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Endocrinology AND Hyperlipidemia [keywords]
- 3,5-diiodo-L-thyronine (3,5-t2) exerts thyromimetic effects on hypothalamus-pituitary-thyroid axis, body composition, and energy metabolism in male diet-induced obese mice. [Journal Article]
- Endocrinology 2015 Jan; 1(1):389-99.
Effective and safe antiobesity drugs are still needed in face of the obesity pandemic worldwide. Recent interventions in rodents revealed 3,5-diiodo-L-thyronine (3,5-T2) as a metabolically active iodothyronine affecting energy and lipid metabolism without thyromimetic side effects typically associated with T3 administration. Accordingly, 3,5-T2 has been proposed as a potential hypolipidemic agent for treatment of obesity and hepatic steatosis. In contrast to other observations, our experiments revealed dose-dependent thyromimetic effects of 3,5-T2 akin to those of T3 in diet-induced obese male C57BL/6J mice. 3,5-T2 treatment exerted a negative feedback regulation on the hypothalamus-pituitary-thyroid axis, similar to T3. This is demonstrated by decreased expression of genes responsive to thyroid hormones (TH) in pituitary resulting in a suppressed thyroid function with lower T4 and T3 concentrations in serum and liver of 3,5-T2-treated mice. Analyses of hepatic TH target genes involved in lipid metabolism revealed T3-like changes in gene expression and increased type I-deiodinase activity after application of 3,5-T2 (2.5 μg/g body weight). Reduced hepatic triglyceride and serum cholesterol concentrations reflected enhanced lipid metabolism. Desired increased metabolic rate and reduction of different fat depots were, however, compromised by increased food intake preventing significant body weight loss. Moreover, enlarged heart weights indicate potential cardiac side effects of 3,5-T2 beyond hepatic thyromimetic actions. Altogether, the observed thyromimetic effects of 3,5-T2 in several mouse TH target tissues raise concern about indiscriminate administration of 3,5-T2 as powerful natural hormone for the treatment of hyperlipidemia and pandemic obesity.
- Ezetimibe prevents the development of non‑alcoholic fatty liver disease induced by high‑fat diet in C57BL/6J mice. [Journal Article]
- Mol Med Rep 2014 Dec; 10(6):2917-23.
There is currently no established treatment for non‑alcoholic fatty liver disease (NAFLD), including its most extreme form, non‑alcoholic steatohepatitis (NASH). Ezetimibe, an inhibitor of Niemann‑Pick C1 Like 1‑dependent cholesterol absorption, improves diet‑induced hyperlipidemia and attenuates liver steatosis and insulin resistance. The aim of the present study was to determine whether ezetimibe treatment is able to inhibit the development of NAFLD, and to elucidate the underlying mechanism, using C57BL/6J (B6) mice maintained on a high‑fat diet. Male B6 mice (20 weeks of age) were divided into the following two groups (n=7 in each group): Mice fed a high‑fat diet for four weeks and mice fed a high‑fat diet with 0.0064% (wt/wt) ezetimibe (5 mg/kg/day) for four weeks. Administration of ezetimibe significantly reduced liver steatosis and fibrosis. Ezetimibe reduced serum cholesterol, hepatic fat accumulation and insulin resistance in the liver of mice fed the high‑fat diet. Furthermore, ezetimibe significantly reduced hepatic mRNA expression of Acc1 and Scd1, which are involved in hepatic fatty acid synthesis. Ezetimibe significantly reduced hepatic Cd36 gene expression, upregulation of which is significantly associated with insulin resistance, hyperinsulinemia and increased steatosis. The protein expression of SKP2, a viable therapeutic target in human cancer, was also reduced by ezetimibe. These findings suggest that ezetimibe may be an effective therapy for high fat‑induced NAFLD, including NASH.
- Deletion of serum amyloid A3 improves high fat high sucrose diet-induced adipose tissue inflammation and hyperlipidemia in female mice. [Journal Article, Research Support, N.I.H., Extramural]
- PLoS One 2014; 9(9):e108564.
