RESUMO
BACKGROUND: Pancreatic cancer risk has been associated with increased serum cholesterol level, which is in turn partially influenced by diet. This study aimed at evaluating the association between pancreatic cancer risk and the adherence to a plant-based cholesterol-lowering diet. METHODS: Data were derived from an Italian case-control study including 258 pancreatic cancer patients and 551 controls. The cholesterol-lowering diet score was based on seven components: high intakes of (i) non-cellulosic polysaccharides (a proxy of viscous fibers), (ii) monounsaturated fatty acids, (iii) legumes, and (iv) seeds/corn oils (a proxy of phytosterols); and low intakes of (v) saturated fatty acids, (vi) dietary cholesterol, and (vii) food with a high glycemic index. The score was calculated adding one point for each fulfilled component, thus ranging from zero (no adherence) to seven (complete adherence). The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated through the logistic regression model. RESULTS: Scores 5-7 were associated with reduced cancer risk (OR = 0.30; 95% CI: 0.18-0.52) compared to scores 0-2. CONCLUSIONS: Adherence to a plant-based cholesterol-lowering diet was associated with a reduced risk of pancreatic cancer.
Assuntos
Neoplasias Pancreáticas , Humanos , Estudos de Casos e Controles , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/prevenção & controle , Neoplasias Pancreáticas/epidemiologia , Idoso , Itália/epidemiologia , Fatores de Risco , Colesterol na Dieta/efeitos adversos , Colesterol na Dieta/administração & dosagem , Cooperação do Paciente , Razão de Chances , Colesterol/sangueRESUMO
Nonalcoholic fatty liver disease (NAFLD), which shows similar symptoms as fatty liver hemorrhage syndrome (FLHS) in chickens, is the most common cause of chronic liver disease and cancer in humans. NAFLD patients and FLHS in chickens have demonstrated severe liver disorders when infected by emerging strains of human hepatitis E virus (HEV) and avian HEV, respectively. We sought to develop a fatty liver disease chicken model by altering the diet of 3-week-old white leghorn chickens. The high cholesterol, and low choline (HCLC) diet included 7.6% fat with additional 2% cholesterol and 800 mg/kg choline in comparison to 5.3% fat, and 1,300 mg/kg choline in the regular diet. Our diet induced fatty liver avian model successfully recapitulates the clinical features seen during NAFLD in humans and FLHS in chickens, including hyperlipidemia and hepatic steatosis, as indicated by significantly higher serum triglycerides, serum cholesterol, liver triglycerides, cholesterol, and fatty acids. By developing this chicken model, we expect to provide a platform to explore the role of lipids in the liver pathology linked with viral infections and contribute to the development of prophylactic interventions.
Assuntos
Galinhas , Colesterol , Colina , Modelos Animais de Doenças , Hepatopatia Gordurosa não Alcoólica , Doenças das Aves Domésticas , Animais , Colina/administração & dosagem , Doenças das Aves Domésticas/virologia , Doenças das Aves Domésticas/etiologia , Hepatopatia Gordurosa não Alcoólica/veterinária , Hepatopatia Gordurosa não Alcoólica/etiologia , Colesterol/sangue , Dieta/veterinária , Ração Animal/análise , Fígado/patologia , Fígado/metabolismo , Fígado Gorduroso/veterinária , Fígado Gorduroso/etiologia , Colesterol na Dieta/efeitos adversos , Colesterol na Dieta/administração & dosagem , Triglicerídeos/sangueRESUMO
Atherosclerosis is one of the most important causes of cardiovascular diseases. A disintegrin and metalloprotease (ADAM)10 and ADAM17 have been identified as important regulators of inflammation in recent years. Our study investigated the effect of inhibiting these enzymes with selective inhibitor and propolis on atherosclerosis. In our study, C57BL/6J mice (n = 16) were used in the control and sham groups. In contrast, ApoE-/- mice (n = 48) were used in the case, water extract of propolis (WEP), ethanolic extract of propolis (EEP), GW280264X (GW-synthetic inhibitor), and solvent (DMSO and ethanol) groups. The control group was fed a control diet, and all other groups were fed a high-cholesterol diet for 16 weeks. WEP (400 mg/kg/day), EEP (200 mg/kg/day), and GW (100 µg/kg/day) were administered intraperitoneally for the last four weeks. Animals were sacrificed, and blood, liver, aortic arch, and aortic root tissues were collected. In serum, total cholesterol (TC), triglycerides (TGs), and glucose (Glu) were measured by enzymatic colorimetric method, while interleukin-1ß (IL-1ß), paraoxonase-1 (PON-1), and lipoprotein-associated phospholipase-A2 (Lp-PLA2) were measured by ELISA. Tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), myeloperoxidase (MPO), interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-12 (IL-12) levels were measured in aortic arch by ELISA and ADAM10/17 activities were measured fluorometrically. In addition, aortic root and liver tissues were examined histopathologically and immunohistochemically (ADAM10 and sortilin primary antibody). In the WEP, EEP, and GW groups compared to the case group, TC, TG, TNF-α, IL-1ß, IL-6, IL-12, PLA2, MPO, ADAM10/17 activities, plaque burden, lipid accumulation, ADAM10, and sortilin levels decreased, while IL-10 and PON-1 levels increased (p < 0.003). Our study results show that propolis can effectively reduce atherosclerosis-related inflammation and dyslipidemia through ADAM10/17 inhibition.
