes Biológicos , Genética Médica , Genoma Humano , Genômica , Hispânico ou Latino , Humanos , Glicemia/genética , Glicemia/metabolismo , Estatura/genética , Índice de Massa Corporal , Interação Gene-Ambiente , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/classificação , Hispânico ou Latino/genética , Homozigoto , México , Fenótipo , Triglicerídeos/sangue , Triglicerídeos/genética , Reino Unido , Genoma Humano/genética
13.
Nature ; 621(7977): 171-178, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37648867

RESUMO

Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the amount of TAGs are associated with obesity, cardiac disease and various other pathologies1,2. In humans, TAGs are synthesized from excess, coenzyme A-conjugated fatty acids by diacylglycerol O-acyltransferases (DGAT1 and DGAT2)3. In other organisms, this activity is complemented by additional enzymes4, but whether such alternative pathways exist in humans remains unknown. Here we disrupt the DGAT pathway in haploid human cells and use iterative genetics to reveal an unrelated TAG-synthesizing system composed of a protein we called DIESL (also known as TMEM68, an acyltransferase of previously unknown function) and its regulator TMX1. Mechanistically, TMX1 binds to and controls DIESL at the endoplasmic reticulum, and loss of TMX1 leads to the unconstrained formation of DIESL-dependent lipid droplets. DIESL is an autonomous TAG synthase, and expression of human DIESL in Escherichia coli endows this organism with the ability to synthesize TAG. Although both DIESL and the DGATs function as diacylglycerol acyltransferases, they contribute to the cellular TAG pool under specific conditions. Functionally, DIESL synthesizes TAG at the expense of membrane phospholipids and maintains mitochondrial function during periods of extracellular lipid starvation. In mice, DIESL deficiency impedes rapid postnatal growth and affects energy homeostasis during changes in nutrient availability. We have therefore identified an alternative TAG biosynthetic pathway driven by DIESL under potent control by TMX1.


Assuntos
Aciltransferases , Triglicerídeos , Animais , Humanos , Camundongos , Aciltransferases/metabolismo , Coenzima A/metabolismo , Diacilglicerol O-Aciltransferase/metabolismo , Escherichia coli/metabolismo , Homeostase , Triglicerídeos/biossíntese , Metabolismo Energético , Nutrientes/metabolismo , Ácidos Graxos/química , Ácidos Graxos/metabolismo
14.
Nature ; 613(7942): 160-168, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36477540

RESUMO

Multilocular adipocytes are a hallmark of thermogenic adipose tissue1,2, but the factors that enforce this cellular phenotype are largely unknown. Here, we show that an adipocyte-selective product of the Clstn3 locus (CLSTN3ß) present in only placental mammals facilitates the efficient use of stored triglyceride by limiting lipid droplet (LD) expansion. CLSTN3ß is an integral endoplasmic reticulum (ER) membrane protein that localizes to ER-LD contact sites through a conserved hairpin-like domain. Mice lacking CLSTN3ß have abnormal LD morphology and altered substrate use in brown adipose tissue, and are more susceptible to cold-induced hypothermia despite having no defect in adrenergic signalling. Conversely, forced expression of CLSTN3ß is sufficient to enforce a multilocular LD phenotype in cultured cells and adipose tissue. CLSTN3ß associates with cell death-inducing DFFA-like effector proteins and impairs their ability to transfer lipid between LDs, thereby restricting LD fusion and expansion. Functionally, increased LD surface area in CLSTN3ß-expressing adipocytes promotes engagement of the lipolytic machinery and facilitates fatty acid oxidation. In human fat, CLSTN3B is a selective marker of multilocular adipocytes. These findings define a molecular mechanism that regulates LD form and function to facilitate lipid utilization in thermogenic adipocytes.


