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1.
J Hazard Mater ; 442: 130082, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-36209609

RESUMO

Neonicotinoid insecticides (NNIs) are the most widely used class of pesticides globally. However, NNIs may cause adverse health effects, including chronic liver disease, and perturbation of the gut microbiota. Thiacloprid (THI) is one of the NNIs widely used in agriculture. Therefore, it is essential to elucidate effects of THI on the microbiota-gut-liver axis to assess the risk of chronic liver disease following exposure to NNIs. This study aimed at investigating whether THI exposure promoted liver injury by altering the gut microbiota and related metabolites. In this study, healthy male quails were exposed to 2 or 4 mg/kg THI or 0.75 % (w/v) saline once daily for 6 weeks, respectively. Metabolomics, 16S rRNA sequencing, and transcriptomic methods were performed to analyze the toxic mechanisms of THI in Japanese quails. We found that THI evoked damage and disruption to intestinal barrier function, leading to increased harmful substances such as lipopolysaccharide (LPS) and phenylacetic acid entering the liver. Besides, our results showed significantly altered hepatic bile acid and cholesterol metabolism in THI-exposed quails, with abnormal liver lipid metabolism, showing severe liver injury, fibrosis, and steatosis compared with the control quails. In conclusion, THI exposure aggravates liver injury via microbiota-gut-liver axis.


Assuntos
Microbioma Gastrointestinal , Inseticidas , Animais , Masculino , Coturnix/genética , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/metabolismo , Lipopolissacarídeos , Inseticidas/metabolismo , Fígado/metabolismo , Neonicotinoides/toxicidade , Neonicotinoides/metabolismo , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/farmacologia , Colesterol/metabolismo , Colesterol/farmacologia
2.
Allergol. immunopatol ; 50(6): 115-121, 01 nov. 2022. ilus, graf
Artigo em Inglês | IBECS | ID: ibc-211512

RESUMO

Background Psoriasis is considered as an inflammatory skin disease accompanied by dyslipidemia comorbidity. B-cell leukemia-3 (Bcl-3) belongs to IκB (inhibitor of nuclear factor kappa B [NF-κB]) family, and regulates inflammatory response through associating with NF-κB. The role of Bcl-3 in psoriasis was investigated in this study. Methods Apolipoprotein E (ApoE)-deficient mice were treated with imiquimod to induce psoriasis and dyslipidemia. Mice were injected intradermally in the back with lentiviral particles encoding Bcl-3 small hairpin RNA (shRNA). Hematoxylin and eosin were used to detect pathological characteristics. The blood lipid levels were determined by automatic biochemical analyzer, and inflammation was assessed by enzyme-linked-immunosorbent serologic assay and real-time quantitative reverse transcription polymerase chain reaction. Results Bcl-3 was elevated in imiquimod-induced ApoE-deficient mice. Injection with lentiviral particles encoding Bcl-3 shRNA reduced Psoriasis area and severity index (PASI) score in ApoE-deficient psoriatic mice. Knockdown of Bcl-3 also ameliorated imiquimod-induced psoriasiform skin lesions in ApoE-deficient mice. Moreover, loss of Bcl-3 enhanced expression of loricrin, an epidermal barrier protein, reduced expression of proliferating cell nuclear antigen (PCNA) and lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1) in imiquimod-induced ApoE-deficient mice. The enhanced levels of blood lipid in ApoE-deficient mice were attenuated by silencing of Bcl-3 with increase of high-density lipoprotein, and reduction of total cholesterol, triglycerides, and low-density lipoprotein cholesterol. Knockdown of Bcl-3 attenuated imiquimod-induced decrease of transforming growth factor beta (TGF-β), and increase of Interleukin (IL)-17A, IL-23, IL-6, and tumor necrosis factor-α (TNF-α) in ApoE-deficient mice. Protein expression of phospho-Akt (p-Akt) and p-GSK3β in ApoE-deficient psoriatic mice was decreased by silencing of Bcl-3 (AU)


Assuntos
Animais , Masculino , Camundongos , Dislipidemias , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Apolipoproteínas E/efeitos adversos , Apolipoproteínas E/metabolismo , Colesterol/metabolismo , Comorbidade , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/metabolismo , Imiquimode/efeitos adversos , Imiquimode/metabolismo , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Proteína Oncogênica v-akt/metabolismo , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo
3.
FASEB J ; 36(12): e22637, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36349989