Assuntos
Proteína ADAM10 , Secretases da Proteína Precursora do Amiloide , Dislipidemias , Inflamação , Camundongos Endogâmicos C57BL , Própole , Animais , Proteína ADAM10/metabolismo , Própole/farmacologia , Inflamação/prevenção & controle , Dislipidemias/tratamento farmacológico , Dislipidemias/etiologia , Camundongos , Masculino , Secretases da Proteína Precursora do Amiloide/metabolismo , Aterosclerose/prevenção & controle , Aterosclerose/etiologia , Colesterol na Dieta/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Proteínas de Membrana/metabolismo , Modelos Animais de DoençasRESUMO
BACKGROUND: Tsumura-Suzuki non-obese (TSNO) mice exhibit a severe form of metabolic dysfunction-associated steatohepatitis (MASH) with advanced liver fibrosis upon feeding a high-fat/cholesterol/cholate-based (iHFC) diet. Another ddY strain, Tsumura-Suzuki diabetes obese (TSOD) mice, are impaired in the progression of iHFC diet-induced MASH. AIM: To elucidate the underlying mechanisms contributing to the differences in MASH progression between TSNO and TSOD mice. METHODS: We analyzed differences in the immune system, gut microbiota, and bile acid metabolism in TSNO and TSOD mice fed with a normal diet (ND) or an iHFC diet. RESULTS: TSOD mice had more anti-inflammatory macrophages in the liver than TSNO mice under ND feeding, and were impaired in the iHFC diet-induced accumulation of fibrosis-associated macrophages and formation of histological hepatic crown-like structures in the liver. The gut microbiota of TSOD mice also exhibited a distinct community composition with lower diversity and higher abundance of Akkermansia muciniphila compared with that in TSNO mice. Finally, TSOD mice had lower levels of bile acids linked to intestinal barrier disruption under iHFC feeding. CONCLUSIONS: The dynamics of liver macrophage subsets, and the compositions of the gut microbiota and bile acids at steady state and post-onset of MASH, had major impacts on MASH development.
Assuntos
Ácidos e Sais Biliares , Dieta Hiperlipídica , Microbioma Gastrointestinal , Fígado , Macrófagos , Animais , Ácidos e Sais Biliares/metabolismo , Fígado/patologia , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversos , Macrófagos/metabolismo , Macrófagos/imunologia , Masculino , Camundongos , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/microbiologia , Akkermansia , Progressão da Doença , Colesterol na Dieta/efeitos adversosRESUMO
Most metastases in breast cancer occur via the dissemination of tumor cells through the bloodstream. How tumor cells enter the blood (intravasation) is, however, a poorly understood mechanism at the cellular and molecular levels. Particularly uncharacterized is how intravasation is affected by systemic nutrients. High levels of systemic LDL-cholesterol have been shown to contribute to breast cancer progression and metastasis in various models, but the cellular and molecular mechanisms involved are still undisclosed. Here we show that a high- cholesterol diet promotes intravasation in two mouse models of breast cancer and that this could be reverted by blocking LDL binding to LDLR in tumor cells. Moreover, we show that LDL promotes vascular invasion in vitro and the intercalation of tumor cells with endothelial cells, a phenotypic change resembling vascular mimicry (VM). At the molecular level, LDL increases the expression of SERPINE2, previously shown to be required for both VM and intravasation. Overall, our manuscript unravels novel mechanisms by which systemic hypercholesterolemia may affect the onset of metastatic breast cancer by favouring phenotypic changes in breast cancer cells and increasing intravasation.
