RESUMEN
Cancer cachexia, the unintentional loss of lean mass, contributes to functional dependency, poor treatment outcomes, and decreased survival. Although its pathogenicity is multifactorial, metabolic dysfunction remains a hallmark of cachexia. However, significant knowledge gaps exist in understanding the role of skeletal muscle lipid metabolism and dynamics in this condition. We examined skeletal muscle metabolic dysfunction, intramyocellular lipid droplet (LD) content, LD morphology and subcellular distribution, and LD-mitochondrial interactions using the Lewis lung carcinoma (LLC) murine model of cachexia. C57/BL6 male mice (n = 20) were implanted with LLC cells (106) in the right flank or underwent PBS sham injections. Skeletal muscle was excised for transmission electron microscopy (TEM; soleus), oil red O/lipid staining [tibialis anterior (TA)], and protein (gastrocnemius). LLC mice had a greater number (232%; P = 0.006) and size (130%; P = 0.023) of intramyocellular LDs further supported by increased oil-red O positive (87%; P = 0.0109) and "very high" oil-red O positive (178%; P = 0.0002) fibers compared with controls and this was inversely correlated with fiber size (R2 = 0.5294; P < 0.0001). Morphological analyses of LDs show increased elongation and complexity [aspect ratio: intermyofibrillar (IMF) = 9%, P = 0.046) with decreases in circularity [circularity: subsarcolemmal (SS) = 6%, P = 0.042] or roundness (roundness: whole = 10%, P = 0.033; IMF = 8%, P = 0.038) as well as decreased LD-mitochondria touch (-15%; P = 0.006), contact length (-38%; P = 0.036), and relative contact (86%; P = 0.004). Furthermore, dysregulation in lipid metabolism (adiponectin, CPT1b) and LD-associated proteins, perilipin-2 and perilipin-5, in cachectic muscle (P < 0.05) were observed. Collectively, we provide evidence that skeletal muscle myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in a preclinical model of cancer cachexia.NEW & NOTEWORTHY We sought to advance our understanding of skeletal muscle lipid metabolism and dynamics in cancer cachexia. Cachexia increased the number and size of intramyocellular lipid droplets (LDs). Furthermore, decreases in LD-mitochondrial touch, contact length, and relative contact along with increased LD shape complexity with decreases in circularity and roundness. Dysregulation in lipid metabolism and LD-associated proteins was also documented. Collectively, we show that myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in cancer cachexia.
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Caquexia , Carcinoma Pulmonar de Lewis , Gotas Lipídicas , Ratones Endogámicos C57BL , Músculo Esquelético , Animales , Caquexia/metabolismo , Caquexia/patología , Caquexia/etiología , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patología , Carcinoma Pulmonar de Lewis/complicaciones , Gotas Lipídicas/metabolismo , Gotas Lipídicas/patología , Ratones , Metabolismo de los Lípidos , Mitocondrias Musculares/metabolismo , Mitocondrias Musculares/patología , Mitocondrias Musculares/ultraestructura , Mitocondrias/metabolismo , Mitocondrias/patología , Mitocondrias/ultraestructuraRESUMEN
Liver injury is closely related to poor outcomes in sepsis patients. Current studies indicate that sepsis is accompanied by metabolic disorders, especially those related to lipid metabolism. It is highly important to explore the mechanism of abnormal liver lipid metabolism during sepsis. As a key regulator of glucose and lipid metabolism, angiopoietin-like 8 (ANGPTL8) is involved in the regulation of multiple chronic metabolic diseases. In the present study, severe liver lipid deposition and lipid peroxidation were observed in the early stages of lipopolysaccharide (LPS) induced liver injury. LPS promotes the expression of ANGPTL8 both in vivo and in vitro. Knockout of Angptl8 reduced hepatic lipid accumulation and lipid peroxidation, improved fatty acid oxidation and liver function, and increased the survival rate of septic mice by activating the PGC1α/PPARα pathway. We also found that the expression of ANGPTL8 induced by LPS depends on TNF-α, and that inhibiting the TNF-α pathway reduces LPS-induced hepatic lipid deposition and lipid peroxidation. However, knocking out Angptl8 improved the survival rate of septic mice better than inhibiting the TNF-α pathway. Taken together, the results of our study suggest that ANGPTL8 functions as a novel cytokine in LPS-induced liver injury by suppressing the PGC1α/PPARα signaling pathway. Therefore, targeting ANGPTL8 to improve liver lipid metabolism represents an attractive strategy for the management of sepsis patients.
