Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. n-3 polyunsaturated fatty acids (n-3-PUFAs) have been reported to ameliorate the progression of NAFLD in experimental studies; however, clinical trials have yielded contradictory results. The aim of our study was to assess the effects of n-3-PUFA administration on lipid metabolism and the progression of NAFLD in patients with metabolic syndrome. Sixty patients with metabolic syndrome and NAFLD were randomized in a double-blind placebo-controlled trial (3.6 g/day n-3-PUFA vs. placebo). During the 1-year follow-up, the patients underwent periodic clinical and laboratory examinations, liver stiffness measurements, magnetic resonance spectroscopy of the liver, and plasma lipidomic analyses. After 12 months of n-3-PUFA administration, a significant decrease in serum GGT activity was recorded compared with the placebo group (2.03 ± 2.8 vs. 1.43 ± 1.6; P < 0.05). Although no significant changes in anthropometric parameters were recorded, a significant correlation between the reduction of liver fat after 12 months of treatment-and weight reduction-was observed; furthermore, this effect was clearly potentiated by n-3-PUFA treatment (P < 0.005). In addition, n-3-PUFA treatment resulted in substantial changes in the plasma lipidome, with n-3-PUFA-enriched triacylglycerols and phospholipids being the most expressed lipid signatures. Conclusion: Twelve months of n-3-PUFA treatment of patients with NAFLD patients was associated with a significant decrease in GGT activity, the liver fat reduction in those who reduced their weight, and beneficial changes in the plasma lipid profile.
Project description:The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Although gene-environment interactions have been implicated in the etiology of several disorders, the impact of paternal and/or maternal metabolic syndrome on the clinical phenotypes of offspring and the underlying genetic and epigenetic contributors of NAFLD have not been fully explored. To this end, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique nondietary model manifesting 3 hallmarks that confer high risk for the development of NAFLD: hyperglycemia, insulin resistance, and dyslipidemia. We report that parental metabolic syndrome epigenetically reprograms members of the TGF-β family, including neuronal regeneration-related protein (NREP) and growth differentiation factor 15 (GDF15). NREP and GDF15 modulate the expression of several genes involved in the regulation of hepatic lipid metabolism. In particular, NREP downregulation increases the protein abundance of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and ATP-citrate lyase (ACLY) in a TGF-β receptor/PI3K/protein kinase B-dependent manner, to regulate hepatic acetyl-CoA and cholesterol synthesis. Reduced hepatic expression of NREP in patients with NAFLD and substantial correlations between low serum NREP levels and the presence of steatosis and nonalcoholic steatohepatitis highlight the clinical translational relevance of our findings in the context of recent preclinical trials implicating ACLY in NAFLD progression.
Project description:The prevalence of metabolic syndrome is increased worldwide. Tobacco smoking increases the risk of developing metabolic syndrome. Waterpipe tobacco smoking has become a global trend of tobacco consumption and is as common as cigarette smoking. In this study, the effect of waterpipe tobacco smoke (WTS) on the development of metabolic syndrome in rats was evaluated. Adult Wistar rats were exposed for 19 weeks to either fresh air (control) or WTS for 1 hour daily/ 5 days per week (WTS). Central obesity, systolic blood pressure, lipid profile, glucose hemostasis and levels of leptin and adiponectin were evaluated. The WTS exposure increased body weight, abdominal circumference, systolic blood pressure and fasting glucose compared to control animals (P<0.05), consistent with inducing metabolic syndrome. The retroperitoneal fat, lipid profile and levels of insulin, leptin and adiponectin were not affected by WTS exposure (P>0.05). In conclusion, exposure to WTS has detrimental health effects leading to the development of metabolic syndrome in experimental animals.
Project description:Ayu-narezushi, a traditional Japanese fermented food, comprises abundant levels of lactic acid bacteria (LAB) and free amino acids. This study aimed to examine the potential beneficial effects of ayu-narezushi and investigated whether ayu-narezushi led to improvements in the Tsumura Suzuki obese diabetes (TSOD) mice model of spontaneous metabolic syndrome because useful LAB are known as probiotics that regulate intestinal function. In the present study, the increased body weight of the TSOD mice was attenuated in those fed the ayu-narezushi-comprised chow (ayu-narezushi group) compared with those fed the normal rodent chow (control group). Serum triglyceride and cholesterol levels were significantly lower in the Ayu-narezushi group than in the control group at 24 weeks of age. Furthermore, hepatic mRNA levels of carnitine-palmitoyl transferase 1 and acyl-CoA oxidase, which related to fatty acid oxidation, were significantly increased in the ayu-narezushi group than in the control group at 24 weeks of age. In conclusion, these results suggested that continuous feeding with ayu-narezushi improved obesity and dyslipidemia in the TSOD mice and that the activation of fatty acid oxidation in the liver might contribute to these improvements.