Assuntos
Neoplasias da Mama , Receptores de LDL , Animais , Receptores de LDL/metabolismo , Receptores de LDL/genética , Feminino , Camundongos , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Invasividade Neoplásica , Colesterol na Dieta/efeitos adversos , LDL-Colesterol/metabolismo , LDL-Colesterol/sangue , Lipoproteínas LDL/metabolismo , Colesterol/metabolismo , Colesterol/sangueRESUMO
Nonalcoholic fatty liver disease (NAFLD) is the most widespread chronic liver disorder globally. Unraveling the pathogenesis of simple fatty liver to nonalcoholic steatohepatitis (NASH) has important clinical significance for improving the prognosis of NAFLD. Here, we explored the role of a high-fat diet alone or combined with high cholesterol in causing NASH progression. Our results demonstrated that high dietary cholesterol intakes accelerate the progression of spontaneous NAFLD and induces liver inflammation in mice. An elevation of hydrophobic unconjugated bile acids cholic acid (CA), deoxycholic acid (DCA), muricholic acid and chenodeoxycholic acid, was observed in high-fat and high-cholesterol diet fed mice. Full-length sequencing of the 16S rDNA gene of gut microbiota revealed a significant increase in the abundance of Bacteroides, Clostridium, and Lactobacillus that possess bile salt hydrolase activity. Furthermore, the relative abundance of these bacterial species was positively correlated with content of unconjugated bile acids in liver. Moreover, the expression of genes related to bile acid reabsorption (organic anion-transporting polypeptides, Na+-taurocholic acid cotransporting polypeptide, apical sodium dependent bile acid transporter and organic solute transporter ß) was found to be increased in mice with a high-cholesterol diet. Lastly, we observed that hydrophobic bile acids CA and DCA induce an inflammatory response in free fatty acids-induced steatotic HepG2 cells. In conclusion, high dietary cholesterol promotes the development of NASH by altering gut microbiota composition and abundance and thereby influencing with bile acid metabolism.
Assuntos
Microbioma Gastrointestinal , Hipercolesterolemia , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Colesterol na Dieta/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Dieta Hiperlipídica/métodos , Microbioma Gastrointestinal/fisiologia , Fígado/metabolismo , Ácidos e Sais Biliares/metabolismo , Ácido Cólico , Hipercolesterolemia/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Atherogenesis leads to the development of atherosclerosis, a progressive chronic disease characterized by subendothelial lipoprotein retention and endothelial impairment in the arterial wall. It develops mainly as a result of inflammation and also many other complex processes, which arise from, among others, oxidation and adhesion. Cornelian cherry (Cornus mas L.) fruits are abundant in iridoids and anthocyanins-compounds with potent antioxidant and anti-inflammatory activity. This study aimed to determine the effect of two different doses (10 mg and 50 mg per kg of body weight, respectively) of iridoid and anthocyanin-rich resin-purified Cornelian cherry extract on the markers that are important in the progress of inflammation, cell proliferation and adhesion, immune system cell infiltration, and atherosclerotic lesion development in a cholesterol-rich diet rabbit model. We used biobank blood and liver samples that were collected during the previous original experiment. We assessed the mRNA expression of MMP-1, MMP-9, IL-6, NOX, and VCAM-1 in the aorta, and the serum levels of VCAM-1, ICAM-1, CRP, PON-1, MCP-1, and PCT. The application of the Cornelian cherry extract at a dose of 50 mg/kg bw resulted in a significant reduction in MMP-1, IL-6, and NOX mRNA expression in the aorta and a decrease in VCAM-1, ICAM-1, PON-1, and PCT serum levels. The administration of a 10 mg/kg bw dose caused a significant decrease in serum ICAM-1, PON-1, and MCP-1. The results indicate the potential usefulness of the Cornelian cherry extract in the prevention or treatment of atherogenesis-related cardiovascular diseases, such as atherosclerosis or metabolic syndrome.