RESUMO

The mitochondrial translocator protein (18 kDa; TSPO) is a high-affinity cholesterol-binding protein that is an integral component of the cholesterol trafficking scaffold responsible for determining the rate of cholesterol import into the mitochondria for steroid biosynthesis. Previous studies have shown that TSPO declines in aging Leydig cells (LCs) and that its decline is associated with depressed circulating testosterone levels in aging rats. However, TSPO's role in the mechanistic decline in LC function is not fully understood. To address the role of TSPO depletion in LC function, we first examined mitochondrial quality in Tspo knockout mouse tumor MA-10 nG1 LCs compared to wild-type MA-10 cells. Tspo deletion caused a disruption in mitochondrial function and membrane dynamics. Increasing mitochondrial fusion via treatment with the mitochondrial fusion promoter M1 or by optic atrophy 1 (OPA1) overexpression resulted in the restoration of mitochondrial function and mitochondrial morphology as well as in steroid formation in TSPO-depleted nG1 LCs. LCs isolated from aged rats form less testosterone than LCs isolated from young rats. Treatment of aging LCs with M1 improved mitochondrial function and increased androgen formation, suggesting that aging LC dysfunction may stem from compromised mitochondrial dynamics caused by the age-dependent LC TSPO decline. These results, taken together, suggest that maintaining or enhancing mitochondrial fusion may provide therapeutic strategies to maintain or restore testosterone levels with aging.


Assuntos
Células Intersticiais do Testículo , Dinâmica Mitocondrial , Camundongos , Masculino , Ratos , Animais , Células Intersticiais do Testículo/metabolismo , Receptores de GABA/genética , Receptores de GABA/metabolismo , Proteínas Mitocondriais/metabolismo , Colesterol/metabolismo , Testosterona/metabolismo
4.
Nat Commun ; 13(1): 7139, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36414669

RESUMO

Emerging evidence suggests that osteoarthritis is associated with high cholesterol levels in some osteoarthritis patients. However, the specific mechanism under this metabolic osteoarthritis phenotype remains unclear. We find that cholesterol metabolism-related gene, LRP3 (low-density lipoprotein receptor-related protein 3) is significantly reduced in high-cholesterol diet mouse's cartilage. By using Lrp3-/- mice in vivo and LRP3 lentiviral-transduced chondrocytes in vitro, we identify that LRP3 positively regulate chondrocyte extracellular matrix metabolism, and its deficiency aggravate the degeneration of cartilage. Regardless of diet, LRP3 overexpression in cartilage attenuate anterior cruciate ligament transection induced osteoarthritis progression in rats and Lrp3 knockout-induced osteoarthritis progression in mice. LRP3 knockdown upregulate syndecan-4 by activating the Ras signaling pathway. We identify syndecan-4 as a downstream molecular target of LRP3 in osteoarthritis pathogenesis. These findings suggest that cholesterol-LRP3- syndecan-4 axis plays critical roles in osteoarthritis development, and LRP3 gene therapy may provide a therapeutic regimen for osteoarthritis treatment.


Assuntos
Proteínas Relacionadas a Receptor de LDL , Osteoartrite , Sindecana-4 , Animais , Camundongos , Ratos , Cartilagem/metabolismo , Colesterol/metabolismo , Regulação para Baixo , Osteoartrite/metabolismo , Sindecana-4/genética , Sindecana-4/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo
5.
PLoS One ; 17(11): e0277058, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36409725

RESUMO

Isomeric lysosphingolipids, galactosylsphingosine (GalSph) and glucosylsphingosine (GlcSph), are present in only minute levels in healthy cells. Due to defects in their lysosomal hydrolysis, they accumulate at high levels and cause cytotoxicity in patients with Krabbe and Gaucher diseases, respectively. Here, we show that GalSph and GlcSph induce lysosomal membrane permeabilization, a hallmark of lysosome-dependent cell death, in human breast cancer cells (MCF7) and primary fibroblasts. Supporting lysosomal leakage as a causative event in lysosphingolipid-induced cytotoxicity, treatment of MCF7 cells with lysosome-stabilizing cholesterol prevented GalSph- and GlcSph-induced cell death almost completely. In line with this, fibroblasts from a patient with Niemann-Pick type C disease, which is caused by defective lysosomal cholesterol efflux, were significantly less sensitive to lysosphingolipid-induced lysosomal leakage and cell death. Prompted by the data showing that MCF7 cells with acquired resistance to lysosome-destabilizing cationic amphiphilic drugs (CADs) were partially resistant to the cell death induced by GalSph and GlcSph, we compared these cell death pathways with each other. Like CADs, GalSph and GlcSph activated the cyclic AMP (cAMP) signalling pathway, and cAMP-inducing forskolin sensitized cells to cell death induced by low concentrations of lysosphingolipids. Contrary to CADs, lysosphingolipid-induced cell death was independent of lysosomal Ca2+ efflux through P2X purinerigic receptor 4. These data reveal GalSph and GlcSph as lysosome-destabilizing lipids, whose putative use in cancer therapy should be further investigated. Furthermore, the data supports the development of lysosome stabilizing drugs for the treatment of Krabbe and Gaucher diseases and possibly other sphingolipidoses.