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Proteína 8 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , Metabolismo de los Lípidos , Lipopolisacáridos , Animales , Ratones , Proteínas Similares a la Angiopoyetina/metabolismo , Proteínas Similares a la Angiopoyetina/deficiencia , Proteínas Similares a la Angiopoyetina/genética , PPAR alfa/metabolismo , PPAR alfa/genética , Masculino , Ratones Noqueados , Hormonas Peptídicas/metabolismo , Hígado/metabolismo , Hígado/patología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Sepsis/metabolismo , Sepsis/inducido químicamente , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Transducción de SeñalRESUMEN
BACKGROUND: In recent years, the incidence rate of nonalcoholic fatty liver disease (NAFLD) has ascended with the increasing number of metabolic diseases such as obesity and diabetes, which will bring great medical burden to society. At present, multiple scientific experiments have found that the CCR4-NOT complex can participate in regulating obesity and energy metabolism. This study is designed to explore the role and mechanism of CCR4-NOT transcription complex subunit 7 (CNOT7), a subunit of the CCR4-NOT complex in liver lipid deposition. METHODS: To establish the NAFLD cell model, palmitic acid (PA) was utilized to stimulate HepG2 cells and LO2 cells, promoting intracellular lipid deposition. CNOT7 was knockdown by siRNA and lentivirus to evaluate the effect of CNOT7 in NAFLD. RESULTS: Our results demonstrated that the expression of CNOT7 was increased in the NAFLD cell model. After knocking down CNOT7, the lipid deposition declined in HepG2 or LO2 cells treated by PA reduced. We found the lipid synthesis genes and the lipid uptake and transport factors in the CNOT7 knockdown group were significantly downregulated compared to the non-knockdown group. Furthermore, knockdown of CNOT7 might promote fatty acid oxidation. CONCLUSION: Knocking down CNOT7 can improve lipid deposition and CNOT7 may be a potential therapeutic target for NAFLD.
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Metabolismo de los Lípidos , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/genética , Células Hep G2 , Técnicas de Silenciamiento del Gen , Ácido Palmítico/metabolismo , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Hígado/metabolismo , Hígado/patología , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , ExorribonucleasasRESUMEN
PURPOSE: To investigated the role of estrogen receptor-1 (ER-1) in maintaining homeostasis in ocular surface. METHODS: ER-1-knockout (ER-1KO) mice were studied at 4 months of age. The ocular surface was examined using a slit lamp. Histological alterations in the meibomian gland (MG) and lacrimal gland (LG) were observed with H&E staining. Protein levels of P-ERK, peroxisome proliferator-activated receptor gamma (PPAR-γ), p-NFκB-P65, IL-1ß, aquaporin 5 (AQP-5), fatty acid-binding protein 5 (Fabp5) and K10 were determined by immunofluorescence and Western blotting. Gene expressions of APO-F, APO-E, K10, ELOVL4, PPAR-γ, SCD-1, and SREBP1 were quantified by qPCR. Conjunctival (CJ) goblet cell alterations were detected by PAS staining. Lipid metabolism in MG and LG was assessed using LipidTox. Apoptosis in MG and LG was analyzed through the TUNEL assay. RESULTS: Both male and female ER-1KO mice demonstrated increased corneal fluorescence staining scores. MG showed abnormal lipid metabolism and ductal dilation. LG displayed lipid deposition and reduced AQP-5 expression. CJ experienced goblet cell loss. MG, LG exhibited signs of inflammation and apoptosis. CONCLUSION: ER1 is pivotal for ocular surface homeostasis in both genders of mice. ER1 deficiency induces inflammation and lipid deposition to MG and LG, culminating in dry eye-like manifestations on the ocular surface.
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Síndromes de Ojo Seco , Aparato Lagrimal , Receptores de Estrógenos , Animales , Femenino , Masculino , Ratones , Síndromes de Ojo Seco/genética , Síndromes de Ojo Seco/metabolismo , Síndromes de Ojo Seco/patología , Inflamación/patología , Aparato Lagrimal/metabolismo , Aparato Lagrimal/patología , Glándulas Tarsales/metabolismo , Glándulas Tarsales/patología , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Lágrimas/metabolismo , Receptores de Estrógenos/metabolismoRESUMEN
Ectopic lipid deposition (ELD) and mitochondrial dysfunction are common causes of metabolic disorders in humans. Consuming too much fructose can result in mitochondrial dysfunction and metabolic disorders. 6-Gingerol, the main component of ginger (Zingiber officinale Roscoe), has been proven to alleviate metabolic disorders. This study seeks to examine the effects of 6-gingerol on metabolic disorders caused by fructose and uncover the underlying molecular mechanisms. In this study, the results showed that 6-Gingerol ameliorated high-fructose-induced metabolic disorders. Moreover, it inhibited CD36 membrane translocation, increased CD36 expression in the mitochondria, and decreased the O-GlcNAc modification of CD36 and OGT expression in vitro and vivo. In addition, 6-Gingerol enhanced the performance of mitochondria in the skeletal muscle and boosted the respiratory capability of L6 myotubes. This study provides a theoretical basis and new insights for the development of lipid-lowering drugs in clinical practice.
