Visfatin and SREBP-1c mRNA Expressions and Serum Levels Among Egyptian Women with Polycystic Ovary Syndrome.

Background: Obesity and insulin resistance are common features accompanying polycystic ovary syndrome (PCOS). Aim: To analyze the impact of obesity on the expression of the visfatin and sterol regulatory element-binding protein (SREBP)-1c genes among a group of Egyptian women with PCOS, and to assess their suitability as PCOS biomarkers. Subject and methods: Seventy healthy women (control group) (35 nonobese and 35 obese) and 140 women with PCOS (70 nonobese and 70 obese) were enrolled in this study. The visfatin and SREBP-1c genes' expression analyses were performed via real-time polymerase chain reaction. Serum visfatin and SREBP-1c protein levels were measured with ELISA kits. Results: Among PCOS patients, upregulation of visfatin and SREBP-1c expression was observed. We did not identify significant differences between the obese and nonobese PCOS patients nor between obese and non-obese controls. The mRNA expression levels of both genes were significantly positively correlated with their serum protein levels, as well as with fasting serum insulin levels, homeostatic model assessments of insulin resistance (HOMA-IR), luteinizing hormone (LH) ratios, LH/follicular stimulating hormone ratios, total testosterone, and free androgens. We observed significant negative correlations between visfatin and SREBP-1c expression levels and sex hormone binding globulin levels in all studied groups. Receiver operating characteristic curve analyses revealed that combining the visfatin and SREBP-1c expression data increased the sensitivity (95.92%) and specificity (93.2%) for PCOS diagnoses. Conclusion: Upregulation of visfatin and SREBP-1c was observed among PCOS patients. These genes may play a role in the pathogenesis of PCOS independent of obesity. Combined visfatin and SREBP-1c analyses could be used as a noninvasive biomarker for PCOS.

A novel plasma lncRNA ENST00000416361 is upregulated in coronary artery disease and is related to inflammation and lipid metabolism.

Coronary artery disease (CAD) is a serious threat to human health and a major cause of mortality worldwide. Long noncoding RNAs (lncRNAs) affect the occurrence and development of CAD via the regulation of cell proliferation and apoptosis, inflammatory responses and lipid metabolism. Screening methods and therapeutic strategies for CAD have been extensively studied. The present study analyzed clinical indexes of 187 patients with CAD and 150 healthy subjects. The data showed significant differences in diabetes mellitus, hypertension, high­density lipoprotein level and smoking history between the CAD group and the control group. A series of differentially expressed lncRNAs were detected in the plasma samples of three patients with CAD by high­throughput sequencing. Reverse transcription­quantitative (RT­q)PCR data revealed that the expression level of the novel lncRNA ENST00000416361 was ~2.3­fold higher in the plasma of 50 patients with CAD compared with the 50 control subjects. Receiver operating characteristic (ROC) curves were generated, and the area under the ROC curve was 0.7902. Knockdown of ENST00000416361 in human umbilical vein endothelial cells markedly downregulated interleukin­6 and tumor necrosis factor­α levels. In addition, sterol regulatory element binding transcription factor (SREBP)1 and SREBP2 were upregulated in patients with CAD, and they were positively correlated with the expression of ENST00000416361. RT­qPCR further demonstrated that knockdown of ENST00000416361 led to the downregulation of SREBP1 and SREBP2. Overall, the novel lncRNA ENST00000416361 may be associated with CAD­induced inflammation and lipid metabolism, and it may serve as a potential biomarker for CAD.

Protective effect of Lycium barbarum polysaccharides against high-fat diet-induced renal injury and lipid deposition in rat kidneys.

This study aimed to explore the protective effect of Lycium barbarum polysaccharides (LBPs) against hyperlipidemia and lipid-induced renal injury in a rat model. Male Sprague-Dawley rats (n=30) were randomly divided into three equal groups: a control group (fed a regular diet) and two experimental groups (fed a high-fat diet). By feeding rats a high-fat diet for 12 weeks, an animal model of hyperlipidemia was established, after which one experimental group received oral LBPs at a dose of 300 mg/kg per day. Blood lipids, renal function, and urinary proteins were measured after 12 weeks. Changes in renal pathology and expression levels of sterol regulatory element binding transcription factor 1 (SREBP-1), interleukin-6 (IL- 6), tumor necrosis factor-alpha (TNF-α), AMP-activated protein kinase (AMPK) were determined. Rats with hyperlipidemia induced by a high-fat diet showed increases in blood lipids and blood urea nitrogen, serum creatinine, and urinary protein, as well as increases in renal levels of SREBP-1, TNF-α, and IL-6 and decreases in renal levels of adiponectin and AMPK. Administration of LBPs restored blood lipid, blood urea nitrogen, serum creatinine, and urinary protein levels, downregulated renal levels of SREBP-1, TNF-α, and IL-6, and upregulated renal levels of adiponectin and AMPK. These results indicate that LBPs may mediate lipid metabolism, enhance anti-inflammatory responses, and ameliorate renal injury caused by lipid metabolism isorders in a rat model of hyperlipidemia.