Assuntos
Doença de Gaucher , Neoplasias , Humanos , Psicosina/metabolismo , Lisossomos/metabolismo , Morte Celular , Doença de Gaucher/metabolismo , AMP Cíclico/metabolismo , Colesterol/metabolismo , Neoplasias/metabolismo
6.
J Vis Exp ; (188)2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36373947

RESUMO

Understanding the function and mechanism of pore-forming toxins (PFTs) is challenging because cells resist the membrane damage caused by PFTs. While biophysical approaches help understand pore formation, they often rely on reductionist approaches lacking the full complement of membrane lipids and proteins. Cultured human cells provide an alternative system, but their complexity and redundancies in repair mechanisms make identifying specific mechanisms difficult. In contrast, the human protozoan pathogen responsible for cutaneous leishmaniasis, Leishmania major, offers an optimal balance between complexity and physiologic relevance. L. major is genetically tractable and can be cultured to high density in vitro, and any impact of perturbations on infection can be measured in established murine models. In addition, L. major synthesizes lipids distinct from their mammalian counterparts, which could alter membrane dynamics. These alterations in membrane dynamics can be probed with PFTs from the best-characterized toxin family, cholesterol-dependent cytolysins (CDCs). CDCs bind to ergosterol in the Leishmania membrane and can kill L. major promastigotes, indicating that L. major is a suitable model system for determining the cellular and molecular mechanisms of PFT function. This work describes methods for testing PFT function in L. major promastigotes, including parasite culture, genetic tools for assessing lipid susceptibility, membrane binding assays, and cell death assays. These assays will enable the rapid use of L. major as a powerful model system for understanding PFT function across a range of evolutionarily diverse organisms and commonalities in lipid organization.


Assuntos
Toxinas Bacterianas , Leishmania major , Humanos , Camundongos , Animais , Toxinas Bacterianas/metabolismo , Leishmania major/genética , Leishmania major/metabolismo , Lipídeos de Membrana , Membrana Celular/metabolismo , Colesterol/metabolismo , Mamíferos/metabolismo
7.
BMC Neurosci ; 23(1): 61, 2022 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-36335301

RESUMO

BACKGROUND: In brain, microvascular endothelial cells are exposed to various forces, including shear stress (SS). However, little is known about the effects of high shear stress (HSS) on human brain microvascular endothelial cells (HBMECs) and the underlying mechanism. The cholesterol efflux regulator ATP-binding cassette subfamily A member 1 (ABCA1) has been demonstrated to exert protective effect on HBMECs. However, whether ABCA1 is involved in the mechanism underneath the effect of HSS on HBMECs remains obscure. In the present study, a series of experiments were performed to better understand the effect of HSS on cellular processes of HBMECs and the possible involvement of ABCA1 and PI3K/Akt/eNOS in the underlying mechanisms. RESULTS: HBMECs were subjected to physiological SS (PSS) or high SS (HSS). Cell migration was evaluated using Transwell assay. Apoptotic HBMECs were detected by flow cytometry or caspase3/7 activity. IL-1ß, IL-6, MCP-1 and TNF-α levels were measured by ELISA. RT-qPCR and western blotting were used for mRNA and protein expression detection, respectively. ROS and NO levels were detected using specific detection kits. Compared to PSS, HBMECs exhibited decreased cell viability and migration and increased cell apoptosis, increased levels of inflammatory cytokines, and improved ROS and NO productions after HSS treatment. Moreover, HSS downregulated ABCA1 but upregulated the cholesterol efflux-related proteins MMP9, AQP4, and CYP46 and activated PI3K/Akt/eNOS pathway. Overexpression of ABCA1 in HBMECS inhibited PI3K/Akt/eNOS pathway and counteracted the deleterious effects of HSS. Contrary effects were observed by ABCA1 silencing. Inhibiting PI3K/Akt/eNOS pathway mimicked ABCA1 effects, suggesting that ABCA1 protects HBMECs from HSS via PI3K/Akt/eNOS signaling. CONCLUSION: These results advanced our understanding on the mechanisms of HSS on HBMECs and potentiated ABCA1/PI3K/Akt/eNOS pathway as therapeutic target for cerebrovascular diseases.


