RESUMO
SCAP plays a central role in controlling lipid homeostasis by activating SREBP-1, a master transcription factor in controlling fatty acid (FA) synthesis. However, how SCAP expression is regulated in human cancer cells remains unknown. Here, we revealed that STAT3 binds to the promoter of SCAP to activate its expression across multiple cancer cell types. Moreover, we identified that STAT3 also concurrently interacts with the promoter of SREBF1 gene (encoding SREBP-1), amplifying its expression. This dual action by STAT3 collaboratively heightens FA synthesis. Pharmacological inhibition of STAT3 significantly reduces the levels of unsaturated FAs and phospholipids bearing unsaturated FA chains by reducing the SCAP-SREBP-1 signaling axis and its downstream effector SCD1. Examination of clinical samples from patients with glioblastoma, the most lethal brain tumor, demonstrates a substantial co-expression of STAT3, SCAP, SREBP-1, and SCD1. These findings unveil STAT3 directly regulates the expression of SCAP and SREBP-1 to promote FA synthesis, ultimately fueling tumor progression.
Assuntos
Ácidos Graxos , Proteínas de Membrana , Fator de Transcrição STAT3 , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1 , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Humanos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Ácidos Graxos/metabolismo , Ácidos Graxos/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Estearoil-CoA Dessaturase/metabolismo , Estearoil-CoA Dessaturase/genética , Animais , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/genética , Regulação para Cima , CamundongosRESUMO
Sphingomyelin synthase (SMS)-related protein (SMSr) is a phosphatidylethanolamine phospholipase C (PE-PLC) that is conserved and ubiquitous in mammals. However, its biological function is still not clear. We previously observed that SMS1 deficiency-mediated glucosylceramide accumulation caused nonalcoholic fatty liver diseases (NAFLD), including nonalcoholic steatohepatitis (NASH) and liver fibrosis. Here, first, we evaluated high-fat diet/fructose-induced NAFLD in Smsr KO and WT mice. Second, we evaluated whether SMSr deficiency can reverse SMS1 deficiency-mediated NAFLD, using Sms1/Sms2 double and Sms1/Sms2/Smsr triple KO mice. We found that SMSr/PE-PLC deficiency attenuated high-fat diet/fructose-induced fatty liver and NASH, and attenuated glucosylceramide accumulation-induced NASH, fibrosis, and tumor formation. Further, we found that SMSr/PE-PLC deficiency reduced the expression of many inflammatory cytokines and fibrosis-related factors, and PE supplementation in vitro or in vivo mimicked the condition of SMSr/PE-PLC deficiency. Furthermore, we demonstrated that SMSr/PE-PLC deficiency or PE supplementation effectively prevented membrane-bound ß-catenin transfer to the nucleus, thereby preventing tumor-related gene expression. Finally, we observed that patients with NASH had higher SMSr protein levels in the liver, lower plasma PE levels, and lower plasma PE/phosphatidylcholine ratios, and that human plasma PE levels are negatively associated with tumor necrosis factor-α and transforming growth factor ß1 levels. In conclusion, SMSr/PE-PLC deficiency causes PE accumulation, which can attenuate fatty liver, NASH, and fibrosis. These results suggest that SMSr/PE-PLC inhibition therapy may mitigate NAFLD.
Assuntos
Neoplasias , Hepatopatia Gordurosa não Alcoólica , Transferases (Outros Grupos de Fosfato Substituídos) , Animais , Humanos , Camundongos , Frutose/efeitos adversos , Glucosilceramidas/metabolismo , Fígado/metabolismo , Cirrose Hepática/patologia , Neoplasias/genética , Neoplasias/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosfatidiletanolaminas/sangue , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo , Camundongos Knockout , Masculino , Feminino , Dieta Hiperlipídica/efeitos adversosRESUMO
Hepatic steatosis associated with high-fat diet, obesity, and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl CoA (AcCoA), a central metabolite and substrate for de novo lipogenesis (DNL), is produced from citrate by ATP-citrate lyase (ACLY) and from acetate through AcCoA synthase short chain family member 2 (ACSS2). However, the relative contributions of these two enzymes to hepatic AcCoA pools and DNL rates in response to high-fat feeding are unknown. We report here that hepatocyte-selective depletion of either ACSS2 or ACLY caused similar 50% decreases in liver AcCoA levels in obese mice, showing that both pathways contribute to the generation of this DNL substrate. Unexpectedly however, the hepatocyte ACLY depletion in obese mice paradoxically increased total DNL flux measured by D2O incorporation into palmitate, whereas in contrast, ACSS2 depletion had no effect. The increase in liver DNL upon ACLY depletion was associated with increased expression of nuclear sterol regulatory element-binding protein 1c and of its target DNL enzymes. This upregulated DNL enzyme expression explains the increased rate of palmitate synthesis in ACLY-depleted livers. Furthermore, this increased flux through DNL may also contribute to the observed depletion of AcCoA levels because of its increased conversion to malonyl CoA and palmitate. Together, these data indicate that in fat diet-fed obese mice, hepatic DNL is not limited by its immediate substrates AcCoA or malonyl CoA but rather by activities of DNL enzymes.