Lipoprotein Profile in Aged Rats Fed Chia Oil- or Hydroxytyrosol-Enriched Pork in High Cholesterol/High Saturated Fat Diets.

Restructuring pork (RP) by adding new functional ingredients, like Chia oil (one of the richest natural source of α-linolenic acid) or hydroxytyrosol (HxT) (potent antioxidant), both with hypolipidemic activities, is one of the strategies that may help to reduce the potential negative effects of high meat products consumption. The aim of this study was to evaluate the Chia oil- or HxT-enriched-RP effect on the lipoprotein profile of aged rats fed high-fat, high-energy, and cholesterol-enriched diets. RP samples were prepared by mixing lean pork and lard with or without Chia oil (152.2 g/kg fresh matter) or HxT (3.6 g/kg fresh matter). Diets were prepared by mixing a semisynthetic diet with freeze-dried RP. Groups of 1-year male Wistar rats were fed the following experimental diets for 8 weeks: C, control-RP diet; HC, cholesterol-enriched-RP diet; and Chia oil-RP (CHIA) and HxT, Chia oil- or hydroxytyrosol-RP, cholesterol-enriched diet. Plasma lipid, lipoprotein profile, SREBP-1c protein, and low-density lipoproteins (LDL) receptor gene (Ldlr) expressions were evaluated. Compared to C diet, the HC diet increased plasma cholesterol, triglycerides, free fatty acids, total lipids, and SREBP-1c expression, but reduced Ldlr expression and significantly modified the lipoprotein profile, giving rise to the presence of high levels of atherogenic cholesterol-enriched very low-density lipoproteins (VLDL) particles. Compared to the HC diet, the HxT diet did not produce significant changes in feed intake but it reduced the body weight. Chia oil and HxT partially arrested the negative effects of the high-fat, high-energy, and cholesterol-enriched meat-based diets on lipemia and lipoproteinemia, mostly by reducing the amount of cholesterol content in VLDL (60% and 74% less in CHIA and HxT vs. HC, respectively) and the VLDL total mass (59% and 63% less in CHIA and HxT vs. HC, respectively). Free fatty acids (FFA) significantly correlated with adipose tissue weight and VLDL total mass (both p < 0.05), and plasma triglycerides, phospholipids, total lipids, and SREBP-1c (all p < 0.001), suggesting the important role of FFA in lipoprotein metabolism. Results support the recommendation to include these ingredients in pork products addressed to reduce the presence of increased atherogenic particles in aged people at CVD risk consuming large amounts of pork.

Ectopic lipid accumulation: potential role in tubular injury and inflammation in diabetic kidney disease.

Emerging studies suggest that lipid accumulates in the kidneys during diabetic kidney disease (DKD). However, the correlation between ectopic lipid accumulation with tubular damage has not been thoroughly elucidated to date. Using Oil Red staining, lipid accumulation was observed in the kidneys of type 2 DKD patients (classes II-III) and db/db mice compared with the control and was predominantly located in the proximal tubular compartment. Immunohistochemistry (IHC) staining showed that the intensity of adipose differentiation related protein (ADRP) and sterol regulatory element binding protein-1 (SREBP-1) was clearly up-regulated, which was positively correlated with the tubulointerstitial damage score and inflammation. Furthermore, the urine ADRP content significantly increased in DKD patients compared with the control, which positively correlated with abnormal lipid metabolism, serum creatinine, urine N-acetyl-ß-glucosaminidase (NAG), albumin excretion (albumin-to-creatinine ratio (ACR)), and tumor necrosis factor-α (TNF-α) expression. However, there was no significant difference observed in plasma ADRP levels. In addition, the expression of SREBP-1 protein was dramatically increased in peripheral blood mononuclear cells (PBMCs) isolated from DKD patients, which was also tightly correlated with urine NAG, ACR, and TNF-α levels. In vitro studies demonstrated increased ADRP and SREBP-1 expression accompanied by lipid accumulation in HK-2 cells cultured in high glucose (HG). HG induced high levels of TNF-α expression, which was partially blocked by transfection of ADRP siRNA or SREBP-1 siRNA. These data indicated that ADRP and SREBP-1 are crucial factors that mediate lipid accumulation with tubular damage and inflammation in DKD, and ectopic lipid accumulation may serve as a novel therapeutic target for amelioration of tubular injury in DKD.