Assuntos
Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Endoteliais , Espécies Reativas de Oxigênio/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico Sintase Tipo III/farmacologia , Encéfalo/metabolismo , Colesterol/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/farmacologia
8.
Mar Drugs ; 20(11)2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36355027

RESUMO

The sulfated echinoside A (EA) and holothurin A (HA) are two prominent saponins in sea cucumber with high hemolytic activity but also superior lipid-lowering activity. Deglycosylated derivatives EA2 and HA2 exhibit low hemolysis compared to EA and HA, but their efficacies on lipid metabolism regulation remains unknown. In this study, fatty acids-treated HepG2 cells and orotic acid-treated rats were used to investigate the lipid-lowering effects of sea cucumber saponin derivatives. Both the saponin and derivatives could effectively alleviate lipid accumulation in HepG2 model, especially EA and EA2. Moreover, though the lipid-lowering effect of EA2 was not equal with EA at the same dosage of 0.05% in diet, 0.15% dosage of EA2 significantly reduced hepatic steatosis rate, liver TC and TG contents by 76%, 41.5%, and 63.7%, respectively, compared to control and reversed liver histopathological features to normal degree according to H&E stained sections. Possible mechanisms mainly included enhancement of fatty acids ß-oxidation and cholesterol catabolism through bile acids synthesis and excretion, suppression of lipogenesis and cholesterol uptake. It revealed that the efficacy of EA2 on lipid metabolism regulation was dose-dependent, and 0.15% dosage of EA2 possessed better efficacy with lower toxicity compared to 0.05% dosage of EA.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Saponinas , Pepinos-do-Mar , Ratos , Animais , Humanos , Pepinos-do-Mar/metabolismo , Ácido Orótico/metabolismo , Ácido Orótico/farmacologia , Saponinas/farmacologia , Saponinas/metabolismo , Ácidos Graxos/metabolismo , Células Hep G2 , Fígado , Metabolismo dos Lipídeos , Colesterol/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo
9.
Nutrients ; 14(22)2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36432620

RESUMO

Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic and environmental variation. APOE*3-Leiden.CETP mice, as part of an inbred mouse model in which mice develop the metabolic syndrome upon being fed a high-fat high-cholesterol diet, show large inter-individual variation in the parameters of the metabolic syndrome, despite a lack of genetic and environmental variation. In the present study, we set out to resolve what mechanisms could underlie this variation. We used measurements of glucose and lipid metabolism from a six-month longitudinal study on the development of the metabolic syndrome. Mice were classified as mice with either high plasma triglyceride (responders) or low plasma triglyceride (non-responders) at the baseline. Subsequently, we fitted the data to a dynamic computational model of whole-body glucose and lipid metabolism (MINGLeD) by making use of a hybrid modelling method called Adaptations in Parameter Trajectories (ADAPT). ADAPT integrates longitudinal data, and predicts how the parameters of the model must change through time in order to comply with the data and model constraints. To explain the phenotypic variation in plasma triglycerides, the ADAPT analysis suggested a decreased cholesterol absorption, higher energy expenditure and increased fecal fatty acid excretion in non-responders. While decreased cholesterol absorption and higher energy expenditure could not be confirmed, the experimental validation demonstrated that the non-responders were indeed characterized by increased fecal fatty acid excretion. Furthermore, the amount of fatty acids excreted strongly correlated with bile acid excretion, in particular deoxycholate. Since bile acids play an important role in the solubilization of lipids in the intestine, these results suggest that variation in bile acid homeostasis may in part drive the phenotypic variation in the APOE*3-Leiden.CETP mice.


Assuntos
Síndrome Metabólica , Camundongos , Humanos , Animais , Síndrome Metabólica/metabolismo , Estudos Longitudinais , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversos , Colesterol/metabolismo , Triglicerídeos , Ácidos e Sais Biliares/metabolismo , Glucose/metabolismo , Fenótipo , Análise de Sistemas , Ácidos Graxos/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/metabolismo
10.
Cell Commun Signal ; 20(1): 189, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36434621