Serum amyloid A (SAA) increases in response to acute inflammatory stimuli and is modestly and chronically elevated in obesity. SAA3, an inducible form of SAA, is highly expressed in adipose tissue in obese mice where it promotes monocyte chemotaxis, providing a mechanism for the macrophage accumulation that occurs with adipose tissue expansion in obesity. Humans do not express functional SAA3 protein, but instead express SAA1 and SAA2 in hepatic as well as extrahepatic tissues, making it difficult to distinguish between liver and adipose tissue-specific SAA effects. SAA3 does not circulate in plasma, but may exert local effects that impact systemic inflammation. We tested the hypothesis that SAA3 contributes to chronic systemic inflammation and adipose tissue macrophage accumulation in obesity using mice deficient for Saa3 (Saa3(-/-)). Mice were rendered obese by feeding a pro-inflammatory high fat, high sucrose diet with added cholesterol (HFHSC). Both male and female Saa3(-/-) mice gained less weight on the HFHSC diet compared to Saa3(+/+) littermate controls, with no differences in body composition or resting metabolism. Female Saa3(-/-) mice, but not males, had reduced HFHSC diet-induced adipose tissue inflammation and macrophage content. Both male and female Saa3(-/-) mice had reduced liver Saa1 and Saa2 expression in association with reduced plasma SAA. Additionally, female Saa3(-/-) mice, but not males, showed improved plasma cholesterol, triglycerides, and lipoprotein profiles, with no changes in glucose metabolism. Taken together, these results suggest that the absence of Saa3 attenuates liver-specific SAA (i.e., SAA1/2) secretion into plasma and blunts weight gain induced by an obesogenic diet. Furthermore, adipose tissue-specific inflammation and macrophage accumulation are attenuated in female Saa3(-/-) mice, suggesting a novel sexually dimorphic role for this protein. These results also suggest that Saa3 influences liver-specific SAA1/2 expression, and that SAA3 could play a larger role in the acute phase response than previously thought.
- Statin therapy and hepatotoxicity: Appraisal of the safety profile of atorvastatin in hyperlipidemic patients. [Journal Article]
- Adv Biomed Res 2014.:168.
Statins are one of the most frequently prescribed medications to reduce the risk of cardiovascular events. Statins appear to be safe however, there are contradictory data regarding their adverse effects, which might be due to genetic variation in their metabolism. Hence, this prospective study was aimed to evaluate the effects of atorvastatin on liver transaminase changes in a clinical setting, in north Iran.This prospective semi-experimental study was performed on hyperlipidemic adults in 2010-2011. Patients received atorvastatin (5-40 mg/d) based on the American National Cholesterol Education Program guidelines. Liver aminotransferases were measured in three occasions of baseline, 8 and 16 weeks period.A total of 206 patients were included in the study. Of which 178 were female and 30 were male. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were in normal range before intervention in the majority, except in 25 (12.1%) and 16 (7.8%) of patients, respectively. In general, ALT and AST remained in normal range over the study period (23.3 IU/L and 21.8 IU/L, respectively). There was found no relationship between different doses of atorvastatin prescribed and ALT/AST changes in the patients. The males' ALT means at baseline (26.9 IU/L), 8 weeks (30 IU/L) and 16 weeks (28.8 IU/L) after statin therapy were significantly higher than females (22 IU/L, 22.2 IU/L and 22.1 IU/L, respectively; P < 0.05 for all).The absence of any hepatic adverse effect in the present study supports safety of atorvastatin and emerging opinion that routine screening of liver function tests is not necessary in patients on statins.
- Disruption of ldlr causes increased LDL-c and vascular lipid accumulation in a zebrafish model of hypercholesterolemia. [Journal Article, Research Support, N.I.H., Extramural]
- J Lipid Res 2014 Nov; 55(11):2242-53.