Assuntos
Aterosclerose , Colesterol na Dieta , Cornus , Dieta Aterogênica , Extratos Vegetais , Animais , Coelhos , Antocianinas/uso terapêutico , Aterosclerose/tratamento farmacológico , Frutas , Inflamação/tratamento farmacológico , Molécula 1 de Adesão Intercelular , Interleucina-6 , Iridoides/uso terapêutico , Metaloproteinase 1 da Matriz , Extratos Vegetais/uso terapêutico , RNA Mensageiro , Molécula 1 de Adesão de Célula VascularRESUMO
Eggs contain high-quality protein, lavish vitamins and other bioactive nutrients but are rich in cholesterol. Our study is designed to assess the association of egg intake with polyp prevalence. A total of 7068 participants at a high risk of CRC from the Lanxi Pre-Colorectal Cancer Cohort Study (LP3C) were recruited. A food frequency questionnaire (FFQ) was utilized to obtain dietary data through a face-to-face interview. Cases of colorectal polyps were identified by electronic colonoscopy. The logistic regression model was exploited to achieve odds ratios (ORs) and 95% confidence intervals (CIs). Overall 2064 cases of colorectal polyps were identified in the 2018-2019 survey of LP3C. A positive association of egg consumption with colorectal polyp prevalence was found after the multivariable adjustment [ORQ4 vs. Q1 (95% CI): 1.23 (1.05-1.44); Ptrend = 0.01]. However, a positive relationship disappeared after further adjustment for dietary cholesterol (Ptrend = 0.37), which explained that the harmful role of eggs could be ascribed to the high content of dietary cholesterol. Besides, a positive trend was found between dietary cholesterol and polyp prevalence [OR (95% CI): 1.21 (0.99-1.47); Ptrend = 0.04]. Furthermore, replacing 1 egg (50 g d-1) with an equal amount of total dairy products was related to 11% lower colorectal polyp prevalence [OR (95% CI): 0.89 (0.80-0.99); P = 0.03]. In summary, higher egg consumption was correlated with a higher polyp prevalence among the Chinese population at a high risk of CRC, which was ascribed to the high content of dietary cholesterol in eggs. Besides, individuals with the highest dietary cholesterol tended to have a higher polyp prevalence. Reducing the consumption of eggs and replacing eggs with total dairy products as alternative protein sources may prevent the occurrence of polyps in China.
Assuntos
Pólipos do Colo , Neoplasias Colorretais , Humanos , Pólipos do Colo/epidemiologia , Fatores de Risco , Colesterol na Dieta , Estudos de Coortes , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controle , DietaRESUMO
Immunoglobulin A (IgA) secretion by plasma cells, terminally differentiated B cells residing in the intestinal lamina propria, assures microbiome homeostasis and protects the host against enteric infections. Exposure to diet-derived and commensal-derived signals provides immune cells with organizing cues that instruct their effector function and dynamically shape intestinal immune responses at the mucosal barrier. Recent data have described metabolic and microbial inputs controlling T cell and innate lymphoid cell activation in the gut; however, whether IgA-secreting lamina propria plasma cells are tuned by local stimuli is completely unknown. Although antibody secretion is considered to be imprinted during B cell differentiation and therefore largely unaffected by environmental changes, a rapid modulation of IgA levels in response to intestinal fluctuations might be beneficial to the host. In the present study, we showed that dietary cholesterol absorption and commensal recognition by duodenal intestinal epithelial cells lead to the production of oxysterols, evolutionarily conserved lipids with immunomodulatory functions. Using conditional cholesterol 25-hydroxylase deleter mouse line we demonstrated that 7α,25-dihydroxycholesterol from epithelial cells is critical to restrain IgA secretion against commensal- and pathogen-derived antigens in the gut. Intestinal plasma cells sense oxysterols via the chemoattractant receptor GPR183 and couple their tissue positioning with IgA secretion. Our findings revealed a new mechanism linking dietary cholesterol and humoral immune responses centered around plasma cell localization for efficient mucosal protection.
Assuntos
Imunidade Inata , Plasmócitos , Animais , Camundongos , Colesterol na Dieta , Células Epiteliais , Imunoglobulina A , Mucosa Intestinal , Receptores Acoplados a Proteínas G , IntestinosRESUMO
Cholesterol and its oxidized forms, oxysterols, are ingested from foods and are synthesized de novo. Cholesterol and oxysterols influence molecular and cellular events and subsequent biological responses of immune cells. The amount of dietary cholesterol influence on the levels of LDL cholesterol and blood oxysterols plays a significant role in the induction of pro-inflammatory state in immune cells, leading to inflammatory disorders, including cardiovascular disease. Cholesterol and oxysterols synthesized de novo in immune cells and stroma cells are involved in immune homeostasis, which may also be influenced by an excess intake of dietary cholesterol. Dietary compounds such as ß-glucan, plant sterols/stanols, omega-3 lipids, polyphenols, and soy proteins, could lower blood cholesterol levels by interfering with cholesterol absorption and metabolism. Such dietary compounds also have potential to exert immune modulation through diverse mechanisms. This review addresses current knowledge about the impact of dietary-derived and de novo synthesized cholesterol and oxysterols on the immune system. Possible immunomodulatory mechanisms elicited by cholesterol-lowering dietary compounds are also discussed.