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Enfermedades Metabólicas , Enfermedades Mitocondriales , Humanos , Músculo Esquelético/metabolismo , Mitocondrias/metabolismo , Alcoholes Grasos/farmacología , Alcoholes Grasos/metabolismo , Catecoles/farmacología , Fructosa/metabolismo , Enfermedades Metabólicas/metabolismo , Enfermedades Mitocondriales/metabolismoRESUMEN
The present study explored the effects of different lipid sources on growth performance, lipid deposition, antioxidant capacity, inflammatory response and disease resistance of largemouth bass (Micropterus salmoides). Four isonitrogenous (crude protein 50.46 %) and isolipidic (crude lipid 11.12 %) diets were formulated to contain 7 % of different oil sources including fish oil (FO) (control), soybean oil (SO), linseed oil (LO) and coconut oil (CO). Largemouth bass with initial body weight of 36.0 ± 0.2 g were randomly distributed into 12 tanks, with 30 fish per tank and 3 tanks per treatment. The fish were fed with the experiment diets twice daily for 8 weeks. The results indicated that the weight gain of largemouth bass fed the FO diet was significantly higher than that of fish fed the LO and CO diets. The liver crude lipid content in FO group was significantly higher than other groups, while the highest liver triglyceride content was showed in SO group and the lowest was detected in LO group. At transcriptional level, expression of lipogenesis related genes (pparγ, srebp1, fas, acc, dgat1 and dgat2) in the SO and CO group were significantly higher than the FO group. However, the expression of lipolysis and fatty acids oxidation related genes (pparα, cpt1, and aco) in vegetable oils groups were significantly higher than the FO group. As to the antioxidant capacity, vegetable oils significantly reduced the malondialdehyde content of largemouth bass. Total antioxidant capacity in the SO and LO groups were significantly increased compared with the FO group. Catalase in the LO group was significantly increased compared with the FO group. Furthermore, the ER stress related genes, such as grp78, atf6α, atf6ß, chop and xbp1 were significantly enhanced in the vegetable oil groups compared with the FO group. The activity of serum lysozyme in vegetable oil groups were significantly higher than in FO group. Additionally, the relative expression of non-specific immune related genes, including tlr2, mapk11, mapk13, mapk14, rela, tgf-ß1, tnfα, 5lox, il-1ß and il10, were all significantly increased in SO and CO groups compared to the other groups. In conclusion, based on the indexes including growth performance, lipid deposition, antioxidant capacity and inflammatory response, SO and LO could be alternative oil sources for largemouth bass.
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Alimentación Animal , Antioxidantes , Lubina , Dieta , Metabolismo de los Lípidos , Animales , Lubina/inmunología , Lubina/crecimiento & desarrollo , Dieta/veterinaria , Alimentación Animal/análisis , Antioxidantes/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Distribución Aleatoria , Suplementos Dietéticos/análisis , Grasas de la Dieta/administración & dosificación , Aceites de Pescado/administración & dosificación , Aceite de Linaza/administración & dosificación , Enfermedades de los Peces/inmunología , Inflamación/veterinaria , Inflamación/inmunología , Aceite de Soja/administración & dosificación , Aceite de Coco/administración & dosificaciónRESUMEN
Selenium is an essential trace element for most organisms, protecting cells from oxidative damage caused by free radicals and serving as an adjunctive treatment for non-alcoholic fatty liver disease (NAFLD). In this study, We used the lactic acid bacterium Lactobacillus acidophilus HN23 to reduce tetra-valent sodium selenite into particulate matter, and analyzed it through inductively coupled plasma mass spectrometry (ICP-MS), scanning electron microscopy (SEM), X-ray diffraction energy dispersive spectrometry (EDS), and Fourier transform infrared spectroscopy (FTIR). We found that it consisted of selenium nanoparticles (SeNPs) with a mass composition of 65.8 % zero-valent selenium and some polysaccharide and polypeptide compounds, with particle sizes ranging from 60 to 300 nm. We also detected that SeNPs were much less toxic to cells than selenite. We further used free fatty acids (FFA)-induced WRL68 fatty liver cell model to study the therapeutic effect of SeNPs on NAFLD. The results show that SeNPs are more effective than selenite in reducing lipid deposition, increasing mitochondrial membrane potential (MMP) and antioxidant capacity of WRL68 cells, which is attributed to the chemical valence state of selenium and organic composition in SeNPs. In conclusion, SeNPs produced by probiotics L. acidophilus had the potential to alleviate NAFLD by reducing hepatocyte lipid deposition and oxidative damage. This study may open a new avenue for SeNPs drug development to treat NAFLD.