Hyperlipidemia and arterial cholesterol accumulation are primary causes of cardiovascular events. Monogenic forms of hyperlipidemia and recent genome-wide association studies indicate that genetics plays an important role. Zebrafish are a useful model for studying the genetic susceptibility to hyperlipidemia owing to conservation of many components of lipoprotein metabolism, including those related to LDL, ease of genetic manipulation, and in vivo observation of lipid transport and vascular calcification. We sought to develop a genetic model for lipid metabolism in zebrafish, capitalizing on one well-understood player in LDL cholesterol (LDL-c) transport, the LDL receptor (ldlr), and an established in vivo model of hypercholesterolemia. We report that morpholinos targeted against the gene encoding ldlr effectively suppressed its expression in embryos during the first 8 days of development. The ldlr morphants exhibited increased LDL-c levels that were exacerbated by feeding a high cholesterol diet. Increased LDL-c was ameliorated in morphants upon treatment with atorvastatin. Furthermore, we observed significant vascular and liver lipid accumulation, vascular leakage, and plaque oxidation in ldlr-deficient embryos. Finally, upon transcript analysis of several cholesterol-regulating genes, we observed changes similar to those seen in mammalian systems, suggesting that cholesterol regulation may be conserved in zebrafish. Taken together, these observations indicate conservation of ldlr function in zebrafish and demonstrate the utility of transient gene knockdown in embryos as a genetic model for hyperlipidemia.
- Variability in myosteatosis and insulin resistance induced by high-fat diet in mouse skeletal muscles. [Journal Article, Research Support, Non-U.S. Gov't]
- Biomed Res Int 2014.:569623.
Nutrient overload leads to impaired muscle oxidative capacity and insulin sensitivity. However, comparative analyses of the effects of dietary manipulation on skeletal muscles with different fiber composition are lacking. This study aimed to investigate the selective adaptations in the soleus and tibialis anterior muscles evoked by administration of high-fat diet for 12 weeks in 10 mice (HFD mice) compared to 10 animals fed with a normal chow diet (control mice). Mice fed with the HFD diet exhibited hyperlipidemia, hyperinsulinemia, hyperglycemia, and lower exercise capacity in comparison to control mice. In control mice, soleus fibers showed higher lipid content than tibialis anterior fibers. In contrast, the lipid content was similar between the two muscles in HFD mice. Significant differences in markers of muscle mitochondrial production and/or activity as well as of lipid synthesis were detected between HFD mice and control mice, especially in the tibialis anterior. Moreover, translocation of GLUT-4 transporter to the plasma membrane and activation of the insulin signaling pathway were markedly inhibited in the tibialis and slightly reduced in the soleus of HFD mice compared to control mice. Overall, these results show that adaptive responses to dietary manipulation occur in a muscle-specific pattern.
- Dietary supplementation with tomato-juice in patients with metabolic syndrome: A suggestion to alleviate detrimental clinical factors. [Journal Article]
- Food Chem Toxicol 2014 Dec.:9-13.
Lycopene, a carotenoid, is known for its antioxidant properties. Little is known, though, about the relationship of dietary tomato-juice intake and risks factors, like inflammation, insulin resistance and hyperlipidemia, implicated in metabolic syndrome. In the present study, we examined whether supplementation with tomato-juice has any implication on the risk status of patients with metabolic syndrome. A comparative study was conducted in 27 individuals diagnosed with metabolic syndrome. Fifteen of them were instructed to use commercially available tomato-juice as refreshment 4 times a week over a period of two months and twelve individuals served as the control group. Several parameters reflective of the metabolic syndrome were monitored both in the group supplemented with tomato juice and in the control group (ADMA for entdothelial function, TNF-α and IL-6 for inflammation, FIRI for insulin resistance). There was a significant improvement in the inflammation status and the endothelial dysfunction of the tomato-juice supplemented patients. At the same time, insulin resistance improved and a pronounced decrease in LDL was recorded, along with a slight increase in HDL. The results of the present study suggest an alleviating effect of tomato-juice with regard to risk factors associated with metabolic syndrome.
- Determinants of VLDL composition and apo B-containing particles in familial combined hyperlipidemia. [Journal Article]
- Clin Chim Acta 2015 Jan 1.:160-5.
