- Small Heterodimer Partner and Fibroblast Growth Factor 19 Inhibit Expression of NPC1L1 in Mouse Intestine and Cholesterol Absorption. [Journal Article]
- GGastroenterology 2018 Dec 03
- CONCLUSIONS: Postprandial FGF19 and SHP inhibit SREBF2, which leads to repression of intestinal NPC1L1 expression and cholesterol absorption. Strategies to increase FGF19 signaling to activate SHP might be developed for treatment of hypercholesterolemia.
- Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women With Normal Body Mass Index: A Secondary Analysis of a Randomized Clinical Trial and Observational Study. [Journal Article]
- JOJAMA Oncol 2018 Dec 06
- CONCLUSIONS: In postmenopausal women with normal BMI, relatively high body fat levels were associated with an elevated risk of invasive breast cancer and altered levels of circulating metabolic and inflammatory factors. Normal BMI categorization may be an inadequate proxy for the risk of breast cancer in postmenopausal women.
- Pegbelfermin (BMS-986036), PEGylated FGF21, in Patients with Obesity and Type 2 Diabetes: Results from a Randomized Phase 2 Study. [Journal Article]
- OObesity (Silver Spring) 2018 Dec 06
- CONCLUSIONS: Twelve-week pegbelfermin treatment did not impact HbA1c concentrations, but QW and higher daily doses were associated with improved metabolic parameters and fibrosis biomarkers in patients with obesity and T2DM predisposed to fatty liver. These results support evaluation of pegbelfermin in patients with obesity-related metabolic diseases (e.g., nonalcoholic steatohepatitis).
- Ezetimibe suppresses development of liver tumors by inhibiting angiogenesis in mice fed a high-fat diet. [Journal Article]
- CSCancer Sci 2018 Dec 06
- Nonalcoholic steatohepatitis (NASH) is a common cause of liver cirrhosis and hepatocellular carcinoma (HCC). However, effective therapeutic strategies for preventing and treating NASH-mediated liver ...
Nonalcoholic steatohepatitis (NASH) is a common cause of liver cirrhosis and hepatocellular carcinoma (HCC). However, effective therapeutic strategies for preventing and treating NASH-mediated liver cirrhosis and HCC are lacking. Cholesterol is closely associated with vascular endothelial growth factor (VEGF), a key factor that promotes HCC. Recent reports have demonstrated that statins could prevent HCC development. In contrast, we have little information on ezetimibe, an inhibitor of cholesterol absorption, in the prevention for NASH-related liver cirrhosis and HCC. In the present study, a steatohepatitis-related HCC model, hepatocyte-specific phosphatase and tensin homolog (Pten)-deficient (PtenΔhep ) mice were fed a high-fat (HF) diet with/without ezetimibe. In the standard-diet group, ezetimibe did not reduce the development of liver tumors in PtenΔhep mice, in which the increase of serum cholesterol levels was mild. Feeding of a HF diet increased serum cholesterol levels markedly and subsequently increased serum levels of VEGF, a crucial component of angiogenesis. The HF diet increased the number of VEGF-positive cells and vascular endothelial cells in the tumors of PtenΔhep mice. Kupffer cells, macrophages in the liver, increased VEGF expression in response to fat overload. Ezetimibe treatment lowered cholesterol levels and these angiogenetic processes. As a result, ezetimibe also suppressed inflammation, liver fibrosis, and tumor growth in PtenΔhep mice on the HF diet. Tumor cells were highly proliferative by HF-diet feeding, which was inhibited by ezetimibe. In conclusion, ezetimibe suppressed development of liver tumors by inhibiting angiogenesis in PtenΔhep mice with hypercholesterolemia. This article is protected by copyright. All rights reserved.
- The role of metabolic syndrome and its components as mediators of the genetic effect on type 2 diabetes: a family-based study in China. [Journal Article]
- JDJ Diabetes 2018 Dec 05
- CONCLUSIONS: Our findings provide evidence on that MetS and its two components (HDL-c, and FBG), might be involved in mediating the genetic predisposition to T2D. Our results emphasize the importance of maintaining normal HDL-c and FBG levels in the prevention of T2D. This article is protected by copyright. All rights reserved.