Assuntos
Diabetes Mellitus Tipo 2 , Lipogênese , Fígado , Proteína de Ligação a Elemento Regulador de Esterol 1 , Animais , Camundongos , Acetilcoenzima A/metabolismo , Trifosfato de Adenosina/metabolismo , ATP Citrato (pro-S)-Liase/genética , ATP Citrato (pro-S)-Liase/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Malonil Coenzima A/metabolismo , Camundongos Obesos , Palmitatos/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
BACKGROUND & AIMS: The prevalence of non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) is rising rapidly, yet its underlying mechanisms remain unclear. Herein, we aim to determine the role of hypoxia-inducible lipid droplet associated protein (HILPDA)/hypoxia-inducible gene 2 (HIG2), a selective inhibitor of intracellular lipolysis, in NASH-driven HCC. METHODS: The clinical significance of HILPDA was assessed in human NASH-driven HCC specimens by immunohistochemistry and transcriptomics analyses. The oncogenic effect of HILPDA was assessed in human HCC cells and in 3D epithelial spheroids upon exposure to free fatty acids and either normoxia or hypoxia. Lipidomics profiling of wild-type and HILPDA knockout HCC cells was assessed via shotgun and targeted approaches. Wild-type (Hilpdafl/fl) and hepatocyte-specific Hilpda knockout (HilpdaΔHep) mice were fed a Western diet and high sugar in drinking water while receiving carbon tetrachloride to induce NASH-driven HCC. RESULTS: In patients with NASH-driven HCC, upregulated HILPDA expression is strongly associated with poor survival. In oxygen-deprived and lipid-loaded culture conditions, HILPDA promotes viability of human hepatoma cells and growth of 3D epithelial spheroids. Lack of HILPDA triggered flux of polyunsaturated fatty acids to membrane phospholipids and of saturated fatty acids to ceramide synthesis, exacerbating lipid peroxidation and apoptosis in hypoxia. The apoptosis induced by HILPDA deficiency was reversed by pharmacological inhibition of ceramide synthesis. In our experimental mouse model of NASH-driven HCC, HilpdaΔHep exhibited reduced hepatic steatosis and tumorigenesis but increased oxidative stress in the liver. Single-cell analysis supports a dual role of hepatic HILPDA in protecting HCC cells and facilitating the establishment of a pro-tumorigenic immune microenvironment in NASH. CONCLUSIONS: Hepatic HILPDA is a pivotal oncometabolic factor in the NASH liver microenvironment and represents a potential novel therapeutic target. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH, chronic metabolic liver disease caused by buildup of fat, inflammation and damage in the liver) is emerging as the leading risk factor and the fastest growing cause of hepatocellular carcinoma (HCC), the most common form of liver cancer. While curative therapeutic options exist for HCC, it frequently presents at a late stage when such options are no longer effective and only systemic therapies are available. However, systemic therapies are still associated with poor efficacy and some side effects. In addition, no approved drugs are available for NASH. Therefore, understanding the underlying metabolic alterations occurring during NASH-driven HCC is key to identifying new cancer treatments that target the unique metabolic needs of cancer cells.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/metabolismo , Ceramidas/metabolismo , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Hipóxia/metabolismo , Fígado/patologia , Neoplasias Hepáticas/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Microambiente TumoralRESUMO
In response to infection or tissue damage, resident peritoneal macrophages (rpMACs) produce inflammatory lipid mediators from the polyunsaturated fatty acid (PUFA), arachidonic acid (AA). Long-chain acyl-CoA synthetase 4 (ACSL4) catalyzes the covalent addition of a CoA moiety to fatty acids, with a strong preference for AA and other PUFAs containing three or more double bonds. PUFA-CoA can be incorporated into phospholipids, which is the source of PUFA for lipid mediator synthesis. In this study, we demonstrated that deficiency of Acsl4 in mouse rpMACs resulted in a significant reduction of AA incorporated into all phospholipid classes and a reciprocal increase in incorporation of oleic acid and linoleic acid. After stimulation with opsonized zymosan (opZym), a diverse array of AA-derived lipid mediators, including leukotrienes, PGs, hydroxyeicosatetraenoic acids, and lipoxins, were produced and were significantly reduced in Acsl4-deficient rpMACs. The