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Nanopartículas , Enfermedad del Hígado Graso no Alcohólico , Selenio , Humanos , Selenio/farmacología , Selenio/química , Lactobacillus acidophilus/metabolismo , Nanopartículas/química , Ácido Selenioso/química , Ácido Selenioso/metabolismo , LípidosRESUMEN
BACKGROUND: Type 2 diabetes mellitus (T2DM) is closely linked to metabolic syndrome, characterised by insulin resistance, hyperglycaemia, abnormal lipid metabolism, and chronic inflammation. Diabetic ulcers (DUs) comprise consequential complications that arise as a result of T2DM. To investigate, db/db mice were used for the disease model. The findings demonstrated that a scaffold made from a combination of rhubarb charcoal-crosslinked chitosan and silk fibroin, designated as RCS/SF, was able to improve the healing process of diabetic wounds in db/db mice. However, previous studies have primarily concentrated on investigating the impacts of the RSC/SF scaffold on wound healing only, while its influence on the entire body has not been fully elucidated. MATERIAL AND METHODS: The silk fibroin/chitosan sponge scaffold containing rhubarb charcoal was fabricated in the present study using a freeze-drying approach. Subsequently, an incision with a diameter of 8 mm was made on the dorsal skin of the mice, and the RCS/SF scaffold was applied directly to the wound for 14 days. Subsequently, the impact of RCS/SF scaffold therapy on hepatic lipid metabolism was assessed through analysis of serum and liver biochemistry, histopathology, quantitative real-time PCR (qRT-PCR), immunohistochemistry, and Western blotting. RESULTS: The use of the RCS/SF scaffold led to an enhancement in the conditions associated with serum glucolipid metabolism in db/db mice. An assessment of hepatic histopathology further confirmed this enhancement. Additionally, the qRT-PCR analysis revealed that treatment with RCS/SF scaffold resulted in the downregulation of genes associated with fatty acid synthesis, fatty acid uptake, triglyceride (TG) synthesis, gluconeogenesis, and inflammatory factors. Moreover, the beneficial effect of the RCS/SF scaffold on oxidative stress was shown by assessing antioxidant enzymes and lipid peroxidation. Additionally, the network pharmacology analysis verified that the adenosine monophosphate-activated protein kinase (AMPK) signalling pathway had a vital function in mitigating non-alcoholic fatty liver disease (NAFLD) by utilizing R. officinale. The measurement of AMPK, sterol regulatory element binding protein 1 (SREBP1), fatty acid synthase (FASN), and acetyl CoA carboxylase (ACC) gene and protein expression provided support for this discovery. Furthermore, the molecular docking investigations revealed a robust affinity between the active components of rhubarb and the downstream targets of AMPK (SREBP1 and FASN). CONCLUSION: By regulating the AMPK signalling pathway, the RCS/SF scaffold applied topically effectively mitigated hepatic lipid accumulation, decreased inflammation, and attenuated oxidative stress. The present study, therefore, emphasises the crucial role of the topical RCS/SF scaffold in regulating hepatic lipid metabolism, thereby confirming the concept of "external and internal reshaping".
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Quitosano , Complicaciones de la Diabetes , Diabetes Mellitus Tipo 2 , Fibroínas , Enfermedad del Hígado Graso no Alcohólico , Rheum , Ratones , Animales , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Rheum/metabolismo , Carbón Orgánico/metabolismo , Carbón Orgánico/farmacología , Carbón Orgánico/uso terapéutico , Fibroínas/metabolismo , Fibroínas/farmacología , Fibroínas/uso terapéutico , Diabetes Mellitus Tipo 2/metabolismo , Simulación del Acoplamiento Molecular , Úlcera/metabolismo , Úlcera/patología , Hígado/metabolismo , Metabolismo de los Lípidos , Enfermedad del Hígado Graso no Alcohólico/patología , Complicaciones de la Diabetes/patología , Inflamación/patología , Ácidos Grasos/metabolismo , Lípidos/uso terapéuticoRESUMEN
1. Two experiments were conducted to measure the response of growing turkeys to dietary protein content. In the first, 960 sexed British United Turkey (BUT 6) poults were used to measure the response to balanced protein from 3 to 6 weeks of age. In the second, 1440 sexed BUT and Hybrid Converter poults were raised from 14 to 17 weeks.2. In both experiments, six levels of dietary protein were fed, with feed intake, body and feather weight gain and changes in body composition measured. The levels of protein chosen ranged from 0.53 to 1.2 of the Aviagen requirements for growing turkeys.3. In the first experiment, six poults were sampled from each sex at the start of the experiment for carcass analysis, and four were sampled from each strain and sex in the second. At the end of each experiment, eight poults from each treatment were sampled. Body composition analyses were made on individual defeathered birds.4. Weight gain increased linearly with protein intake in the early period and exponentially in the later period. In both periods, feed intake decreased as protein content reduced.5. In the early period, body lipid content increased from 20.2 to 41.5 g/kg body weight, as dietary protein content decreased, but there was no change in the later period. Efficiency of utilisation of dietary protein declined linearly with an increase in dietary protein content, from 0.87 to 0.46 g/g in the first, and from 0.43 to 0.27 g/g in the later period.6. The inability of the growing turkey to increase feed intake on marginally limiting feeds may have been due to a genetic constraints to store excess energy consumed as body lipid, resulting in the observed decrease in feed intake as dietary protein content is reduced.