- Impact of systemic and tumor lipid metabolism on everolimus efficacy in advanced pancreatic neuroendocrine tumors (pNETs). [Journal Article]
- IJInt J Cancer 2018 Dec 05
- The mTOR inhibitor everolimus is effective against advanced pancreatic neuroendocrine tumors (pNETs). However, it can cause metabolic adverse events, such as hyperglycemia, hypertriglyceridemia and h...
The mTOR inhibitor everolimus is effective against advanced pancreatic neuroendocrine tumors (pNETs). However, it can cause metabolic adverse events, such as hyperglycemia, hypertriglyceridemia and hypercholesterolemia. In this work we aimed at evaluating the impact of systemic and tumor lipid metabolism on everolimus efficacy. We carried out a monocentric, retrospective study to correlate plasma triglyceride and cholesterol levels with the progression free survival (PFS) of advanced pNET patients treated with everolimus. In formalin fixed, paraffin embedded (FFPE) tumor specimens, we also assessed by mRNA quantification and immunohistochemistry the expression of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN), two enzymes crucially involved in fatty acid biosynthesis, and we analyzed their impact on PFS. We evaluated 58 consecutive pNET patients who started everolimus between December 2006 and January 2015. Patients with higher plasma triglycerides during the first three months of treatment had an increased risk of disease progression (aHR 3.08, 95% CIs 1.15-8.21; p = 0.025). In 23 FFPE tumor specimens amenable for IHC evaluations, we found a positive correlation between ACC1 and FASN at both mRNA (r = 0.87, p = 0.00045) and protein (r = 0.68, p = 0.0004) level. Patients with higher ACC1 protein expression in metastatic lesions had significantly lower PFS when compared to patients with lower ACC1 levels (5.5 vs 36 months; aHR 4.49, 95% CIs 1.08-18.72; p = 0.039). In conclusion, systemic and tumor lipid metabolism are associated with the PFS of everolimus-treated patients with advanced pNETs; based on these findings, dietary and pharmacological interventions targeting lipid metabolism could improve everolimus efficacy in this patient population. Pancreatic neuroendocrine tumors (pNETs) are highly heterogeneous, so to improve treatment, it's critical to learn more about how different tumor types respond to therapy. The mTOR inhibitor everolimus is a standard therapy for pNETs. Here, the authors conducted a retrospective study to evaluate how circulating triglyceride and cholesterol levels affect the efficacy of everolimus. Patients with higher plasma triglyceride levels at the start of treatment, they found, had worse outcomes. In addition, they noted a correlation between disease progression and higher intratumoral levels of ACC1, a key enzyme in fatty acid biosynthesis. This article is protected by copyright. All rights reserved.
- The effect of chronic kidney disease on lipid metabolism. [Review]
- IUInt Urol Nephrol 2018 Dec 05
- The major cause of death among chronic kidney disease patients is cardiovascular diseases. Cardiovascular and kidney disease are interrelated and increase the severity of each other. Dyslipidemia is ...
The major cause of death among chronic kidney disease patients is cardiovascular diseases. Cardiovascular and kidney disease are interrelated and increase the severity of each other. Dyslipidemia is one the major causes of cardiovascular disease among chronic kidney disease patients along with diabetes and hypertension. The relationship between dyslipidemia and chronic kidney disease is reciprocal. Dyslipidemia is known to be a risk factor for chronic kidney disease and chronic kidney disease causes major alterations on lipoprotein profile, defined as the "dyslipidemic profile" of chronic kidney disease patients. Increased triglyceride, very low density lipoprotein and oxidized low density lipoprotein as well as decreased high density lipoprotein and changes in the composition of lipoproteins contribute to the "dyslipidemic profile." Treatment strategies targeting the "dyslipidemic profile" of chronic kidney disease could contribute to prevent cardiovascular diseases. Current therapy is based on the patient kidney function and consist mainly of statins. This review focuses on the effects of chronic kidney disease on the lipoprotein profile and how this may impact novel therapeutic approaches to cardiovascular risk.