Acsl4-deficient rpMACs stimulated with opZym also demonstrated an acute reduction in mRNA expression of the inflammatory cytokines, Il6, Ccl2, Nos2, and Ccl5 When Acsl4-deficient rpMACs were incubated in vitro with the TLR4 agonist, LPS, the levels of leukotriene B4 and PGE2 were also significantly decreased. In LPS-induced peritonitis, mice with myeloid-specific Acsl4 deficiency had a significant reduction in leukotriene B4 and PGE2 levels in peritoneal exudates, which was coupled with reduced infiltration of neutrophils in the peritoneal cavity as compared with wild-type mice. Our data demonstrate that chronic deficiency of Acsl4 in rpMACs reduces the incorporation of AA into phospholipids, which reduces lipid mediator synthesis and inflammation.
Assuntos
Ácido Araquidônico/imunologia , Coenzima A Ligases/imunologia , Inflamação/imunologia , Fosfolipídeos/imunologia , Zimosan/biossíntese , Animais , Coenzima A Ligases/deficiência , Camundongos , Camundongos TransgênicosRESUMO
Nonalcoholic steatohepatitis (NASH) is a severe liver disorder characterized by triglyceride accumulation, severe inflammation, and fibrosis. With the recent increase in prevalence, NASH is now the leading cause of liver transplant, with no approved therapeutics available. Although the exact molecular mechanism of NASH progression is not well understood, a widely held hypothesis is that fat accumulation is the primary driver of the disease. Therefore, diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in triglyceride synthesis, has been explored as a NASH target. RNAi-based therapeutics is revolutionizing the treatment of liver diseases, with recent chemical advances supporting long-term gene silencing with single subcutaneous administration. Here, we identified a hyper-functional, fully chemically stabilized GalNAc-conjugated small interfering RNA (siRNA) targeting DGAT2 (Dgat2-1473) that, upon injection, elicits up to 3 months of DGAT2 silencing (>80%-90%, p < 0.0001) in wild-type and NSG-PiZ "humanized" mice. Using an obesity-driven mouse model of NASH (ob/ob-GAN), Dgat2-1473 administration prevents and reverses triglyceride accumulation (>85%, p < 0.0001) without increased accumulation of diglycerides, resulting in significant improvement of the fatty liver phenotype. However, surprisingly, the reduction in liver fat did not translate into a similar impact on inflammation and fibrosis. Thus, while Dgat2-1473 is a practical, long-lasting silencing agent for potential therapeutic attenuation of liver steatosis, combinatorial targeting of a second pathway may be necessary for therapeutic efficacy against NASH.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Modelos Animais de Doenças , Fibrose , Inflamação/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/terapia , Obesidade/genética , Obesidade/terapia , Terapêutica com RNAi , Triglicerídeos/metabolismo , Triglicerídeos/uso terapêuticoRESUMO
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and a decline in activities of daily life. Ventricular enlargement has been associated with worse performance on global cognitive tests and AD. Our previous studies demonstrated that brain sulfatides, myelin-enriched lipids, are dramatically reduced in subjects at the earliest clinically recognizable AD stages via an apolipoprotein E (APOE)-dependent and isoform-specific process. Herein, we provided pre-clinical evidence that sulfatide deficiency is causally associated with brain ventricular enlargement. Specifically, taking advantage of genetic mouse models of global and adult-onset sulfatide deficiency, we demonstrated that sulfatide losses cause ventricular enlargement without significantly affecting hippocampal or whole brain volumes using histological and magnetic resonance imaging approaches. Mild decreases in sulfatide content and mild increases in ventricular areas were also observed in human APOE4 compared to APOE2 knock-in mice. Finally, we provided Western blot and immunofluorescence evidence that aquaporin-4, the most prevalent aquaporin channel in the central nervous system (CNS) that provides fast water transportation and regulates cerebrospinal fluid in the ventricles, is significantly increased under sulfatide-deficient conditions, while other major brain aquaporins (e.g., aquaporin-1) are not altered. In short, we unraveled a novel and causal association between sulfatide deficiency and ventricular enlargement. Finally, we propose putative mechanisms by which sulfatide deficiency may induce ventricular enlargement.
Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Animais , Camundongos , Sulfoglicoesfingolipídeos , Doença de Alzheimer/patologia , Lipidômica , Encéfalo/patologiaRESUMO
Mitochondrial dysfunction underlies many heritable diseases, acquired pathologies, and aging-related declines in health. Szeto-Schiller (SS) peptides comprise a class of amphipathic tetrapeptides that are efficacious toward a wide array of mitochondrial disorders and are believed to target mitochondrial membranes because they are enriched in the anionic phospholipid cardiolipin (CL). However, little is known regarding how SS peptides interact with or alter the physical properties of lipid bilayers. In this study, using biophysical and computational approaches, we have analyzed the interactions of the lead compound SS-31 (elamipretide) with model and mitochondrial membranes. Our results show that this polybasic peptide partitions into the membrane interfacial region with an affinity and a lipid binding density that are directly related to surface charge. We found that SS-31 binding does not destabilize lamellar bilayers even at the highest binding concentrations; however, it did cause saturable alterations in lipid packing. Most notably, SS-31 modulated the surface electrostatics of both model and mitochondrial membranes. We propose nonexclusive mechanisms by which the tuning of surface charge could underpin the mitoprotective properties of SS-31, including alteration of the distribution of ions and basic proteins at the interface, and/or modulation of bilayer physical properties. As a proof of concept, we show that SS-31 alters divalent cation (calcium) distribution within the interfacial region and reduces the energetic burden of calcium stress in mitochondria. The mechanistic details of SS-31 revealed in this study will help inform the development of future compound variants with enhanced efficacy and bioavailability.
Assuntos
Bicamadas Lipídicas/química , Oligopeptídeos/química , Cálcio/metabolismo , Mitocôndrias/metabolismo , Saccharomyces cerevisiae/metabolismo , Eletricidade EstáticaRESUMO
APOE4 is a strong genetic risk factor for Alzheimer's disease and Dementia with Lewy bodies; however, how its expression impacts pathogenic pathways in a human-relevant system is not clear. Here using human iPSC-derived cerebral organoid models, we find that APOE deletion increases α-synuclein (αSyn) accumulation accompanied with synaptic loss, reduction of GBA levels, lipid droplet accumulation and dysregulation of intracellular organelles. These phenotypes are partially rescued by exogenous apoE2 and apoE3, but not apoE4. Lipidomics analysis detects the increased fatty acid utilization and cholesterol ester accumulation in apoE-deficient cerebral organoids. Furthermore, APOE4 cerebral organoids have increased αSyn accumulation compared to those with APOE3. Carrying APOE4 also increases apoE association with Lewy bodies in postmortem brains from patients with Lewy body disease. Our findings reveal the predominant role of apoE in lipid metabolism and αSyn pathology in iPSC-derived cerebral organoids, providing mechanistic insights into how APOE4 drives the risk for synucleinopathies.
