Polyphenols: Novel Signaling Pathways

Background: Cardiovascular disease (CVD) is currently the leading cause of death globally. The metabolic syndrome (MetS), a clustering of risk factors including hypertension, hyperglycemia, elevated low-density lipoprotein (LDL) cholesterol, reduced high-density lipoprotein (HDL) cholesterol and increased visceral adiposity, is a significant risk factor for the development of CVD. Non-alcoholic fatty liver disease (NAFLD), often referred to as the hepatic manifestation of MetS, is a constellation of progressive liver disorders closely linked to obesity, diabetes, and insulin resistance. NAFLD initially presents as relatively benign, non-progressive hepatic steatosis, but it may, in certain individuals, progress to nonalcoholic steatohepatitis, fibrosis, cirrhosis, or hepatocellular carcinoma. Currently, there are no validated treatments for NAFLD. Polyphenols are important bioactive dietary compounds and may represent a natural complementary and integrative therapy for the treatment of CVDassociated risk factors, including elevated serum cholesterol and triglyceride levels, as well as NAFLD. Understanding their molecular mechanisms of action is important in the design of future human intervention studies. Methods: Several studies utilizing in vitro and in vivo models have helped to identify underlying molecular mechanisms of action of polyphenols. Results: This review will highlight recent advances regarding the molecular actions of dietary procyanidins, with a special focus on those originating from procyanidin-rich grape seed extracts, with a focus on the signaling pathways utilized to exert beneficial metabolic effects. Conclusion: Modulation of nuclear receptor activity and histone deacetylase inhibition has been identified as underlying mechanisms contributing to procyanidin-mediated amelioration of dyslipidemia and steatosis.

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Glucose Transporter 8 (GLUT8) Regulates Enterocyte Fructose Transport and Global Mammalian Fructose Utilization

Endocrinology ◽

10.1210/en.2012-1541 ◽

2012 ◽

Vol 153 (9) ◽

pp. 4181-4191 ◽

Cited By ~ 42

Author(s):

Brian J. DeBosch ◽

Maggie Chi ◽

Kelle H. Moley

Keyword(s):

Glucose Transporter ◽

Serum Insulin ◽

Density Lipoprotein ◽

Wild Type ◽

In Vivo Models ◽

The Metabolic Syndrome ◽

High Fructose

Enterocyte fructose absorption is a tightly regulated process that precedes the deleterious effects of excess dietary fructose in mammals. Glucose transporter (GLUT)8 is a glucose/fructose transporter previously shown to be expressed in murine intestine. The in vivo function of GLUT8, however, remains unclear. Here, we demonstrate enhanced fructose-induced fructose transport in both in vitro and in vivo models of enterocyte GLUT8 deficiency. Fructose exposure stimulated [14C]-fructose uptake and decreased GLUT8 protein abundance in Caco2 colonocytes, whereas direct short hairpin RNA-mediated GLUT8 knockdown also stimulated fructose uptake. To assess GLUT8 function in vivo, we generated GLUT8-deficient (GLUT8KO) mice. GLUT8KO mice exhibited significantly greater jejunal fructose uptake at baseline and after high-fructose diet (HFrD) feeding vs. wild-type mice. Strikingly, long-term HFrD feeding in GLUT8KO mice exacerbated fructose-induced increases in blood pressure, serum insulin, low-density lipoprotein and total cholesterol vs. wild-type controls. Enhanced fructose uptake paralleled with increased abundance of the fructose and glucose transporter, GLUT12, in HFrD-fed GLUT8KO mouse enterocytes and in Caco2 cultures exposed to high-fructose medium. We conclude that GLUT8 regulates enterocyte fructose transport by regulating GLUT12, and that disrupted GLUT8 function has deleterious long-term metabolic sequelae. GLUT8 may thus represent a modifiable target in the prevention and treatment of malnutrition or the metabolic syndrome.

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Study on health risk factors as a basis to implement programs that promote a nutritional culture in students of the la Sabana University

Roczniki Państwowego Zakładu Higieny ◽

10.32394/rpzh.2021.0153 ◽

2021 ◽

pp. 89-94

Keyword(s):

Physical Activity ◽

Risk Factors ◽

Type 2 Diabetes ◽

Metabolic Syndrome ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Blood Chemistry ◽