Assuntos
Oxisteróis , Fitosteróis , beta-Glucanas , LDL-Colesterol , Proteínas de Soja , Polifenóis , Colesterol na Dieta , Colesterol/metabolismo , Fitosteróis/farmacologia , Sistema Imunitário/metabolismoRESUMO
BACKGROUND: Hepatic caveolin-1 (CAV1) is reduced in cholesterol gallstone disease (CGD). Mice with CAV1 deficiency were prone to develop CGD. However, it remains unknown whether restored hepatic CAV1 expression prevents the development of CGD. METHODS: C57BL/6 mice were injected with adeno-associated virus 2/8 (AAV2/8) vectors carrying the CAV1 gene (AAV2/8CAV1) via intravenous (i.v.) or intraperitoneal (i.p.) route and then subjected to a lithogenic diet (LD) for 8 weeks. Uninjected mice were used as controls. The functional consequences of rescuing CAV1 expression by either i.v. or i.p. AAV2/8CAV1 treatment for CGD prevention and its subsequent molecular mechanisms were examined. RESULTS: CAV1 expression was reduced in the liver and gallbladder of LD-fed CGD mice. We discovered that AAV2/8CAV1 i.p. delivery results in higher transduction efficiency in the gallbladder than tail vein administration. Although either i.v. or i.p. injection of AAV2/8CAV1 improved liver lipid metabolic abnormalities in CGD mice but did not affect LD feeding-induced bile cholesterol supersaturation. In comparison with i.v. administration route, i.p. administration of AAV2/8CAV1 obviously increased CAV1 protein levels in the gallbladder of LD-fed mice, and i.p. delivery of AAV2/8CAV1 partially improved gallbladder cholecystokinin receptor (CCKAR) responsiveness and impeded bile cholesterol nucleation via the activation of adenosine monophosphate-activated protein kinase (AMPK) signaling, which induced a reduction in gallbladder mucin-1 (MUC1) and MUC5ac expression and gallbladder cholesterol accumulation. CONCLUSION: CGD prevention by i.p. AAV2/8CAV1 injection in LD-fed mice was associated with the improvement of gallbladder stasis, which again supported the notion that supersaturated bile is required but not sufficient for the formation of cholesterol gallstones. Additionally, AAV treatment via the local i.p. injection offers particular advantages over the systemic i.v. route for much more effective gallbladder gene delivery, which will be an excellent tool for conducting preclinical functional studies on the maintenance of normal gallbladder function to prevent CGD.
Assuntos
Caveolina 1 , Cálculos Biliares , Animais , Camundongos , Caveolina 1/genética , Caveolina 1/metabolismo , Colesterol/metabolismo , Colesterol na Dieta , Dependovirus/genética , Dependovirus/metabolismo , Vesícula Biliar/metabolismo , Cálculos Biliares/genética , Cálculos Biliares/prevenção & controle , Fígado/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Excessive dietary cholesterol is preferentially stored in the liver, favoring the development of nonalcoholic steatohepatitis (NASH), characterized by progressive hepatic inflammation and fibrosis. Emerging evidence indicates a critical contribution of hepatic macrophages to NASH severity. However, the impact of cholesterol on these cells in the setting of NASH remains elusive. Here, we demonstrate that the dietary cholesterol content directly affects hepatic macrophage global gene expression. Our findings suggest that the modifications triggered by prolonged high cholesterol intake induce long-lasting hepatic damage and support the expansion of a dysfunctional pro-fibrotic restorative macrophage population even after cholesterol reduction. The present work expands the understanding of the modulatory effects of cholesterol on innate immune cell transcriptome and may help identify novel therapeutic targets for NASH intervention.
Assuntos
Hipercolesterolemia , Hepatopatia Gordurosa não Alcoólica , Animais , Colesterol/metabolismo , Colesterol na Dieta/efeitos adversos , Colesterol na Dieta/metabolismo , Modelos Animais de Doenças , Humanos , Macrófagos , Hepatopatia Gordurosa não Alcoólica/metabolismoRESUMO
PURPOSE OF REVIEW: Several recent studies have corroborated a strong association between diet and gastric cancer risk; investigators have also identified dietary factors that protect against gastric cancer. This review summarizes the literature on this topic and guides future research directions. RECENT FINDINGS: High-salt intake disrupts the gastric mucosal defense barrier, promoting Helicobacter pylori colonization and penetration of other carcinogenic compounds. Processed foods, processed meats, red meat, alcohol, foods with high dietary fat, and dietary cholesterol increase the risk of gastric carcinogenesis. On the other hand, increased consumption of fruits, vegetables, whole grains, nuts, and a low-salt diet may offer a protective effect. SUMMARY: Despite decreases in gastric cancer incidence because of increased identification and treatment of H. pylori , gastric cancer remains one of the most common cancers worldwide with a high mortality rate. This disturbing statistic highlights the importance of reducing and eliminating other risk factors for gastric cancer. There is a strong body of evidence that alcohol, processed foods, high salt intake, high fat intake, and foods with animal products (meats, eggs, and dairy) increase the risk of gastric cancer. A diet that is high in whole grains, fruits, vegetables, nuts and is low in salt may reduce the risk of gastric cancer.