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Pollos , Pavos , Animales , Aumento de Peso , Proteínas en la Dieta/metabolismo , Lípidos , Alimentación Animal/análisisRESUMEN
This study investigated the protective effect of tanshinone â ¡_A(TSâ ¡_A) on the liver in the rat model of non-alcoholic fatty liver disease(NAFLD) and the mechanism of TSâ ¡_A in regulating ferroptosis via the nuclear factor E2-related factor 2(Nrf2) signaling pathway. The rat model of NAFLD was established with a high-fat diet for 12 weeks. The successfully modeled rats were assigned into model group, low-and high-dose TSâ ¡_A groups, and inhibitor group, and normal control group was set. Enzyme-linked immunosorbent assay was employed to determine the content of superoxide dismutase(SOD) and malondialdehyde(MDA) in the serum of rats in each group. A biochemical analyzer was used to measure the content of aspartate aminotransferase(AST), alaninl aminotransferase(ALT), total cholesterol(TC), and triglycerides(TG). Hematoxylin-eosin(HE) staining was used to detect pathological damage in liver tissue. Terminal-deoxynucleoitidyl transferase-mediated nick end labeling(TUNEL) was employed to examine the apoptosis of the liver tissue. Oil red O staining, MitoSOX staining, and Prussian blue staining were conducted to reveal lipid deposition, the content of reactive oxygen species(ROS), and iron deposition in liver tissue. Western blot was employed to determine the expression of Nrf2, heme oxygenase-1(HO-1), glutathione peroxidase 4(GPX4), ferroptosis suppressor protein 1(FSP1), B cell lymphoma-2(Bcl-2), and Bcl-2 associated X protein(Bax) in the liver tissue. The result showed that TSâ ¡_A significantly reduced the content of MDA, AST, ALT, TC, and TG in the serum, increased the activity of SOD, decreased the apoptosis rate, lipid deposition, ROS, and iron deposition in the liver tissue, up-regulated the expression of Nrf2, HO-1, FSP1, GPX, and Bcl-2, and inhibited the expression of Bax in the liver tissue of NAFLD rats. However, ML385 partially reversed the protective effect of TSâ ¡_A on the liver tissue. In conclusion, TSâ ¡_A could inhibit ferroptosis in the hepatocytes and decrease the ROS and lipid accumulation in the liver tissue of NAFLD rats by activating the Nrf2 signaling pathway.
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Abietanos , Ferroptosis , Enfermedad del Hígado Graso no Alcohólico , Ratas , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Hígado , Transducción de Señal , Triglicéridos/metabolismo , Superóxido Dismutasa/metabolismo , Hierro/metabolismoRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by excessive deposition of fatty acids in the liver. Further deterioration leads to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma, creating a heavy burden on human health and the social economy. Currently, there are no effective and specific drugs for the treatment of NAFLD. Therefore, it is important to further investigate the pathogenesis of NAFLD and explore effective therapeutic targets for the prevention and treatment of the disease. Six-transmembrane epithelial antigen of prostate 3 (STEAP3), a STEAP family protein, is a metalloreductase. Studies have shown that it can participate in the regulation of liver ischemia-reperfusion injury, hepatocellular carcinoma, myocardial hypertrophy, and other diseases. In this study, we found that the expression of STEAP3 is upregulated in NAFLD. Deletion of STEAP3 inhibits the development of NAFLD in vivo and in vitro, whereas its overexpression promotes palmitic acid/oleic acid stimulation-induced lipid deposition in hepatocytes. Mechanistically, it interacts with transforming growth factor beta-activated kinase 1 (TAK1) to regulate the progression of NAFLD by promoting TAK1 phosphorylation and activating the TAK1-c-Jun N-terminal kinase/p38 signaling pathway. Taken together, our results provide further insight into the involvement of STEAP3 in liver pathology.
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Carcinoma Hepatocelular , Resistencia a la Insulina , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Masculino , Carcinoma Hepatocelular/patología , Hepatocitos/metabolismo , Hígado/metabolismo , Neoplasias Hepáticas/patología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Próstata/metabolismoRESUMEN
CYP46A1 is a CNS-specific enzyme, which eliminates cholesterol from the brain and retina by metabolism to 24-hydroxycholesterol, thus contributing to cholesterol homeostasis in both organs. 2-Hydroxypropyl-ß-cyclodextrin (HPCD), a Food and Drug Administration-approved formulation vehicle, is currently being investigated off-label for treatment of various diseases, including retinal diseases. HPCD was shown to lower retinal cholesterol content in mice but had not yet been evaluated for its therapeutic benefits. Herein, we put Cyp46a1-/- mice on high fat cholesterol-enriched diet from 1 to 14 months of age (control group) and at 12 months of age, started to treat a group of these animals with HPCD until the age of 14 months. We found that as compared with mature and regular chow-fed Cyp46a1-/- mice, control group had about 6-fold increase in the retinal total cholesterol content, focal cholesterol and lipid deposition in the photoreceptor-Bruch's membrane region, and retinal macrophage activation. In addition, aged animals had cholesterol crystals at the photoreceptor-retinal pigment epithelium interface and changes in the Bruch's membrane ultrastructure. HPCD treatment mitigated all these manifestations of retinal cholesterol dyshomeostasis and altered the abundance of six groups of proteins (genetic information transfer, vesicular transport, and cytoskeletal organization, endocytosis and lysosomal processing, unfolded protein removal, lipid homeostasis, and Wnt signaling). Thus, aged Cyp46a1-/- mice on high fat cholesterol-enriched diet revealed pathological changes secondary to retinal cholesterol overload and supported further studies of HPCD as a potential therapeutic for age-related macular degeneration and diabetic retinopathy associated with retinal cholesterol dyshomeostasis.