RESUMO

BACKGROUND: Autophagy is an intracellular degradation process crucial for homeostasis. During autophagy, a double-membrane autophagosome fuses with lysosome through SNARE machinery STX17 to form autolysosome for degradation of damaged organelle. Whereas defective autophagy enhances cholesterol accumulation in the lysosome and impaired autophagic flux that results Niemann-Pick type C1 (NPC1) disease. However, exact interconnection between NPC1 and autophagic flux remain obscure due to the existence of controversial reports. RESULTS: This study aimed at a comparison of the effects of three autophagic inhibitor drugs, including chloroquine, U18666A, and bafilomycin A1, on the intracellular cholesterol transport and autophagy flux. Chloroquine, an autophagic flux inhibitor; U1866A, a NPC1 inhibitor, and bafilomycin A, a lysosomotropic agent are well known to inhibit autophagy by different mechanism. Here we showed that treatment with U1866A and bafilomycin A induces lysosomal cholesterol accumulation that prevented autophagic flux by decreasing autophagosome-lysosome fusion. We also demonstrated that accumulation of cholesterol within the lysosome did not affect lysosomal pH. Although the clearance of accumulated cholesterol by cyclodextrin restored the defective autophagosome-lysosome fusion, the autophagy flux restoration was possible only when lysosomal acidification was not altered. In addition, a failure of STX17 trafficking to autophagosomes plays a key role in prevention of autophagy flux caused by intracellular cholesterol transport inhibitors. CONCLUSIONS: Our data provide a new insight that the impaired autophagy flux does not necessarily result in lysosomal cholesterol accumulation even though it prevents autophagosome-lysosome fusion. Video abstract.


Assuntos
Autofagossomos , Autofagia , Autofagossomos/metabolismo , Lisossomos/metabolismo , Cloroquina/farmacologia , Cloroquina/metabolismo , Colesterol/metabolismo
11.
Int J Mol Sci ; 23(22)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36430205

RESUMO

Lipid rafts are specialized microdomains in cell membranes, rich in cholesterol and sphingolipids, and play an integrative role in several physiological and pathophysiological processes. The integrity of rafts can be disrupted via their cholesterol content-with methyl-ß-cyclodextrin (MCD) or with our own carboxamido-steroid compound (C1)-or via their sphingolipid content-with sphingomyelinase (SMase) or with myriocin (Myr). We previously proved by the fluorescent spectroscopy method with LAURDAN that treatment with lipid raft disruptors led to a change in cell membrane polarity. In this study, we focused on the alteration of parameters describing membrane fluidity, such as generalized polarization (GP), characteristic time of the GP values change-Center of Gravity (τCoG)-and rotational mobility (τrot) of LAURDAN molecules. Myr caused a blue shift of the LAURDAN spectrum (higher GP value), while other agents lowered GP values (red shift). MCD decreased the CoG values, while other compounds increased it, so MCD lowered membrane stiffness. In the case of τrot, only Myr lowered the rotation of LAURDAN, while the other compounds increased the speed of τrot, which indicated a more disordered membrane structure. Overall, MCD appeared to increase the fluidity of the membranes, while treatment with the other compounds resulted in decreased fluidity and increased stiffness of the membranes.


Assuntos
Fluidez de Membrana , Microdomínios da Membrana , Espectrometria de Fluorescência , Microdomínios da Membrana/metabolismo , Membrana Celular/metabolismo , Colesterol/metabolismo
12.
Int J Mol Sci ; 23(22)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36430223

RESUMO

ABCG1 has been proposed to play a role in HDL-dependent cellular sterol regulation; however, details of the interaction between the transporter and its potential sterol substrates have not been revealed. In the present work, we explored the effect of numerous sterol compounds on the two isoforms of ABCG1 and ABCG4 and made efforts to identify the molecular motifs in ABCG1 that are involved in the interaction with cholesterol. The functional readouts used include ABCG1-mediated ATPase activity and ABCG1-induced apoptosis. We found that both ABCG1 isoforms and ABCG4 interact with several sterol compounds; however, they have selective sensitivities to sterols. Mutational analysis of potential cholesterol-interacting motifs in ABCG1 revealed altered ABCG1 functions when F571, L626, or Y586 were mutated. L430A and Y660A substitutions had no functional consequence, whereas Y655A completely abolished the ABCG1-mediated functions. Detailed structural analysis of ABCG1 demonstrated that the mutations modulating ABCG1 functions are positioned either in the so-called reentry helix (G-loop/TM5b,c) (Y586) or in its close proximity (F571 and L626). Cholesterol molecules resolved in the structure of ABCG1 are also located close to Y586. Based on the experimental observations and structural considerations, we propose an essential role for the reentry helix in cholesterol sensing in ABCG1.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Colesterol , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Colesterol/metabolismo , Esteróis , Adenosina Trifosfatases/metabolismo
13.
Molecules ; 27(21)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36364321

RESUMO

Isoliquiritigenin (ISL) is a flavonoid with a chalcone structure extracted from the natural herb Glycyrrhiza glabra. Its anti-inflammatory, antibacterial, antioxidant, and anticancer activities have been extensively studied. Moreover, ISL also possess hypolipidemic and atherosclerosis-reducing effects. However, its cholesterol-lowering mechanisms have not been reported yet. Niemann Pick C1 Like 1 (NPC1L1) is a specific transporter of cholesterol uptake. In this study, we found for the first time that ISL downregulates NPC1L1 expression and competitively inhibits cellular cholesterol uptake by binding to NPC1L1 in a concentration-dependent manner in vitro. This study provides a theoretical basis for further investigation of the molecular mechanisms of its cholesterol-lowering effect in vivo and inspired emerging drug research for cholesterol-lowering purposes through NPC1L1 inhibition.