Assuntos
Helicobacter pylori , Neoplasias Gástricas , Animais , Carcinogênese , Colesterol na Dieta , Dieta/efeitos adversos , Gorduras na Dieta , Humanos , Fatores de Risco , Cloreto de Sódio na Dieta , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/prevenção & controle , VerdurasRESUMO
Evidence suggests a role of serum cholesterol in prostate cancer (PCa) development and of lipid lowering medications in PCa risk reduction. We developed a score for adherence to an established cholesterol-lowering diet and evaluated its association with PCa risk in a multicentric hospital-based case-control study (1294 cases; 1451 matched controls) in Italy (1992-2001). The score was derived from seven dietary indicators which have been reported to lower cholesterol levels: high intake of non-cellulosic polysaccharides (viscous fibres), monounsaturated fatty acids, legumes, seeds/corn oil; low intake of saturated fatty acids, dietary cholesterol, and glycaemic index. Odds ratios (ORs) and corresponding confidence intervals (CIs) were calculated through the unconditional logistic regression model. Although most of the dietary indicators alone were not significantly associated with reduced PCa risk, men who fulfilled 5 to 7 dietary indicators (187 cases and 281 controls) showed a 43% reduction in PCa risk compared to those with 0 to 2 indicators (OR: 0.57; 95% CI: 0.43-0.77). This association was not modified by socio-demographic characteristics or lifestyle factors. In conclusion, adherence to a cholesterol-lowering diet is a favourable factor against the risk of PCa, providing support to dietary guidelines that promote cholesterol reduction through plant-based diets.
Assuntos
Dieta , Neoplasias da Próstata , Estudos de Casos e Controles , Colesterol , Colesterol na Dieta , Gorduras na Dieta , Humanos , Masculino , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/prevenção & controleRESUMO
BACKGROUND: Despite substantial research highlighting the importance of exogenous dietary cholesterol intake and endogenous serum cholesterol level in human health, a thorough evaluation of the associations is lacking. Our study objective was to examine overall and cause-specific mortality in relation to dietary and serum cholesterol, as well as egg consumption, and conduct an updated meta-regression analysis of cohort studies. METHODS: We conducted a prospective analysis of 27 078 men in the ATBC Study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention). Multivariable-controlled cause-specific Cox proportional hazards regression models were used to calculate hazard ratios and 31-year absolute mortality risk differences. A systematic review and meta-analysis of cohort studies was also performed (PROSPERO [URL: https://www.crd.york.ac.uk/prospero/; Unique identifier: CRD42021272756]). RESULTS: Based on 482 316 person-years of follow-up, we identified 22 035 deaths, including 9110 deaths from cardiovascular disease (CVD). Greater dietary cholesterol and egg consumption were associated with increased risk of overall and CVD-related mortality. Hazard ratios for each additional 300 mg cholesterol intake per day were 1.10 and 1.13 for overall and CVD-related mortality, respectively; for each additional 50-g egg consumed daily, hazard ratios were 1.06 and 1.09, respectively, for overall and CVD-related mortality (all P values<0.0001). After multivariable adjustment, higher serum total cholesterol concentrations were associated with increased risk of CVD-related mortality (hazard ratios per 1 SD increment, 1.14; P<0.0001). The observed associations were generally similar across cohort subgroups. The updated meta-analysis of cohort studies on the basis of 49 risk estimates, 3 601 401 participants, and 255 479 events showed consumption of 1 additional 50-g egg daily was associated with significantly increased CVD risk (pooled relative risk, 1.04 [95% CI, 1.00-1.08]; I2=80.1%). In the subgroup analysis of geographic regions (Pinteraction=0.02), an increase of 50-g egg consumed daily was associated with a higher risk of CVD in US cohorts (pooled relative risk, 1.08 [95% CI, 1.02-1.14]) and appeared related to a higher CVD risk in European cohorts with borderline significance (pooled relative risk, 1.05), but was not associated with CVD risk in Asian cohorts. CONCLUSIONS: In this prospective cohort study and updated meta-analysis, greater dietary cholesterol and egg consumption were associated with increased risk of overall and CVD-related mortality. Our findings support restricted consumption of dietary cholesterol as a means to improve long-term health and longevity.