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Degeneración Macular , Retina , Ratones , Animales , 2-Hidroxipropil-beta-Ciclodextrina , Colesterol 24-Hidroxilasa/metabolismo , Retina/metabolismo , Degeneración Macular/metabolismo , Modelos Animales de Enfermedad , Colesterol/metabolismoRESUMEN
Doxorubicin (DOX) is extensively used for the treatment of kinds of cancers, and cardiovascular toxicity is one of the side effects. However, it is unclear whether DOX causes impairment of cardiac function by promoting atherosclerosis. Thus, we investigated the role of DOX in regulating the lipid deposition of macrophages and its molecular mechanism. RAW 264.7 cell line was stimulated with DOX in the presence or absence of low-density lipoprotein (LDL). We found that DOX increased miR-33 and reduced ATP binding cassette transporter A1 (ABCA1) protein. Moreover, cholesterol efflux was suppressed by DOX, which was more efficient under a high-cholesterol condition. After transfecting mimics or inhibitors of miR-33 into cells, ABCA1 protein was respectively decreased and increased, and intracellular lipid accumulation was correspondingly regulated. Overall, DOX suppresses the expression of ABCA1 protein by upregulating miR-33, promoting an intracellular lipid deposition in macrophages, which is a sign of early atherosclerosis. This provides new insights for clinical observation and evaluation of the side effects of DOX.
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Aterosclerosis , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Colesterol/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Aterosclerosis/metabolismo , Doxorrubicina/farmacologíaRESUMEN
BACKGROUND: Rupture and hemorrhage is the most serious complication of cerebral arteriovenous malformation(cAVMs), and have a significant impact on quality of life. OBJECTIVES: We investigated the hematoxylin and eosin staining and ultrastructural features of cAVMs and characterized the abnormal vascular structure of cAVMs. METHODS: Light and electron microscopy were performed on a series of pathological specimens obtained from 12 patients with cAVMs who underwent surgical resection for the first time without radiosurgery or embolization therapy. RESULTS: In tunica intima, we found that the vascular endothelial cells of cAVMs were damaged, and the lysis of the cell body occurred in multiple regions. In tunica media, the arrangement of the elastic layer was disordered, and the thickness was uneven. Part of the structure of the elastic lamina was missing. The part of tunica adventitia was fractured and discontinuous. In addition, we also observed the phenomenon that different blood vessels share the same vascular wall. Macrophage phagocytosis and lymphocyte infiltration in the adventitial region of ruptured cAVMs. Abnormal lipid deposition in vascular endothelial cells and smooth muscle cells. CONCLUSIONS: The structural incompleteness of cAVMs may be an important cause of hemorrhage.
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Células Endoteliales , Malformaciones Arteriovenosas Intracraneales , Humanos , Células Endoteliales/patología , Calidad de Vida , Malformaciones Arteriovenosas Intracraneales/patología , Estudios RetrospectivosRESUMEN
The current study aims to confirm the positive effects of dietary nano-Se on nutrients deposition and muscle fibre formation in grass carp fed with high-fat diet (HFD) before overwintering and to reveal its possible molecular mechanism. The lipid deposition, protein synthesis and muscle fibre formation in grass carp fed with regular diet (RD), HFD or HFD supplemented with nano-Se (0·3 or 0·6 mg/kg) for 60 d were tested. Results show that nano-Se significantly reduced lipid content, dripping loss and fibre diameter (P < 0·05), but increased protein content, post-mortem pH24 h and muscle fibre density (P < 0·05) in muscle of grass carp fed with HFD. Notably, dietary nano-Se decreased lipid deposition in the muscle by regulating amp-activated protein kinase activity and increased protein synthesis and fibre formation in muscle by activating target of rapamycin and myogenic determining factors pathways. In summary, dietary nano-Se can regulate the nutrients deposition and muscle fibre formation in grass carp fed with HFD, which exhibit potential benefit for improving flesh quality of grass carp fed with HFD.