Ground Beef High in Total Fat and Saturated Fatty Acids Decreases X Receptor Signaling Targets in Peripheral Blood Mononuclear Cells of Men and Women.

We hypothesized that consumption of saturated fatty acids in the form of high-fat ground beef for 5 weeks would depress liver X receptor signaling targets in peripheral blood mononuclear cells (PBMC) and that changes in gene expression would be associated with the corresponding changes in lipoprotein cholesterol (C) concentrations. Older men (n = 5, age 68.0 ± 4.6 years) and postmenopausal women (n = 7, age 60.9 ± 3.1 years) were assigned randomly to consume ground-beef containing 18% total fat (18F) or 25% total fat (25F), five patties per week for 5 weeks with an intervening 4-week washout period. The 25F and 18F ground-beef increased (p < 0.05) the intake of saturated fat, monounsaturated fat, palmitic acid, and stearic acid, but the 25F ground-beef increased only the intake of oleic acid (p < 0.05). The ground-beefs 18F and 25F increased the plasma concentration of palmitic acid (p < 0.05) and decreased the plasma concentrations of arachidonic, eicosapentaenoic, and docosahexaenic acids (p < 0.05). The interventions of 18F and 25F ground-beef decreased very low-density lipoprotein C concentrations and increased particle diameters and low-density lipoprotein (LDL)-I-C and LDL-II-C concentrations (p < 0.05). The ground-beef 25F decreased PBMC mRNA levels for the adenosine triphosphate (ATP) binding cassette A, ATP binding cassette G1, sterol regulatory element binding protein-1, and LDL receptor (LDLR) (p < 0.05). The ground-beef 18F increased mRNA levels for stearoyl-CoA desaturase-1 (p < 0.05). We conclude that the increased LDL particle size and LDL-I-C and LDL-II-C concentrations following the 25F ground-beef intervention may have been caused by decreased hepatic LDLR gene expression.

(-)-Hydroxycitric acid reduced fat deposition via regulating lipid metabolism-related gene expression in broiler chickens.

BACKGROUND: Chicken as a delicious food for a long history, and it is well known that excess fat deposition in broiler chickens will not only induced metabolic diseases, but also lead to adverse effect in the consumer's health. (-)-Hydroxycitric acid (HCA), a major active ingredient of Garcinia Cambogia extracts, had shown to suppress fat accumulation in animals and humans. While, the precise physiological mechanism of HCA has not yet been full clarified, especially its action in broiler chickens. Thus, this study aimed to assess the effect of (-)-HCA on lipid metabolism in broiler chickens. METHODS: A total of 120 1-day-old broiler chickens were randomly allocated to four groups, with each group was repeated three times with 10 birds. Birds received a commercial diet supplemented with (-)-HCA at 0, 1000, 2000 or 3000 mg/kg, respectively, for a period of 4 weeks ad libitum. RESULTS: Body weight (BW) in the 2000 and 3000 mg/kg (-)-HCA groups was significantly decreased (P < 0.05) than that in control group. A significantly decreased of serum triglyceride (TG) and density lipoprotein-cholesterol (LDL-C) content were observed in 3000 mg/kg (-)-HCA group (P < 0.05). Broiler chickens supplmented with 2000 and 3000 mg/kg (-)-HCA had pronouncedly higher hepatic lipase (HL) activity, hepatic glycogen and non-esterified fatty acid (NEFA) contents in liver (P < 0.05). Serum free triiodothyronine (FT3) and thyroxin (T4) contents were significantly higher in 3000 mg/kg (-)-HCA group (P < 0.05) compared with the control group. Supplemental (-)-HCA markedly decreased fatty acid synthase (FAS) and sterol regulatory element binding protein-1c (SREBP-1c) (P < 0.05) mRNA levels, while the mRNA abundance of adenosine 5'-monophosphate-activated protein kinaseß2 (AMPKß2) (P < 0.05) was significantly increased. In addition, ATP-citrate lyase (ACLY) mRNA level (P < 0.05) was significantly decreased in broiler chickens supplemented with 3000 mg/kg (-)-HCA. No differences was observed on carnitine palmitoyl transferase-I(CPT-I), while peroxisome proliferators-activated receptor α (PPARα) mRNA level (P < 0.05) was significantly increased in broiler chickens supplemented with 2000 and 3000 mg/kg (-)-HCA. CONCLUSIONS: Supplemental (-)-HCA inhibited lipogenesis by inhibiting ACLY, SREBP-1c and FAS expression, and accelerated lipolysis through enhancing HL activity and PPARα expression, which eventually led to the reduced abdominal fat deposition in broiler chickens. Graphical abstract Mechanism of (-)-HCA effect on hepatic lipids metabolism.