Monitoring And Control ◽

The Metabolic Syndrome

Background. Nowadays the importance of lifestyles in the prevention of type 2 diabetes and the metabolic syndrome has been largely accertained. Objective. The purpose of our work is to implement programs that promote a nutritional culture in adolescents and young adults of the La Sabana University. Methods. The methodology entailed, after the corresponding informed consent, taking measures of the triceps and supraescapular skinfolds, waist circumference, body mass index (BMI), lean mass, and fat mass. Fasting blood samples were also taken to quantify cholesterol, triglycerides, high density lipoprotein (HDL) and low density lipoprotein (LDL). Results. The results obtained show that of the 165 students, 10.3% were underweight, 13.93% were overweight and 0.6% were obese. With regards to gender, 4.8% of the men and 9% of the women were overweight, 3% of the men and 7.2% of the women were underweight, and 0.6% of the women were obese. The blood chemistry showed that 30% had hypercholesterolemia, 18% hypertriglyceridemia, 17% reported low HDL levels and 67% reported high LDL levels. Of all the cases studied, 40% are at risk of a metabolic syndrome. 60% claimed not to practice any physical activity - especially women who reported 44.70%. Conclusions. These findings have allowed us at the institution to implement a culture of healthy habits. The have also allowed us to identify students with risk factors for type 2 diabetes and metabolic syndrome. This is why the cardiometabolic monitoring and control based on healthy eating and physical activity are important.

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Biochemistry and Molecular Biology of Mechanisms of Action of Fibrates – An Overview

International Journal of Biochemistry Research & Review ◽

10.9734/ijbcrr/2019/v26i230094 ◽

2019 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

A.S. V. Prasad

Keyword(s):

Mechanism Of Action ◽

Molecular Mechanisms ◽

Organic Anion ◽

Density Lipoprotein ◽

The United States ◽

Mechanisms Of Action ◽

Lipid Lowering ◽

Intervention Trial ◽

Ligand Interaction ◽

Cholesterol Acyl Transferase

Fibrates are a class of medication that mainly lowers the blood triglyceride levels. They reduce the LDL and increase the levels of HDL C, in the blood. Clofibrate, the first member to be discovered in 1962 , and introduced in USA in 1967, is withdrawn in 2002, due to unexplained hepatomegaly, hepato-toxicity and possible risk of hepatic cancer. Other fibrates are introduced in the late 1970s and early 1980s, such as gemfibrozil in the United States and bezafibrate and ciprofibrate in Europe. Their lipid lowering effects are found to decrease CVS risk , progression of atherosclerosis and metabolic syndrome, macrovascular and microvascular diabetic complications like stroke, myocardial infarction, peripheral vascular disease and diabetic retinopathy .Various clinical trials like VA-HIT trial (Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial) , FIELD trail. (the Fenofibrate Intervention and Event Lowering in Diabetes) Helsinki Heart Study, ACCORD -Lipid trial (The lipid component of the Action to Control Cardiovascular Risk in Diabetes trial ) and BIP (Bezafibrate Infarction Prevention Study) trial and angiography trials, like LOCAT (Lopid Coronary Angiography Trial) and BECLAIT (Bezafibrate Coronary Atherosclerosis Intervention Trial) demonstrated the beneficial effects of gemfibrozil and fenofibrate. Their mechanism of action remained obscure for three decades, ie till 1990s, when their mode of action was found. The Mechanism of action of fibrates include limitation of substrate availability for triglyceride synthesis in the liver, promotion of the action of lipoprotein lipase, (LPL) modulation of low density lipoprotein receptor/ligand interaction and stimulation of reverse cholesterol transport The biochemical and molecular mechanisms involving the various enzymes like LCAT (Lecithin-cholesterol acyl transferase) and CYP7A1 etc. (cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) ) , transporters like ABC , CETP (ATP-binding cassette transporter, Cholesterol ester binding protein) and NTCP, OATP (Na+-dependent taurocholate transporter / organic anion transporters) . These are the.) and nuclear factors like LXR, PPAR alfa etc. (liver orphan receptor α , and peroxisome proliferative nuclear factor) , in relation to the mechanisms of action of fibrates are discussed . Areas of current interests in literature are briefed.

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Impact of Low-Fat and Full-Fat Dairy Intake on Cardiovascular Disease Risk Factors: A Randomized Controlled Trial

Current Developments in Nutrition ◽

10.1093/cdn/nzaa046_063 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 563-563

Author(s):

Kelsey Schmidt ◽

Gail Cromer ◽

Maggie Burhans ◽

Jessica Kuzma ◽

Derek Hagman ◽

...