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Carpas , Dieta Alta en Grasa , Animales , Dieta Alta en Grasa/efectos adversos , Dieta , Suplementos Dietéticos , Lípidos , Fibras Musculares Esqueléticas , Alimentación Animal/análisisRESUMEN
In omnivorous fish, the pyruvate dehydrogenase kinases (PDKs)-pyruvate dehydrogenase E1α subunit (PDHE1α) axis is essential in the regulation of carbohydrate oxidative catabolism. Among the existing research, the role of the PDKs-PDHE1α axis in carnivorous fish with poor glucose utilization is unclear. In the present study, we determined the effects of PDK inhibition on the liver glycolipid metabolism of largemouth bass (Micropterus salmoides). DCA is a PDK-specific inhibitor that inhibits PDK by binding the allosteric sites. A total of 160 juvenile largemouth bass were randomly divided into two groups, with four replicates of 20 fish each, fed a control diet and a control diet supplemented with dichloroacetate (DCA) for 8 weeks. The present results showed that DCA supplementation significantly decreased the hepatosomatic index, triglycerides in liver and serum, and total liver lipids of largemouth bass compared with the control group. In addition, compared with the control group, DCA treatment significantly down-regulated gene expression associated with lipogenesis. Furthermore, DCA supplementation significantly decreased the mRNA expression of pdk3a and increased PDHE1α activity. In addition, DCA supplementation improved glucose oxidative catabolism and pyruvate oxidative phosphorylation (OXPHOS) in the liver, as evidenced by low pyruvate content in the liver and up-regulated expressions of glycolysis-related and TCA cycle/OXPHOS-related genes. Moreover, DCA consumption decreased hepatic malondialdehyde (MDA) content, enhanced the activities of superoxide dismutase (SOD), and increased transforming growth factor beta (tgf-ß), glutathione S-transferase (gst), and superoxide dismutase 1 (sod1) gene expression compared with the control diet. This study demonstrated that inhibition of PDKs by DCA promoted glucose utilization, reduced hepatic lipid deposition, and improved oxidative stress in largemouth bass by increasing pyruvate OXPHOS. Our findings contribute to the understanding of the underlying mechanism of the PDKs-PDHE1α axis in glucose metabolism and improve the utilization of dietary carbohydrates in farmed carnivorous fish.
Asunto(s)
Lubina , Glucosa , Animales , Glucosa/metabolismo , Ácido Pirúvico/metabolismo , Ácido Pirúvico/farmacología , Fosforilación Oxidativa , Estrés Oxidativo , Hígado/metabolismo , Triglicéridos/metabolismoRESUMEN
As an important factor secreted by skeletal muscle, myonectin can regulate lipid metabolism and energy metabolism, but its role in the utilization of peripheral free fatty acids (FFAs) by porcine intramuscular fat cells remains to be further investigated. In this study, porcine intramuscular adipocytes were treated with recombinant myonectin and palmitic acid (PA), either alone or in combination, and then were examined for their uptake of exogenous FFAs, intracellular lipid synthesis and catabolism, and mitochondrial oxidation of fatty acids. The results showed that myonectin decreased the area of lipid droplets in intramuscular adipocytes (p < 0.05) and significantly increased (p < 0.05) the expression levels of hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL). Moreover, myonectin can up-regulate the expression of p38 mitogen-activated protein kinase (p38 MAPK). Myonectin significantly promoted the uptake of peripheral FFAs (p < 0.01), improved (p < 0.05) the expression of fatty transport protein 1 (FATP1) and fatty acid binding protein 4 (FABP4) in intramuscular adipocytes. Myonectin also significantly increased (p < 0.05) the expression levels of fatty acid oxidation markers: transcription factor (TFAM), uncoupling protein-2 (UCP2) and oxidative respiratory chain marker protein complex I (NADH-CoQ) in mitochondria of intramuscular adipocytes. In summary, myonectin promoted the absorption, transport, and oxidative metabolism of exogenous FFAs in mitochondria, thereby inhibiting lipid deposition in porcine intramuscular adipocytes.
Asunto(s)
Ácidos Grasos no Esterificados , Regulación de la Expresión Génica , Porcinos , Animales , Ácidos Grasos no Esterificados/farmacología , Ácidos Grasos no Esterificados/metabolismo , Adipocitos/metabolismo , Diferenciación Celular , Músculo Esquelético/metabolismo , Ácidos Grasos/farmacologíaRESUMEN
The objective of this study was to investigate the mechanism by which the α-lactalbumin peptides Gly-Ile-Asn-Tyr (GINY) and Asp-Gln-Trp (DQW) ameliorate free fatty acid-induced lipid deposition in HepG2 cells. The results show that GINY and DQW reduced triglyceride, total cholesterol, and free fatty acid levels significantly in free fatty acid-treated HepG2 cells. Based on proteomic analysis, GINY and DQW alleviated lipid deposition and oxidative stress mainly through the peroxisome proliferator-activated receptor (PPAR) pathway, fatty acid metabolism, oxidative phosphorylation, and response to oxidative stress. In vitro experiments confirmed that GINY and DQW upregulated the mRNA and protein expression of fatty acid ß-oxidation-related and oxidative stress-related genes, and downregulated the mRNA and protein expression of lipogenesis-related genes by activating peroxisome proliferator-activated receptor α (PPARα). Meanwhile, GINY and DQW reduced free fatty acid-induced lipid droplet accumulation and reactive oxygen species generation, and enhanced the mitochondrial membrane potential and ATP levels. Furthermore, GINY and DQW enhanced carnitine palmitoyl-transferase 1a (CPT-1a) and superoxide dismutase activities, and diminished acetyl-coenzyme A carboxylase 1 (ACC1) and fatty acid synthase (FASN) activities in a PPARα-dependent manner. Interestingly, GW6471 (a PPARα inhibitor) weakened the effects of GINY and DQW on the PPARα pathway. Hence, our findings suggest that GINY and DQW have the potential to alleviate nonalcoholic fatty liver disease by activating the PPARα pathway.