In familial combined hyperlipidemia (FCHL) the severity of the dyslipidemia is determined by an overproduction of VLDL (very low density lipoprotein) particles and by its abnormal lipid composition. However, few are known regarding the metabolic factors that determine these abnormalities. We investigated the impact of metabolic factors on the number of atherogenic particles (apolipoprotein B level (apoB)) and the triglyceride content of very low-density lipoproteins (VLDLs-TG).A cross-sectional study done in FCHL subjects and gender and age-matched healthy subjects. A clinical assessment, lipid profile and plasma concentrations of insulin, apolipoprotein CIII (apo CIII), apolipoprotein AII (apo AII), high sensitive C-reactive protein (HS-CRP), adiponectin and leptin were documented in 147 FCHL patients and 147 age-matched healthy subjects. Multivariate regression models were performed to investigate the independent determinants of VLDL-TG and apo B levels adjusting for confounding factors.The variables that determined the VLDL-triglyceride content as a surrogate of VLDL composition were apo CIII (β=0.365, p<0.001), insulin (β=0.281, p<0.001), Apo AII (β=0.145, p<0.035), and adiponectin levels (β=-0.255, p<0.001). This model explained 34% of VLDL composition (VLDL-TG) variability. However, none of these variables were independent contributors of apo B-containing particles.In patients with FCHL apo CIII, apo AII and adiponectin are major novel factors determining the VLDL particle composition. However, such factors do not explain apo B-containing particles.
- Lowered cutoff points of obesity indicators are better predictors of hypertension and diabetes mellitus in premenopausal Taiwanese women. [JOURNAL ARTICLE]
- Obes Res Clin Pract 2014 Aug 22.
In previous study, we found that in order to prevent MS in women aged <65 years, the cutoff points of obesity indicators should be lowered.To investigate whether our proposed cutoff points of obesity indicators predict the occurrence of hypertension (HT), diabetes mellitus (DM), and hyperlipidemia in premenopausal women with greater sensitivity and specificity compared to reference cutoff points of obesity that are currently being used.Using the database of the "2002 Survey on the Prevalence of Hypertension, Hyperglycemia and Hyperlipidemia in Taiwan" provided by the Bureau of Health Promotion, Taiwan as research material, data from 2270 premenopausal women aged 20-65 years were used for the analyses. The receiver-operating characteristic curves (ROC) of the body-mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were used to predict HT, DM, and hyperlipidemia.Obesity is not a good predictor of the occurrence of hyperlipidemia in premenopausal women aged <65 years. However, our proposed cutoff points had greater sensitivity and specificity than did the reference cutoff points. To prevent the risk of HT and DM in premenopausal women, the cutoff points of obesity indicators should be reduced. The proposed values are as follows: a WHR of 0.79; a WC of 74.7cm; a WHtR of 0.49; and a BMI of 22.3kg/m(2).
- Preliminary study: Evaluation of melatonin secretion in children and adolescents with type 1 diabetes mellitus. [Journal Article]
- Indian J Endocrinol Metab 2014 Jul; 18(4):565-8.
Melatonin is an indolamine hormone, synthesized from tryptophan in the pineal gland primarily. Melatonin exerts both antioxidative and immunoregulatory roles but little is known about melatonin secretion in patients with type 1 diabetes mellitus (T1DM). The aim of this study was to measure serum melatonin levels in patients with T1DM and investigates their relationship with type 1 diabetes mellitus.Forty children and adolescents with T1DM (18 boys and 22 girls) and 30 healthy control subjects (17 boys and 13 girls) participated in the study. All patients followed in Pediatric Endocrinology and Metabolism Unit of Gaziantep University Faculty of Medicine and also control subjects had no hypertension, obesity, hyperlipidemia, anemia, and infection. Blood samples were collected during routine analysis, after overnight fasting. Serum melatonin levels were analyzed with ELISA.There were no statistically significant differences related with age, sex, BMI distribution between diabetic group and control group. Mean diabetic duration was 2.89 ± 2.69 years. The variables were in the equation. Mean melatonin level in diabetic group was 6.75 ± 3.52 pg/ml and mean melatonin level in control group was 11.51 ± 4.74 pg/ml. Melatonin levels were significantly lower in diabetic group compared to controls (P < 0.01).Melatonin was associated with type 1 diabetes mellitus significantly. Because of the varied roles of melatonin in human metabolic rhythms, these results suggest a role of melatonin in maintaining normal rhythmicity. Melatonin may play role in preventing process of inflammation and oxidative stress.