Assuntos
Anticolesterolemiantes , Chalconas , Chalconas/farmacologia , Transporte Biológico , Proteínas de Membrana Transportadoras/metabolismo , Colesterol/metabolismo , Anticolesterolemiantes/farmacologia
14.
Nature ; 611(7937): 769-779, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36385529

RESUMO

APOE4 is the strongest genetic risk factor for Alzheimer's disease1-3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer's disease4-8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2-6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease.


Assuntos
Apolipoproteína E4 , Encéfalo , Colesterol , Fibras Nervosas Mielinizadas , Oligodendroglia , Animais , Humanos , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Colesterol/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Autopsia , Células-Tronco Pluripotentes Induzidas , Neurônios/metabolismo , Neurônios/patologia , Heterozigoto , Transporte Biológico , Homeostase , Análise de Célula Única , Memória , Envelhecimento/genética , Perfilação da Expressão Gênica , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia
15.
Food Funct ; 13(23): 12194-12207, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36331041

RESUMO

Polysaccharides from Enteromorpha prolifera (EP) possess multiple biological activities, while the role of EP in hypercholesterolemia and its relationship with the gut microbiota have not been elucidated. To address this issue, fifty male C57BL/6J mice were randomly subjected to a basal diet and a high-fat and high-cholesterol diet, and 3 treatment groups were fed an HFHC diet supplemented with different dosages of EP (100, 200 and 300 mg kg-1 day-1) for 12 weeks. Here we show that EP intervention lowered serum concentrations of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and inhibited hepatic cholesterol deposition. EP intervention also upregulated the gene expression related to the hepatic cholesterol uptake and bile acid synthetic pathway. Apart from that, EP altered the gut microbiota, pre-dominantly increasing microbes associated with bile acid metabolism, such as norank_f_ Muribaculaceae. Moreover, bile acid profile analysis revealed that EP could alter the fecal bile acid profile and reduce fecal conjugated bile acids. Further correlation analysis indicated the negative correlation of Bacteroides, norank_f_ Muribaculaceae and Ileibacterium abundance with the levels of fecal conjugated bile acids and serum TC and LDL-C, while the abundance of Proteobacteria and Lachnoclosteridium showed a positive association with conjugated bile acids and serum TC. To sum up, the above findings revealed that EP may alleviate hypercholesterolemia and regulate cholesterol metabolism in ways that promote a favorable fecal microbiota composition and modulate bile acid metabolism.


Assuntos
Microbioma Gastrointestinal , Hipercolesterolemia , Masculino , Camundongos , Animais , Microbioma Gastrointestinal/fisiologia , LDL-Colesterol/metabolismo , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Metabolismo dos Lipídeos , Ácidos e Sais Biliares/metabolismo , Polissacarídeos , Fígado/metabolismo
16.
Nutrients ; 14(21)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36364926

RESUMO

Ascophyllum nodosum and Fucus vesiculosus both contain unique polyphenols called phlorotannins. Phlorotannins reportedly possess various pharmacological activities. A previous study reported that the activity of phlorotannin is strongly correlated with the normalization of metabolic function, and phlorotannins are extremely promising nutrients for use in the treatment of metabolic syndrome. To date, no study has explored the antihyperlipidemic effects of phlorotannins from A. nodosum and F. vesiculosus in animal models. Therefore, in the present study, we investigated the effects of phlorotannins using a rat model of high-energy diet (HED)-induced hyperlipidemia. The results showed that the rats that were fed an HED and treated with phlorotannin-rich extract from A. nodosum and F. vesiculosus had significantly lower serum fasting blood sugar (FBS), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triacylglyceride (TG) and free fatty acids (FFAs) levels and hepatic TG level and had higher serum insulin, high-density lipoprotein cholesterol (HDL-C) levels and lipase activity in their fat tissues than in the case with the rats that were fed the HED alone. A histopathological analysis revealed that phlorotannin-rich extract could significantly reduce the size of adipocytes around the epididymis. In addition, the rats treated with phlorotannin-rich extract had significantly lowered interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels and increased superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities than did those in the HED group. These results suggested that the phlorotannin-rich extract stimulated lipid metabolism and may have promoted lipase activity in rats with HED-induced hyperlipidemia. Our results indicated that A. nodosum and F. vesiculosus, marine algae typically used as health foods, have strong antihyperlipidemic effects and may, therefore, be useful for preventing atherosclerosis. These algae may be incorporated into antihyperlipidemia pharmaceuticals and functional foods.