Assuntos
Adipócitos , Proteínas de Ligação ao Cálcio , Metabolismo dos Lipídeos , Proteínas de Membrana , Animais , Feminino , Humanos , Camundongos , Adipócitos/citologia , Adipócitos/metabolismo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/metabolismo , Proteínas de Ligação ao Cálcio/deficiência , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/metabolismo , Placenta , Triglicerídeos/metabolismo , Retículo Endoplasmático/metabolismo , Gotículas Lipídicas/metabolismo , Ácidos Graxos/metabolismo , Hipotermia/metabolismo , Termogênese
15.
Mol Cell ; 81(18): 3820-3832.e7, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34233158

RESUMO

A metabolic imbalance between lipid synthesis and degradation can lead to hepatic lipid accumulation, a characteristic of patients with non-alcoholic fatty liver disease (NAFLD). Here, we report that high-fat-diet-induced sterol regulatory element-binding protein (SREBP)-1c, a key transcription factor that regulates lipid biosynthesis, impairs autophagic lipid catabolism via altered H2S signaling. SREBP-1c reduced cystathionine gamma-lyase (CSE) via miR-216a, which in turn decreased hepatic H2S levels and sulfhydration-dependent activation of Unc-51-like autophagy-activating kinase 1 (ULK1). Furthermore, Cys951Ser mutation of ULK1 decreased autolysosome formation and promoted hepatic lipid accumulation in mice, suggesting that the loss of ULK1 sulfhydration was directly associated with the pathogenesis of NAFLD. Moreover, silencing of CSE in SREBP-1c knockout mice increased liver triglycerides, confirming the connection between CSE, autophagy, and SREBP-1c. Overall, our results uncover a 2-fold mechanism for SREBP-1c-driven hepatic lipid accumulation through reciprocal activation and inhibition of hepatic lipid biosynthesis and degradation, respectively.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Fígado Gorduroso/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Autofagia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/fisiologia , Linhagem Celular Tumoral , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/fisiopatologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia , Lipogênese , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de Sinais/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/fisiologia , Triglicerídeos/metabolismo
16.
Nature ; 606(7916): 968-975, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35676490

RESUMO

Branched fatty acid (FA) esters of hydroxy FAs (HFAs; FAHFAs) are recently discovered lipids that are conserved from yeast to mammals1,2. A subfamily, palmitic acid esters of hydroxy stearic acids (PAHSAs), are anti-inflammatory and anti-diabetic1,3. Humans and mice with insulin resistance have lower PAHSA levels in subcutaneous adipose tissue and serum1. PAHSA administration improves glucose tolerance and insulin sensitivity and reduces inflammation in obesity, diabetes and immune-mediated diseases1,4-7. The enzyme(s) responsible for FAHFA biosynthesis in vivo remains unknown. Here we identified adipose triglyceride lipase (ATGL, also known as patatin-like phospholipase domain containing 2 (PNPLA2)) as a candidate biosynthetic enzyme for FAHFAs using chemical biology and proteomics. We discovered that recombinant ATGL uses a transacylation reaction that esterifies an HFA with a FA from triglyceride (TG) or diglyceride to produce FAHFAs. Overexpression of wild-type, but not catalytically dead, ATGL increases FAHFA biosynthesis. Chemical inhibition of ATGL or genetic deletion of Atgl inhibits FAHFA biosynthesis and reduces the levels of FAHFA and FAHFA-TG. Levels of endogenous and nascent FAHFAs and FAHFA-TGs are 80-90 per cent lower in adipose tissue of mice in which Atgl is knocked out specifically in the adipose tissue. Increasing TG levels by upregulating diacylglycerol acyltransferase (DGAT) activity promotes FAHFA biosynthesis, and decreasing DGAT activity inhibits it, reinforcing TGs as FAHFA precursors. ATGL biosynthetic transacylase activity is present in human adipose tissue underscoring its potential clinical relevance. In summary, we discovered the first, to our knowledge, biosynthetic enzyme that catalyses the formation of the FAHFA ester bond in mammals. Whereas ATGL lipase activity is well known, our data establish a paradigm shift demonstrating that ATGL transacylase activity is biologically important.