Assuntos
Apolipoproteínas E/metabolismo , Metabolismo dos Lipídeos/fisiologia , Organoides/patologia , Sinucleinopatias/metabolismo , alfa-Sinucleína/metabolismo , Animais , Humanos , Células-Tronco Pluripotentes Induzidas , Camundongos , Organoides/metabolismo , Isoformas de Proteínas/metabolismo , Sinucleinopatias/patologiaRESUMO
Lipids are the critical components of cellular and plasma membrane, which constitute an impermeable barrier of cellular compartments, and play important roles on numerous cellular processes including cell growth, proliferation, differentiation, and signaling. Alterations in lipid metabolism have been implicated in the development and progression of cancers. However, unlike other biomolecules, the diversity in the structures and characteristics of lipid species results in the limited understanding of their metabolic alterations in cancers. Lipidomics is an emerging discipline that studies lipids in a large scale based on analytical chemistry principles and technological tools. Multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) uses direct infusion to avoid difficulties from alterations in concentration, chromatographic anomalies, and ion-pairing alterations to improve resolution and achieve rapid and accurate qualitative and quantitative analysis. In this chapter, lipids and lipid metabolism relevant to cancer research are introduced, followed by a brief description of MDMS-SL and other shotgun lipidomics techniques and some applications for cancer research.
Assuntos
Metabolismo dos Lipídeos , Neoplasias , Lipidômica , Lipídeos , Espectrometria de Massas , MetabolômicaRESUMO
We retrospectively examined a large cohort of esophageal carcinoma patients who received early enteral nutrition (EEN) to clarify the validity of EEN compared with total parenteral nutrition (TPN). Included were a total of 665 consecutive patients with histologically confirmed carcinoma of the esophagus or esophagogastric junction; and all patients underwent esophagectomy. The patients were divided into two groups: TPN (n = 262) and EEN (n = 403). The TPN group consisted of patients who only received intravenous nutrition support after operation. The postoperative length of hospital stay (PLOS), anastomotic leakage, mortality after surgery, and hospital charges were reviewed and analyzed. Compared with the TPN group, the EEN group had significantly shorter mean PLOS (15.6 days vs. 22.5 days; P < 0.01). Multivariable linear regression analysis revealed EEN to be associated with shorter PLOS even after adjustment for tumor histology, tumor location, type of esophagectomy, and postoperative albumin infusion. Hospital charges were also significantly less for those in the EEN group than the TPN group. There was no significant difference between the two groups regarding the complication of anastomotic leakage and clinical outcome after surgery. These findings suggest that EEN reduces PLOS and hospital charges of Chinese esophageal cancer patients who had an esophagectomy.
Assuntos
Nutrição Enteral , Neoplasias Esofágicas/cirurgia , Esofagectomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Povo Asiático , Estudos de Coortes , Neoplasias Esofágicas/terapia , Feminino , Hospitalização/economia , Humanos , Masculino , Pessoa de Meia-Idade , Nutrição Parenteral/métodos , Cuidados Pós-Operatórios , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The protective effect of dietary carotenoid intake on the risk of breast cancer is inconclusive. Moreover, data on dietary carotenoids in relation to breast cancer in non-Western populations are scarce. The aim of the present study was to examine the association between dietary carotenoid intake and the risk of breast cancer among Chinese women. A total of 561 cases and 561 controls who were frequency matched by age (5-year interval) and residence were recruited in the present case-control study. Dietary intake information was collected by a face-to-face interview using a validated FFQ. The OR and 95 % CI were assessed by multivariate logistic regression after adjusting for various potential confounders. An inverse association was observed between the consumption of α-carotene, ß-carotene, ß-cryptoxanthin and lutein/zeaxanthin and the risk of breast cancer. The multivariate-adjusted OR for the highest quartile of intake compared with the lowest quartile of intake were 0·61 (95 % CI 0·43, 0·88) for α-carotene, 0·54 (95 % CI 0·38, 0·78) for ß-carotene, 0·38 (95 % CI 0·26, 0·52) for ß-cryptoxanthin and 0·49 (95 % CI 0·34, 0·71) for lutein/zeaxanthin. Lycopene intake was not found to be associated with the risk of breast cancer, with the adjusted OR of 0·89 (95 % CI 0·61, 1·30). These inverse associations were more evident among pre-menopausal women and women who were exposed to second-hand smoke. The protective effect of specific carotenoid intake was observed for all subtypes of hormone receptor status of breast cancer. The present study indicated that a greater intake of specific carotenoids was associated with a decreased risk of breast cancer among Chinese women residing in Guangdong.