Assuntos
Doenças Cardiovasculares , Colesterol na Dieta , Causas de Morte , Colesterol na Dieta/efeitos adversos , Ovos/efeitos adversos , Humanos , Masculino , Estudos Prospectivos , Fatores de RiscoRESUMO
Cholesterol is an essential lipid in vertebrates, but excess blood cholesterol promotes atherosclerosis. In the liver, cholesterol is metabolized to bile acids by cytochrome P450, family 7, subfamily a, polypeptide 1 (CYP7A1), the transcription of which is negatively regulated by the ERK pathway. Fibroblast growth factor 21 (FGF21), a hepatokine, induces ERK phosphorylation and suppresses Cyp7a1 transcription. Taurine, a sulfur-containing amino acid, reportedly promotes cholesterol metabolism and lowers blood and hepatic cholesterol levels. However, the influence of long-term feeding of taurine on cholesterol levels and metabolism remains unclear. Here, to evaluate the more chronic effects of taurine on cholesterol levels, we analyzed mice fed a taurine-rich diet for 14-16 weeks. Long-term feeding of taurine lowered plasma cholesterol and bile acids without significantly changing other metabolic parameters, but hardly affected these levels in the liver. Moreover, taurine upregulated Cyp7a1 levels, while downregulated phosphorylated ERK and Fgf21 levels in the liver. Likewise, taurine-treated Hepa1-6 cells, a mouse hepatocyte line, exhibited downregulated Fgf21 levels and upregulated promoter activity of Cyp7a1. These results indicate that taurine promotes cholesterol metabolism by suppressing the FGF21/ERK pathway followed by upregulating Cyp7a1 expression. Collectively, this study shows that long-term feeding of taurine lowers both plasma cholesterol and bile acids, reinforcing that taurine effectively prevents hypercholesterolemia.
Assuntos
Ácidos e Sais Biliares , Taurina , Animais , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Colesterol na Dieta/metabolismo , Dieta , Fígado/metabolismo , Camundongos , Taurina/metabolismo , Taurina/farmacologiaRESUMO
Atherosclerosis is considered as a chronic inflammatory disease. MircoRNA-126-5p (miR-126-5p) may be pathophysiological relevant with the apoptotic processes in the endothelial cells in the arterial wall. Here, this study determined the role of circulating atherosclerosis-regulatory miR-126-5p in atherosclerotic mice and explored the possible mechanism in human aortic endothelial cells (HAECs). Atherosclerotic mice model was established, oxidative stress-induced apoptosis of HAECs was analyzed, and nuclear factor kappa B (NF-κB)/PI3K/AKT/mTOR signaling pathway was investigated both in vitro and in vivo. This study showed that miR-126-5p mice had less coronary atherosclerotic plaque and lower blood lipid than control mice after being induced by high cholesterol diet. Apoptosis of endothelial cells was inhibited and NF-κB/PI3K/AKT/mTOR signal pathway was downregulated in miR-126-5p mice compared to control. MiR-126-5p increased proliferation and inhibited apoptosis of HAECs induced by oxidative stress. In vitro assay showed that miR-126-5p regulated apoptosis of HAECs via downregulation of NF-κB-mediated PI3K/AKT/mTOR signaling pathway. In conclusion, these data indicated that transfection of miR-126-5p rescued apoptosis of HAECs and limited atherosclerosis, introducing a potential therapeutic approach for atherosclerosis.
Assuntos
Apoptose , Aterosclerose/prevenção & controle , Células Endoteliais/patologia , Regulação da Expressão Gênica/fisiologia , MicroRNAs/genética , Subunidade p50 de NF-kappa B/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Western Blotting , Células Cultivadas , Colesterol na Dieta , Modelos Animais de Doenças , Regulação para Baixo , Marcação In Situ das Extremidades Cortadas , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , TransfecçãoRESUMO
Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of hepatocellular carcinoma (HCC). Although the intracellular cholesterol accumulation has been demonstrated to regulate the gene expression responsible for steatohepatitis, the role played by cholesterol in the development of NAFLD-associated HCC has not been fully elucidated. In this study, using microarray analysis, we investigated the molecular mechanisms governing cholesterol-mediated progression of NAFLD. To ensure hepatic cholesterol accumulation, either a high-fat and high-cholesterol (HFHC) diet or a high-fat and high-cholesterol with cholic acid (HFHCCA) diet was fed to diethylnitrosamine (DEN)-injected C57BL/6J mice for 10 weeks. While an HFHC diet increased hepatic triglyceride levels, an HFHCCA diet induced hepatic cholesterol accumulation by reducing bile acid biosynthesis in DEN-injected mice. Livers from both HFHC and HFHCCA groups exhibited increases in steatosis and necrosis; however, histological features of HCC were not observed in any of the experimental groups. Hepatic gene expression profile of the HFHCCA group was different from those of other groups. Functional analysis showed that cholic acid supplementation upregulated differentially expressed genes (DEGs) associated with inflammation, proliferation, apoptosis, chemical drug response, and cancer signaling pathway. Downregulated DEGs were associated with steroid metabolism, mitochondrial function, and oxidative phosphorylation pathway. Furthermore, hepatic cholesterol accumulation lowered the expression of DEGs associated with energy and macronutrient metabolism, especially amino acid metabolism. In this study, the results of a global gene expression profile demonstrated that feeding the HFHCCA diet to DEN-injected mice accelerated the carcinogenic progression of NAFLD, implicating the critical role played by hepatic accumulation of cholesterol.