Assuntos
Ascophyllum , Fucus , Hiperlipidemias , Doenças Metabólicas , Masculino , Ratos , Animais , Ascophyllum/metabolismo , Metabolismo dos Lipídeos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/etiologia , Doenças Metabólicas/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Inflamação/tratamento farmacológico , Dieta , Lipase/metabolismo , Hipolipemiantes/uso terapêutico , Colesterol/metabolismo
17.
Lipids Health Dis ; 21(1): 97, 2022 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-36209166

RESUMO

BACKGROUND: Cholesterol gallstone disease (CGD) is accompanied by biliary cholesterol supersaturation. Hepatic Niemann-Pick C1-like 1 (NPC1L1), which is present in humans but not in wild-type (WT) mice, promotes hepatocyte cholesterol uptake and decreases biliary cholesterol supersaturation. In contrast, intestinal NPC1L1 promotes intestinal cholesterol absorption, increasing biliary cholesterol supersaturation. Ezetimibe (EZE) can inhibit both hepatic and intestinal NPC1L1. However, whether hepatic NPC1L1 can affect CGD progress remains unknown. METHODS: Mice expressing hepatic NPC1L1 (NPC1L1hepatic-OE mice) were generated using Adeno-associated viruses (AAV) gene delivery. The protein level and function of hepatic NPC1L1 were examined under chow diet, high fat-cholesterol diet (HFCD), and lithogenic diet (LD) feeding. Gallstone formation rates were examined with or without EZE treatment. Fibroblast growth factor 15 (FGF15) treatment and inhibition of fibroblast growth factor receptor 4 (FGFR4) were applied to verify the mechanism of hepatic NPC1L1 degradation. RESULTS: The HFCD-fed NPC1L1hepatic-OE mice retained the biliary cholesterol desaturation function of hepatic NPC1L1, whereas EZE treatment decreased biliary cholesterol saturation and did not cause CGD. The ubiquitination and degradation of hepatic NPC1L1 were discovered in LD-fed NPC1L1hepatic-OE mice. Treatment of FGF15 during HFCD feeding and inhibition of FGFR4 during LD feeding could affect the protein level and function of hepatic NPC1L1. CONCLUSIONS: LD induces the ubiquitination and degradation of hepatic NPC1L1 via the FGF15-FGFR4 pathway. EZE may act as an effective preventative agent for CGD.


Assuntos
Proteínas de Membrana Transportadoras , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos , Animais , Colesterol/metabolismo , Dieta Hiperlipídica , Ezetimiba/farmacologia , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo
18.
Pharm Biol ; 60(1): 1960-1968, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36205548

RESUMO

CONTEXT: Swertia mussotii Franch. (Gentianaceae) is a source of the traditional Tibetan medicine, ZangYinChen, and is used to treat chronic hepatitis and many types of jaundice. OBJECTIVE: This study explored the therapeutic effects and mechanism of S. mussotii on non-alcoholic fatty liver disease in diet-induced hypercholesterolaemia. MATERIALS AND METHODS: After a week of adaptive feeding, 32 Sprague-Dawley rats were divided into four groups: (1) Control, (2) Control-S, (3) Model, and (4) Model-S. During the 12 experimental weeks, we established the Model using a high-fat diet. Control-S and Model-S were given 1.0 g/kg S. mussotii water extract via gavage starting in the fifth week until the end of experiment. RESULTS: When compared with Model rats, the S. mussotii water extract led to a reduction in high-density lipoproteins (43.9%) and albumin (13.9%) and a decrease in total cholesterol (54.0%), triglyceride (45.6%), low-density lipoproteins (8.6%), aspartate aminotransferase (11.0%), alanine aminotransferase (15.5%), alkaline phosphatase (19.1%), total protein (6.4%), and glucose (20.8%) in serum. A reduction in three cytokines (IL-1ß, IL-6, and TNFα) was detected. Histopathological examination showed that liver steatosis was significantly relieved in S. mussotii-treated high-fat diet rats. S. mussotii also caused a downregulation in the expression of TLR4 (43.2%), MyD88 (33.3%), and a decrease in phosphorylation of NF-κB. DISCUSSION AND CONCLUSIONS: Our findings indicate that S. mussotii may act as a potential anti-inflammation drug via inhibition of the TLR4/MyD88/NF-κB pathway. Further in vivo and in vitro studies are needed to validate its potential in clinical medicine.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Swertia , Alanina Transaminase/metabolismo , Albuminas/metabolismo , Albuminas/farmacologia , Fosfatase Alcalina , Animais , Aspartato Aminotransferases , Colesterol/metabolismo , Dieta Hiperlipídica , Glucose/metabolismo , Interleucina-6/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL/farmacologia , Lipoproteínas LDL/metabolismo , Fígado , Fator 88 de Diferenciação Mieloide , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Fosforilação , Ratos , Ratos Sprague-Dawley , Swertia/metabolismo , Receptor 4 Toll-Like/metabolismo , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Água/farmacologia
19.
Oxid Med Cell Longev ; 2022: 6595989, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36199423