- Hawthorn Extract Alleviates Atherosclerosis through Regulating Inflammation and Apoptosis Related Factors: An Experimental Study. [Journal Article]
- CJChin J Integr Med 2018 Dec 05
- CONCLUSIONS: Hawthorn extract has anti-atherosclerosis and stabilizing unstable plaque effects. The mechanism may be related to the inflammation and apoptosis signaling pathways.
- Differential expression of MicroRNA let-7e and 296-5p in plasma of Egyptian patients with essential hypertension. [Journal Article]
- HHeliyon 2018; 4(11):e00969
- Essential hypertension is a chronic medical condition affecting thousands of people worldwide. Hypertension results from interplay of genetic and environmental factors. MicroRNAs regulate gene expres...
Essential hypertension is a chronic medical condition affecting thousands of people worldwide. Hypertension results from interplay of genetic and environmental factors. MicroRNAs regulate gene expression and can be biomarkers for disease. MicroRNA let-7e and microRNA 296-5p have been linked to different cardiovascular diseases. This study aimed to determine association of serum miRNA let-7e and miRNA 296-5p with essential hypertension in Egyptian patients. MicroRNA let-7e and miRNA-296-5p expression was determined in sera of 25 hypertensive patients and 25 normotensive controls by quantitative real-time polymerase chain reaction. Hypertensive patients showed significantly higher expression of miRNA let-7e (3.23-fold increase, p = 0.036) in comparison with normotensive controls. In hypertensive patients, miRNA let-7e expression was positively correlated with increased systolic and diastolic blood pressure. Furthermore, miRNA 296-5p expression was negatively correlated with serum total cholesterol and low-density lipoprotein. Results from this study indicate that miRNA let-7e can potentially be a biomarker for essential hypertension.
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- Complement Factor H and Apolipoprotein E Participate in Regulation of Inflammation in THP-1 Macrophages. [Journal Article]
- FIFront Immunol 2018; 9:2701
- The alternative pathway (AP) of complement is constantly active in plasma and can easily be activated on self surfaces and trigger local inflammation. Host cells are protected from AP attack by Facto...
The alternative pathway (AP) of complement is constantly active in plasma and can easily be activated on self surfaces and trigger local inflammation. Host cells are protected from AP attack by Factor H (FH), the main AP regulator in plasma. Although complement is known to play a role in atherosclerosis, the mechanisms of its contribution are not fully understood. Since FH via its domains 5-7 binds apoliporotein E (apoE) and macrophages produce apoE we examined how FH could be involved in the antiatherogenic effects of apoE. We used blood peripheral monocytes and THP-1 monocyte/macrophage cells which were also loaded with acetylated low-density lipoprotein (LDL) to form foam cells. Binding of FH and apoE on these cells was analyzed by flow cytometry. High-density lipoprotein (HDL)-mediated cholesterol efflux of activated THP-1 cells was measured and transcriptomes of THP-1 cells using mRNA sequencing were determined. We found that binding of FH to human blood monocytes and cholesterol-loaded THP-1 macrophages increased apoE binding to these cells. Preincubation of fluorescent cholesterol labeled THP-1 macrophages in the presence of FH increased cholesterol efflux and cholesterol-loaded macrophages displayed reduced transcription of proinflammatory/proatherogenic factors and increased transcription of anti-inflammatory/anti-atherogenic factors. Further incubation of THP-1 cells with serum reduced C3b/iC3b deposition. Overall, our data indicate that apoE and FH interact with monocytic cells in a concerted action and this interaction reduces complement activation and inflammation in the atherosclerotic lesions. By this way FH may participate in mediating the beneficial effects of apoE in suppressing atherosclerotic lesion progression.