Assuntos
Aciltransferases , Ésteres , Ácidos Graxos , Hidroxiácidos , Aciltransferases/genética , Aciltransferases/metabolismo , Tecido Adiposo/química , Tecido Adiposo/metabolismo , Animais , Diglicerídeos , Esterificação , Ésteres/química , Ésteres/metabolismo , Ácidos Graxos/biossíntese , Ácidos Graxos/química , Humanos , Hidroxiácidos/química , Hidroxiácidos/metabolismo , Resistência à Insulina , Camundongos , Triglicerídeos
17.
N Engl J Med ; 391(10): 899-912, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-38804517

RESUMO

BACKGROUND: Persons with mixed hyperlipidemia are at risk for atherosclerotic cardiovascular disease due to an elevated non-high-density lipoprotein (HDL) cholesterol level, which is driven by remnant cholesterol in triglyceride-rich lipoproteins. The metabolism and clearance of triglyceride-rich lipoproteins are down-regulated through apolipoprotein C3 (APOC3)-mediated inhibition of lipoprotein lipase. METHODS: We carried out a 48-week, phase 2b, double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy of plozasiran, a hepatocyte-targeted APOC3 small interfering RNA, in patients with mixed hyperlipidemia (i.e., a triglyceride level of 150 to 499 mg per deciliter and either a low-density lipoprotein [LDL] cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). The participants were assigned in a 3:1 ratio to receive plozasiran or placebo within each of four cohorts. In the first three cohorts, the participants received a subcutaneous injection of plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12 (quarterly doses). In the fourth cohort, participants received 50 mg of plozasiran or placebo on day 1 and at week 24 (half-yearly dose). The data from the participants who received placebo were pooled. The primary end point was the percent change in fasting triglyceride level at week 24. RESULTS: A total of 353 participants underwent randomization. At week 24, significant reductions in the fasting triglyceride level were observed with plozasiran, with differences, as compared with placebo, in the least-squares mean percent change from baseline of -49.8 percentage points (95% confidence interval [CI], -59.0 to -40.6) with the 10-mg-quarterly dose, -56.0 percentage points (95% CI, -65.1 to -46.8) with the 25-mg-quarterly dose, -62.4 percentage points (95% CI, -71.5 to -53.2) with the 50-mg-quarterly dose, and -44.2 percentage points (95% CI, -53.4 to -35.0) with the 50-mg-half-yearly dose (P<0.001 for all comparisons). Worsening glycemic control was observed in 10% of the participants receiving placebo, 12% of those receiving the 10-mg-quarterly dose, 7% of those receiving the 25-mg-quarterly dose, 20% of those receiving the 50-mg-quarterly dose, and 21% of those receiving the 50-mg-half-yearly dose. CONCLUSIONS: In this randomized, controlled trial involving participants with mixed hyperlipidemia, plozasiran, as compared with placebo, significantly reduced triglyceride levels at 24 weeks. A clinical outcomes trial is warranted. (Funded by Arrowhead Pharmaceuticals; MUIR ClinicalTrials.gov number NCT04998201.).


Assuntos
Apolipoproteína C-III , Hiperlipidemias , RNA Interferente Pequeno , Terapêutica com RNAi , Triglicerídeos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Apolipoproteína C-III/antagonistas & inibidores , Apolipoproteína C-III/genética , LDL-Colesterol/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/efeitos adversos , Triglicerídeos/sangue , Terapêutica com RNAi/efeitos adversos , Terapêutica com RNAi/métodos
18.
N Engl J Med ; 391(10): 913-925, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-38809174

RESUMO

BACKGROUND: Angiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. ANGPTL3 loss-of-function carriers have lower levels of triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol and a lower risk of atherosclerotic cardiovascular disease than noncarriers. Zodasiran is an RNA interference (RNAi) therapy targeting expression of ANGPTL3 in the liver. METHODS: We conducted a double-blind, placebo-controlled, dose-ranging phase 2b trial to evaluate the safety and efficacy of zodasiran in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). Eligible patients were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24. RESULTS: A total of 204 patients underwent randomization. At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, -54 percentage points with 50 mg, -70 percentage points with 100 mg, and -74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, -51 percentage points, -57 percentage points, and -63 percentage points, respectively) (P<0.001 for all comparisons). Other differences in change from baseline as compared with placebo included the following: for non-HDL cholesterol level, -29 percentage points with 50 mg, -29 percentage points with 100 mg, and -36 percentage points with 200 mg; for apolipoprotein B level, -19 percentage points, -15 percentage points, and -22 percentage points, respectively; and for LDL cholesterol level, -16 percentage points, -14 percentage points, and -20 percentage points, respectively. We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran. CONCLUSIONS: In patients with mixed hyperlipidemia, zodasiran was associated with significant decreases in triglyceride levels at 24 weeks. (Funded by Arrowhead Pharmaceuticals; ARCHES-2 ClinicalTrials.gov number, NCT04832971.).