Asunto(s)
Lactalbúmina , Enfermedad del Hígado Graso no Alcohólico , Animales , Humanos , Células Hep G2 , Lactalbúmina/farmacología , Lactalbúmina/metabolismo , PPAR alfa/genética , Ácidos Grasos no Esterificados/metabolismo , Proteómica , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/veterinaria , Estrés Oxidativo , Metabolismo de los Lípidos , Péptidos/farmacología , Péptidos/metabolismo , ARN Mensajero/metabolismo , Hígado/metabolismoRESUMEN
As a heavy metal, copper is toxic to aquatic organisms in water, causing oxidative stress and lipid deposition. However, there is currently no effective dietary strategy to prevent damage caused by copper exposure. Here, copper bioaccumulation, antioxidant enzymes, lipogenic enzymes, lipid metabolism-related gene expression levels and metabolic pathways were synthesized and evaluated in copper-exposed largemouth bass (Micropterus salmoides) after hydrolysis fish peptides (HFP) pretreatment. The results showed that supplementation with 1% (P < 0.05), 3% (P < 0.01) and 5% (P < 0.05) HFP significantly reduced the copper bioaccumulation in largemouth bass. Hydrolysis fish peptides supplementation significantly reduced the activities of total antioxidant capacity (P < 0.01) and catalase (P < 0.01) and the contents of glutathione (P < 0.01) and malondialdehyde (P < 0.05). Fatty acid synthetase concentration was significantly reduced in fish supplemented with 3% (P < 0.05) and 5% HFP (P < 0.05). Similarly, fish fed 3% (P < 0.05) and 5% (P < 0.01) HFP significantly reduced the glucose-6-phosphate dehydrogenase concentration. Serum metabolomics revealed that 85, 144 and 207 differential metabolites were obtained in fish supplemented with 1%, 3% and 5% HFP, respectively. The differential metabolites were mainly lipids and lipid-like molecules, which were associated with the lipid metabolism pathways. The expression levels of fatty acid synthase (P < 0.01), sterol regulatory element binding protein-1c (P < 0.05), liver X receptor (P < 0.001), peroxisome proliferator activated γ (P < 0.01), apolipoprotein B (P < 0.001) and fatty acid-binding protein 1 (P < 0.01) were significantly down-regulated and the expression levels of carnitine palmitoyltransferase 1α (P < 0.01), hormone-sensitive lipase (P < 0.001), apolipoprotein A 1 (P < 0.05) were significantly up-regulated in fish fed with 3% HFP. Additionally, supplementation with 3% (P < 0.01) and 5% (P < 0.001) HFP significantly up-regulated the expression level of B-cell lymphoma-2 with a dose-dependent effect. In conclusion, our study confirmed that HFP supplementation was closely associated with oxidative stress, enzymatic activities and related pathways of lipid metabolism, and apoptosis, and in general alleviated lipid deposition caused by copper exposure in largemouth bass.
Asunto(s)
Lubina , Animales , Cobre/toxicidad , Bioacumulación , Antioxidantes , Hidrólisis , Estrés Oxidativo , Péptidos , Metabolómica , Apolipoproteína A-IRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is a major health problem. However, no effective treatments are currently available. Thus, there is a critical need to develop novel drugs that can prevent and treat NAFLD with few side effects. In this study, Tussilagone (TUS), a natural sesquiterpene isolated from Tussilago farfara L, was explored in vitro and in vivo for its potential to treat NAFLD. Our results showed that in vitro TUS reduced oleic acid palmitate acid-induced triglyceride and cholesterol synthesis in HepG2 cells, reduced intracellular lipid droplet accumulation, improved glucose metabolism disorders and increased energy metabolism and reduced oxidative stress levels. In vivo, TUS significantly reduced fat accumulation and improved liver injury in high-fat diet (HFD)-induced mice. TUS treatment significantly increased liver mitochondrial counts and antioxidant levels compared to the HFD group of mice. In addition, TUS was found to reduce the expression of genes involved in lipid synthesis sterol regulatory element binding protein-1 (SREBP1), fatty acid synthase (FASN), and stearoy-CoA desaturase 1 (SCD1) in vitro and in vivo. Our results suggest that TUS may be helpful in the treatment of NAFLD, suggesting that TUS is a promising compound for the treatment of NAFLD. Our findings provided novel insights into the application of TUS in regulating lipid metabolism.