Eicosapentaenoic acid-enriched phospholipid ameliorates insulin resistance and lipid metabolism in diet-induced-obese mice.

BACKGROUND: Over the past two decades, a striking increase in the number of people with metabolic syndrome (MS) has taken place worldwide. With the elevated risk of not only diabetes but also cardiovascular morbidity and mortality, there is urgent need for strategies to prevent this emerging global epidemic. The present study was undertaken to investigate the effects of dietary eicosapentaenoic acid-enriched phospholipid (EPA-PL) on metabolic disorders. METHODS: Male C57BL/6J mice (n = 7) were fed one of the following 4 diets for a period of 4 weeks: 1) a modified AIN-96G diet with 5% corn oil (control diet); 2) a high fat (20%, wt/wt) and high fructose (20%, wt/wt) diet (HF diet); 3) the HF diet containing 1% SOY-PL (SOY-PL diet); 4) the HF diet containing 1% EPA-PL (EPA-PL diet). The oral glucose tolerance test was performed. Plasma TG, TC, glucose, NEFA, insulin, leptin, adiponectin, TNF-α and IL-6 levels were assessed. In addition, hepatic lipid levels, lipogenic, and lipidolytic enzyme activities and gene expressions were evaluated. RESULTS: Both EPA-PL and SOY-PL significantly inhibited body weight gain and white adipose tissue accumulation, alleviated glucose intolerance, and lowered both serum fasting glucose and NEFA levels substantially. Only EPA-PL significantly reduced serum TNF-α and IL-6 levels, and increased serum adiponectin level. EPA-PL was more effective in reducing hepatic and serum TG and TC levels than SOY-PL. Both EPA-PL and SOY-PL reduced the activities of hepatic lipogenic enzymes, such as FAS and G6PDH, but only EPA-PL significantly increased CPT, peroxisomal ß-oxidation enzymes activities and CPT-1a mRNA level. Alterations of hepatic lipogenic gene expressions, such as FAS, G6PDH, ACC, SCD-1 and SREBP-1c were consistent with changes in related enzyme activities. CONCLUSIONS: According to our study, EPA-PL supplementation was efficacious in suppressing body fat accumulation, and alleviating insulin resistance and hepatic steatosis by modulating the secretion of adipocytokines and inflammatory cytokines, suppression of SREBP-1c mediated lipogenesis and enhancement of fatty acid ß-oxidation. These results demonstrate that EPA-PL is a novel beneficial food component for the prevention and improvement of metabolic disorders.

Increased plasma thyroid hormone concentrations in LDL receptor deficient mice may be explained by inhibition of aryl hydrocarbon receptor-dependent expression of hepatic UDP-glucuronosyltransferases.

BACKGROUND: Overexpression of SREBP-1 causes a repression of hepatic genes involved in phase II metabolism. In LDL receptor deficient (LDLR(-/-)) mice, active levels of SREBP-1 in the liver are increased. We investigated the hypothesis that LDLR(-/-) mice have increased concentrations of thyroid hormones in plasma due to a reduced hepatic glucuronidation. METHODS: Female LDLR(-/-) and wild-type mice were used to study the effect of the LDLR(-/-) genotype on thyroid hormone metabolism. RESULTS: LDLR(-/-) mice had a higher concentration of nuclear SREBP-1, higher concentrations of thyroxine and triiodothyronine in plasma, a lower expression of relevant UGT1A isoforms, reduced activities of pNP-UGT, T(3)-UGT and T(4)-UGT and a lower mRNA and protein concentration of AhR in the liver than wild-type mice (P<0.05). Plasma concentration of TSH, mRNA concentrations of various genes involved in thyroid hormone synthesis in the thyroid, activity of deiodinase and mRNA concentrations of two thyroid hormone responsive genes, CYP7A1 and Na(+)/K(+)-ATPase, in the liver did not differ between both genotypes. CONCLUSIONS: This study shows that LDLR(-/-) mice have increased concentrations of thyroid hormones in plasma. This effect is probably due to an inhibition of thyroid hormone glucuronidation, which might be caused by down-regulation of UGT genes due to a reduced expression of AhR. However, with respect to plasma TSH concentration and expression of thyroid hormone responsive genes no overt hyperthyroidism was detected. GENERAL SIGNIFICANCE: LDL receptor deficiency leads to a reduced glucuronidation of thyroid hormones in the liver which causes a moderate increase of plasma thyroid hormone concentrations.