RESUMO

Objective: To offer new prognostic evaluations by exploring potentially distinctive genetic features of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Methods: There were 12 samples for gene expression profiling processes in this study. These included three HCC lesion samples and their matched adjacent nontumor liver tissues obtained from patients with HCC, as well as three ICC samples and their controls collected similarly. In addition to the expression matrix generated on our own, profiles of other cohorts from The Cancer Genome Atlas (TCGA) program and the Gene Expression Omnibus (GEO) were also employed in later bioinformatical analyses. Differential analyses, functional analyses, protein interaction network analyses, and gene set variation analyses were used to identify key genes. To establish the prognostic models, univariate/multivariate Cox analyses and subsequent stepwise regression were applied, with the Akaike information criterion evaluating the goodness of fitness. Results: The top three pathways enriched in HCC were all metabolism-related; they were fatty acid degradation, retinol metabolism, and arachidonic acid metabolism. In ICC, on the other hand, additional pathways related to fat digestion and absorption and cholesterol metabolism were identified. Consistent characteristics of such a metabolic landscape were observed across different cohorts. A prognostic risk score model for calculating HCC risk was constructed, consisting of ADH4, ADH6, CYP2C9, CYP4F2, and RDH16. This signature predicts the 3-year survival with an AUC area of 0.708 (95%CI = 0.644 to 0.772). For calculating the risk of ICC, a prognostic risk score model was built upon the expression levels of CYP26A1, NAT2, and UGT2B10. This signature predicts the 3-year survival with an AUC area of 0.806 (95% CI = 0.664 to 0.947). Conclusion: HCC and ICC share commonly abrupted pathways associated with the metabolism of fatty acids, retinol, arachidonic acids, and drugs, indicating similarities in their pathogenesis as primary liver cancers. On the flip side, these two types of cancer possess distinctive promising biomarkers for predicting overall survival or potential targeted therapies.


Assuntos
Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Ácido Araquidônico/metabolismo , Arilamina N-Acetiltransferase , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/química , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Colesterol/metabolismo , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glucuronosiltransferase , Humanos , Neoplasias Hepáticas/patologia , Família Multigênica , Prognóstico , Ácido Retinoico 4 Hidroxilase/genética , Ácido Retinoico 4 Hidroxilase/metabolismo , Vitamina A
20.
Sci Rep ; 12(1): 16707, 2022 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-36202928

RESUMO

In our previous study, enterohepatic 12α-hydroxylated (12α) bile acid (BA) levels were found to be correlated with hepatic triacylglycerol concentration in rats fed high-fat (HF) diet. Since BA composition is diverse depending on animal species, we evaluated whether such a relationship is applicable in mice in response to an HF diet. C57BL/6JJmsSLC (B6) male mice were fed HF diet for 13 weeks and analyzed for triacylglycerol, cholesterol, oxysterols, and other metabolites in the liver. The BA composition was determined in the liver, small intestinal contents, portal plasma, aortic plasma, and feces. Neutral sterols were also measured in the feces. The ratio of 12α BA/non-12 BA increased in the liver, portal plasma, small intestinal contents, and feces of HF-fed B6 mice. Moreover, a positive correlation was observed between the ratio of fecal 12α BAs/non-12 BAs and hepatic triacylglycerol concentration. The concentration of 7α-hydroxycholesterol was increased in the liver of HF-fed B6 mice, whereas no increase was observed in the hepatic expression of cytochrome P450 family 7 subfamily A member 1. The present study showed that the ratio of 12α BA/non-12 BA in feces is closely associated with hepatic triacylglycerol accumulation in B6 mice fed HF diet.


Assuntos
Ácidos e Sais Biliares , Oxisteróis , Animais , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Família 7 do Citocromo P450 , Dieta Hiperlipídica , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxisteróis/metabolismo , Ratos , Triglicerídeos/metabolismo
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