Assuntos
Anticarcinógenos/uso terapêutico , Neoplasias da Mama/prevenção & controle , Carotenoides/uso terapêutico , Dieta , Adulto , Fatores Etários , Idoso , Anticarcinógenos/administração & dosagem , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etnologia , Neoplasias da Mama/etiologia , Carotenoides/administração & dosagem , Estudos de Casos e Controles , China/epidemiologia , Criptoxantinas , Dieta/etnologia , Feminino , Hospitais Gerais , Hospitais de Ensino , Humanos , Luteína/administração & dosagem , Luteína/uso terapêutico , Pessoa de Meia-Idade , Risco , Poluição por Fumaça de Tabaco/efeitos adversos , Xantofilas/administração & dosagem , Xantofilas/uso terapêutico , Zeaxantinas , beta Caroteno/administração & dosagem , beta Caroteno/uso terapêuticoRESUMO
Fatty acid esters of hydroxy fatty acid (FAHFA) are anti-diabetic and anti-inflammatory lipokines. Recently FAHFAs were also found to predict cardiorespiratory fitness in a cross-sectional study of recreationally trained runners. Here we report the influences of body composition and gender on static FAHFA abundances in circulation. We compared the association between circulating FAHFA concentrations and body composition, determined by dual x-ray absorptiometry, in female recreational runners who were lean (BMI < 25 kg/m2, n = 6), to those who were overweight (BMI ≥ 25 kg/m2, n = 7). To characterize the effect of gender we also compared circulating FAHFAs in lean male recreational runners (n = 8) to recreationally trained lean female (n = 6) runner group. Circulating FAHFAs were increased in females in a manner that was modulated by specific adipose depot sizes, blood glucose, and lean body mass. As expected, circulating FAHFAs were diminished in the overweight group, but strikingly, within the lean cohort, increases in circulating FAHFAs were promoted by increased fat mass, relative to lean mass, while the overweight group showed a significantly attenuated relationship. These studies suggest multimodal regulation of circulating FAHFAs and raise hypotheses to test endogenous FAHFA dynamic sources and sinks in health and disease, which will be essential for therapeutic target development. Baseline circulating FAHFA concentrations could signal sub-clinical metabolic dysfunction in metabolically healthy obesity.
Assuntos
Composição Corporal , Corrida , Humanos , Feminino , Corrida/fisiologia , Masculino , Adulto , Ácidos Graxos/sangue , Fatores Sexuais , Sobrepeso/sangue , Absorciometria de Fóton , Estudos Transversais , Índice de Massa Corporal , Caracteres SexuaisRESUMO
Acetyl-CoA synthetase short-chain family member 1 (ACSS1) uses acetate to generate mitochondrial acetyl-CoA and is regulated by deacetylation by sirtuin 3. We generated an ACSS1-acetylation (Ac) mimic mouse, where lysine-635 was mutated to glutamine (K635Q). Male Acss1K635Q/K635Q mice were smaller with higher metabolic rate and blood acetate and decreased liver/serum ATP and lactate levels. After a 48-hour fast, Acss1K635Q/K635Q mice presented hypothermia and liver aberrations, including enlargement, discoloration, lipid droplet accumulation, and microsteatosis, consistent with nonalcoholic fatty liver disease (NAFLD). RNA sequencing analysis suggested dysregulation of fatty acid metabolism, cellular senescence, and hepatic steatosis networks, consistent with NAFLD. Fasted Acss1K635Q/K635Q mouse livers showed increased fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1), both associated with NAFLD, and increased carbohydrate response element-binding protein binding to Fasn and Scd1 enhancer regions. Last, liver lipidomics showed elevated ceramide, lysophosphatidylethanolamine, and lysophosphatidylcholine, all associated with NAFLD. Thus, we propose that ACSS1-K635-Ac dysregulation leads to aberrant lipid metabolism, cellular senescence, and NAFLD.