Assuntos
Carcinogênese , Colesterol na Dieta , Colesterol/metabolismo , Ácido Cólico/administração & dosagem , Dieta Hiperlipídica , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Aminoácidos/metabolismo , Animais , Carcinoma Hepatocelular/fisiopatologia , Suplementos Nutricionais , Dietilnitrosamina/farmacologia , Progressão da Doença , Regulação da Expressão Gênica , Metabolismo dos Lipídeos , Fígado/patologia , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , TranscriptomaRESUMO
Cholesterol has been implicated in the pathophysiology and progression of several cancers now, although the mechanisms by which it influences cancer biology are just emerging. Two likely contributing mechanisms are the ability for cholesterol to directly regulate signaling molecules within the membrane, and certain metabolites acting as signaling molecules. One such metabolite is the oxysterol 27-hydroxycholesterol (27HC), which is a primary metabolite of cholesterol synthesized by the enzyme Cytochrome P450 27A1 (CYP27A1). Physiologically, 27HC is involved in the regulation of cholesterol homeostasis and contributes to cholesterol efflux through liver X receptor (LXR) and inhibition of de novo cholesterol synthesis through the insulin-induced proteins (INSIGs). 27HC is also a selective modulator of the estrogen receptors. An increasing number of studies have identified its importance in cancer progression of various origins, especially in breast cancer. In this review, we discuss the physiological roles of 27HC targeting these two nuclear receptors and the subsequent contribution to cancer progression. We describe how 27HC promotes tumor growth directly through cancer-intrinsic factors, and indirectly through its immunomodulatory roles which lead to decreased immune surveillance and increased tumor invasion. This review underscores the importance of the cholesterol metabolic pathway in cancer progression and the potential therapeutic utility of targeting this metabolic pathway.
Assuntos
Biomarcadores Tumorais/metabolismo , Hidroxicolesteróis/metabolismo , Neoplasias/metabolismo , Animais , Anticolesterolemiantes/uso terapêutico , Colestanotriol 26-Mono-Oxigenase/metabolismo , Colesterol na Dieta/efeitos adversos , Colesterol na Dieta/metabolismo , Humanos , Neoplasias/induzido quimicamente , Neoplasias/tratamento farmacológicoRESUMO
Non-alcoholic fatty liver disease (NAFLD) constitutes a metabolic disorder with high worldwide prevalence and increasing incidence. The inflammatory progressive state, non-alcoholic steatohepatitis (NASH), leads to liver fibrosis and carcinogenesis. Here, we evaluated whether tyrosinase mutation underlies NASH pathophysiology. Tyrosinase point-mutated B6 (Cg)-Tyrc-2J/J mice (B6 albino) and C57BL/6J black mice (B6 black) were fed with high cholesterol diet (HCD) for 10 weeks. Normal diet-fed mice served as controls. HCD-fed B6 albino exhibited high NASH susceptibility compared to B6 black, a phenotype not previously reported. Liver injury occurred in approximately 50% of B6 albino from one post HCD feeding, with elevated serum alanine aminotransferase and aspartate aminotransferase levels. NASH was induced following 2 weeks in severe-phenotypic B6 albino (sB6), but B6 black exhibited no symptoms, even after 10 weeks. HCD-fed sB6 albino showed significantly higher mortality rate. Histological analysis of the liver revealed significant inflammatory cell and lipid infiltration and severe fibrosis. Serum lipoprotein analysis revealed significantly higher chylomicron and very low-density lipoprotein levels in sB6 albino. Moreover, significantly higher small intestinal lipid absorption and lower fecal lipid excretion occurred together with elevated intestinal NPC1L1 expression. As the tyrosinase point mutation represents the only genetic difference between B6 albino and B6 black, our work will facilitate the identification of susceptible genetic factors for NASH development and expand the understanding of NASH pathophysiology.