Assuntos
Proteína 3 Semelhante a Angiopoietina , Hiperlipidemias , RNA Interferente Pequeno , Terapêutica com RNAi , Triglicerídeos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 3 Semelhante a Angiopoietina/antagonistas & inibidores , Proteína 3 Semelhante a Angiopoietina/genética , Proteína 3 Semelhante a Angiopoietina/metabolismo , LDL-Colesterol/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Injeções Subcutâneas , Fígado/metabolismo , Terapêutica com RNAi/efeitos adversos , Terapêutica com RNAi/métodos , Resultado do Tratamento , Triglicerídeos/sangue , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/efeitos adversos
19.
N Engl J Med ; 390(19): 1781-1792, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38587247

RESUMO

BACKGROUND: Familial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III. METHODS: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis. RESULTS: A total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group. CONCLUSIONS: In patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.).


Assuntos
Apolipoproteína C-III , Hiperlipoproteinemia Tipo I , Pancreatite , Triglicerídeos , Humanos , Pancreatite/tratamento farmacológico , Masculino , Feminino , Método Duplo-Cego , Apolipoproteína C-III/sangue , Pessoa de Meia-Idade , Adulto , Triglicerídeos/sangue , Hiperlipoproteinemia Tipo I/tratamento farmacológico , Hiperlipoproteinemia Tipo I/sangue , Hiperlipoproteinemia Tipo I/complicações , Doença Aguda , Oligonucleotídeos/uso terapêutico , Oligonucleotídeos/efeitos adversos , Idoso , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/sangue , Adulto Jovem
20.
N Engl J Med ; 390(19): 1770-1780, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38587249

RESUMO

BACKGROUND: Reducing the levels of triglycerides and triglyceride-rich lipoproteins remains an unmet clinical need. Olezarsen is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), a genetically validated target for triglyceride lowering. METHODS: In this phase 2b, randomized, controlled trial, we assigned adults either with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) in a 1:1 ratio to either a 50-mg or 80-mg cohort. Patients were then assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the percent change in the triglyceride level from baseline to 6 months, reported as the difference between each olezarsen group and placebo. Key secondary outcomes were changes in levels of APOC3, apolipoprotein B, non-high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. RESULTS: A total of 154 patients underwent randomization at 24 sites in North America. The median age of the patients was 62 years, and the median triglyceride level was 241.5 mg per deciliter. The 50-mg and 80-mg doses of olezarsen reduced triglyceride levels by 49.3 percentage points and 53.1 percentage points, respectively, as compared with placebo (P<0.001 for both comparisons). As compared with placebo, each dose of olezarsen also significantly reduced the levels of APOC3, apolipoprotein B, and non-HDL cholesterol, with no significant change in the LDL cholesterol level. The risks of adverse events and serious adverse events were similar in the three groups. Clinically meaningful hepatic, renal, or platelet abnormalities were uncommon, with similar risks in the three groups. CONCLUSIONS: In patients with predominantly moderate hypertriglyceridemia at elevated cardiovascular risk, olezarsen significantly reduced levels of triglycerides, apolipoprotein B, and non-HDL cholesterol, with no major safety concerns identified. (Funded by Ionis Pharmaceuticals; Bridge-TIMI 73a ClinicalTrials.gov number, NCT05355402.).


Assuntos
Apolipoproteína C-III , Doenças Cardiovasculares , Hipertrigliceridemia , Oligonucleotídeos , Triglicerídeos , Humanos , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/complicações , Hipertrigliceridemia/sangue , Pessoa de Meia-Idade , Masculino , Feminino , Apolipoproteína C-III/sangue , Triglicerídeos/sangue , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/etiologia , Oligonucleotídeos/uso terapêutico , Oligonucleotídeos/efeitos adversos , Idoso , Adulto , Método Duplo-Cego , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos Antissenso/efeitos adversos , Fatores de Risco de Doenças Cardíacas , LDL-Colesterol/sangue , Hipolipemiantes/uso terapêutico , Hipolipemiantes/efeitos adversos , Apolipoproteínas B/sangue
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