Assuntos
Senescência Celular , Mitocôndrias , Hepatopatia Gordurosa não Alcoólica , Estearoil-CoA Dessaturase , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Camundongos , Senescência Celular/genética , Acetilação , Mitocôndrias/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Estearoil-CoA Dessaturase/genética , Masculino , Acetato-CoA Ligase/metabolismo , Acetato-CoA Ligase/genética , Técnicas de Introdução de Genes , Fígado/metabolismo , Fígado/patologia , Metabolismo dos Lipídeos , Sirtuína 3/metabolismo , Sirtuína 3/genética , Modelos Animais de Doenças , Coenzima A Ligases , Ácido Graxo Sintase Tipo IRESUMO
Few epidemiological studies have evaluated the association of choline and betaine intake with breast cancer risk and the results remain inconsistent. This study aimed to assess the relationship between dietary intake of choline and betaine and the risk of breast cancer among Chinese women. A two-stage case-control study was conducted, with 807 cases and 807 age- (5-year interval) and residence (rural/urban)-matched controls. A validated food frequency questionnaire was used to assess dietary intake by face-to-face interview. An unconditional logistic regression model was used to calculate multivariate-adjusted odds ratios (OR) and 95% confidence intervals (CI). A significant inverse association was found between dietary choline and betaine consumption and breast cancer risk. The adjusted OR for the highest quartile of intake compared with the lowest were 0.40 (95% CI = 0.28-0.57, P(trend) < 0.001) for total choline intake, 0.58 (95% CI = 0.42-0.80, P(trend) < 0.001) for betaine intake and 0.38 (0.27-0.53, P(trend) < 0.001) for choline plus betaine intake, respectively. Intakes of individual choline compouds, choline from glycerophosphocholine, phosphocholine, phosphatidylcholine, sphingomyelin and free choline were also negatively associated with breast cancer risk. The inverse association between choline intake and breast cancer risk was primarily confined to participants with low folate level (<242 g/day), with an OR (95% CI) of 0.46 (0.23-0.91) comparing the fourth quartile with the first quartile of choline intake (P(trend) = 0.005). The present study suggests that consumption of choline and betaine is inversely associated with the risk of breast cancer. The association of choline intake with breast cancer risk is probably modified by folate intake.
Assuntos
Betaína/administração & dosagem , Neoplasias da Mama/epidemiologia , Colina/administração & dosagem , Estudos de Casos e Controles , China/epidemiologia , Dieta , Ingestão de Alimentos , Feminino , Ácido Fólico/metabolismo , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
Fatty acid esters of hydroxy fatty acid (FAHFA) are anti-diabetic and anti-inflammatory lipokines. Recently FAHFAs were also found to predict cardiorespiratory fitness in trained runners. Here we compared the association between circulating FAHFA baseline concentrations and body composition, determined by dual x-ray absorptiometry, in female runners who were lean (BMI < 25 kg/m2, n = 6), to those who were overweight (BMI ≥ 25 kg/m2, n = 7). We also compared circulating FAHFAs in lean male runners (n = 8) to the same trained lean female (n = 6) runner group. Circulating FAHFAs were increased in females in a manner that was modulated by specific adipose depot sizes, blood glucose, and lean body mass. As expected, circulating FAHFAs were diminished in the overweight group, but, strikingly, in both lean and overweight cohorts, increases in circulating FAHFAs were promoted by increased fat mass, relative to lean mass. These studies suggest multimodal regulation of circulating FAHFAs and raise hypotheses to test endogenous FAHFA dynamic sources and sinks in health and disease, which will be essential for therapeutic target development. Baseline circulating FAHFA concentrations could signal sub-clinical metabolic dysfunction in metabolically healthy obesity.
RESUMO
Cell membrane phosphatidylcholine (PC) composition is regulated by lysophosphatidylcholine acyltransferase (LPCAT); changes in membrane PC saturation are implicated in metabolic disorders. Here, we identified LPCAT3 as the major isoform of LPCAT in adipose tissue and created adipocyte-specific Lpcat3-knockout mice to study adipose tissue lipid metabolism. Transcriptome sequencing and plasma adipokine profiling were used to investigate how LPCAT3 regulates adipose tissue insulin signaling. LPCAT3 deficiency reduced polyunsaturated PCs in adipocyte plasma membranes, increasing insulin sensitivity. LPCAT3 deficiency influenced membrane lipid rafts, which activated insulin receptors and AKT in adipose tissue, and attenuated diet-induced insulin resistance. Conversely, higher LPCAT3 activity in adipose tissue from ob/ob, db/db, and high-fat diet-fed mice reduced insulin signaling. Adding polyunsaturated PCs to mature human or mouse adipocytes in vitro worsened insulin signaling. We suggest that targeting LPCAT3 in adipose tissue to manipulate membrane phospholipid saturation is a new strategy to treat insulin resistance.