Project description:Adipose tissue (AT) is a key organ in the regulation of total body lipid homeostasis, which is responsible for the storage and release of fatty acids according to metabolic needs. We aimed to investigate the effect of the quantity and quality of dietary fat on the lipogenesis and lipolysis processes in the AT of metabolic syndrome (MetS) patients. A randomized, controlled trial conducted within the LIPGENE study assigned MetS patients to one of four diets: (a) high-saturated fatty acid (HSFA) (b) high-monounsaturated fatty acid, and (c, d) two low-fat, high-complex carbohydrate diets supplemented with long chain (LC) n-3 (LFHCC n-3) polyunsaturated fatty acids (PUFA) or placebo (LFHCC), for 12 weeks each. A fat challenge reflecting the same fatty acid composition as the original diets was conducted post-intervention. Long-term consumption of the LFHCC diet induced an increase in the fasting expression levels of the sterol regulatory element binding protein-1 and stearoyl-CoA desaturase D9-desaturase genes, whereas the supplementation of this diet with n-3 PUFA reversed this effect (p = 0.007). In contrast, long-term consumption of the HSFA diet increased the expression of the adipose triglyceride lipase (ATGL) gene, at both fasting and postprandial states (both, p < 0.001). Our results showed the anti-lipogenic effect exerted by LC n-3 PUFA when administered together with a LFHCC diet. Conversely, a diet high in saturated fat increased the expression of the lipolytic gene ATGL relative to the other diets.
Project description:BackgroundOur objective was to find single nucleotide polymorphisms (SNPs), within transcriptional pathways of glucose and lipid metabolism, which are related to multiple features of the metabolic syndrome (MetS).Methods373 SNPs were measured in 3575 subjects of the Doetinchem cohort. Prevalence of MetS features, i.e. hyperglycemia, abdominal obesity, decreased HDL-cholesterol levels and hypertension, were measured twice in 6 years. Associations between the SNPs and the individual MetS features were analyzed by log-linear models. For SNPs related to multiple MetS features (P < 0.01), we investigated whether these associations were independent of each other.ResultsTwo SNPs, CETP Ile405Val and APOE Cys112Arg, were associated with both the prevalence of low HDL-cholesterol level (Ile405Val P = < .0001; Cys112Arg P = 0.001) and with the prevalence of abdominal obesity (Ile405Val P = 0.007; Cys112Arg P = 0.007). For both SNPs, the association with HDL-cholesterol was partly independent of the association with abdominal obesity and vice versa.ConclusionTwo SNPs, mainly known for their role in lipid metabolism, were associated with two MetS features i.e., low HDL-cholesterol concentration, as well as, independent of this association, abdominal obesity. These SNPs may help to explain why low HDL-cholesterol levels and abdominal obesity frequently co-occur.
Project description:Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. It is currently unknown when, and if, individual premutation carriers will develop FXTAS. Thus, with the aim of identifying biomarkers for early diagnosis, development, and progression of FXTAS, we performed global metabolomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct categories: those who developed symptoms of FXTAS (converters, CON) at subsequent visits and those who did not (non-converters, NCON) and we compared to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern Blot and PCR analysis. Metabolomic profile was obtained by ultra-performance liquid chromatography, accurate mass spectrometer, and an Orbitrap mass analyzer. In this study we found 47 metabolites were significantly dysregulated between HC and the premutation groups (PM). Importantly, we identified 24 metabolites that showed significant changes in expression in the CON as compared to the NCON both at V1 and V2, and 70 metabolites in CON as compared to NCON but only at V2. These findings suggest the potential role of the identified metabolites as biomarkers for early diagnosis and for FXTAS disease progression, respectively. Interestingly, the majority of the identified metabolites were lipids, followed by amino acids. To our knowledge, this the first report of longitudinal metabolic profiling and identification of unique biomarkers of FXTAS. The lipid metabolism and specifically the sub pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered in FXTAS.