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Density Lipoprotein ◽

Cvd Risk Factors ◽

Low Fat ◽

Cvd Risk ◽

Intervention Effect ◽

Dairy Foods ◽

Dairy Fat ◽

The Metabolic Syndrome

Abstract Objectives Dairy fat has been hypothesized to promote cardiovascular disease (CVD) due to its high saturated fat content, contributing to recommendations to consume low-fat dairy foods. However, emerging evidence indicates that dairy fat does not negatively impact CVD risk, particularly when consumed in foods with a complex matrix. Though, few trials have directly compared the effect of low-fat versus full-fat dairy foods. Therefore, we aimed to test the effects of diets rich in low-fat or full-fat dairy on CVD risk factors, compared to a limited dairy diet. We hypothesized that diets rich in dairy would not impact CVD risk factors. Methods Seventy-two participants with the metabolic syndrome completed a 4-week wash-in period; limiting their dairy intake to ≤ 3 servings of skim milk per week. Participants were then randomized to either continue the limited dairy diet or switch to a diet containing 3.3 servings per day of either low-fat or full-fat milk, yogurt, and cheese for 12-weeks. The plasma lipid profile and blood pressure were assessed before and after the intervention period. Results In the per protocol analysis (n = 66), there was no intervention effect on fasting plasma total-, low-density lipoprotein-, and high-density lipoprotein-cholesterol, triglycerides, free fatty acids, or cholesterol content in 38 isolated lipoprotein fractions (p > 0.1 for all variables). There was also no intervention effect on diastolic blood pressure. There was a significant difference among the diet interventions for systolic blood pressure (P = 0.045), with a trend for a decrease in the low-fat dairy diet compared to the limited dairy diet in post hoc testing after adjustment for multiple testing. Conclusions In individuals with the metabolic syndrome, consuming 3.3 servings of dairy per day, regardless of fat content, did not affect blood lipids and modestly improved blood pressure compared to a diet virtually free of dairy. This provides further evidence that dairy fat, when consumed as part of complex whole foods, does not significantly impact CVD risk factors. Funding Sources This work was supported by the National Dairy Council, Dairy Farmers of Canada, the Dutch Dairy Association, Dairy Australia, and the French Dairy Interbranch Organization.

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Intestine-Specific Overexpression of LDLR Enhances Cholesterol Excretion and Induces Metabolic Changes in Male Mice

Endocrinology ◽

10.1210/en.2018-00098 ◽

2018 ◽

Vol 160 (4) ◽

pp. 744-758 ◽

Cited By ~ 1

Author(s):

Luca Meoli ◽

Danny Ben-Zvi ◽

Courtney Panciotti ◽

Stephanie Kvas ◽

Palmenia Pizarro ◽

...

Keyword(s):

Molecular Mechanisms ◽

Cholesterol Metabolism ◽

Treatment Options ◽

Density Lipoprotein ◽

Cholesterol Absorption ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Metabolic Effects ◽

Cholesterol Levels ◽

Cholesterol Excretion

Abstract Roux-en-Y gastric bypass (RYGB) surgery is one of the most effective treatment options for severe obesity and related comorbidities, including hyperlipidemia, a well-established risk factor of cardiovascular diseases. Elucidating the molecular mechanisms underlying the beneficial effects of RYGB may facilitate development of equally effective, but less invasive, treatments. Recent studies have revealed that RYGB increases low-density lipoprotein receptor (LDLR) expression in the intestine of rodents. Therefore, in this study we first examined the effects of RYGB on intestinal cholesterol metabolism in human patients, and we show that they also exhibit profound changes and increased LDLR expression. We then hypothesized that the upregulation of intestinal LDLR may be sufficient to decrease circulating cholesterol levels. To this end, we generated and studied mice that overexpress human LDLR specifically in the intestine. This perturbation significantly affected intestinal metabolism, augmented fecal cholesterol excretion, and induced a reciprocal suppression of the machinery related to luminal cholesterol absorption and bile acid synthesis. Circulating cholesterol levels were significantly decreased and, remarkably, several other metabolic effects were similar to those observed in RYGB-treated rodents and patients, including improved glucose metabolism. These data highlight the importance of intestinal cholesterol metabolism for the beneficial metabolic effects of RYGB and for the treatment of hyperlipidemia.

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Bile acids and the metabolic syndrome

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/0004563218817798 ◽

2019 ◽

Vol 56 (3) ◽

pp. 326-337 ◽

Cited By ~ 6

Author(s):

Emma Rose McGlone ◽

Stephen R Bloom

Keyword(s):

Diabetes Mellitus ◽

Bile Acid ◽

Bile Acids ◽

Fatty Liver Disease ◽

Metabolic Diseases ◽

Metabolic Effects ◽

Alcoholic Fatty Liver ◽

The Metabolic Syndrome ◽

Alcoholic Fatty Liver Disease

Bile acids have important roles in the regulation of lipid, glucose and energy metabolism. Metabolic diseases linked to obesity, including type 2 diabetes mellitus and non-alcoholic fatty liver disease, are associated with dysregulation of bile acid homeostasis. Here, the basic chemistry and regulation of bile acids as well as their metabolic effects will be reviewed. Changes in circulating bile acids associated with obesity and related diseases will be reviewed. Finally, pharmaceutical manipulation of bile acid homeostasis as therapy for metabolic diseases will be outlined.

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The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation

AJP Cell Physiology ◽

10.1152/ajpcell.00125.2016 ◽

2016 ◽

Vol 311 (3) ◽

pp. C392-C403 ◽

Cited By ~ 57

Author(s):

Philippe A. Bilodeau ◽

Erin S. Coyne ◽

Simon S. Wing

Keyword(s):

Signaling Pathways ◽

Muscle Atrophy ◽

Molecular Mechanisms ◽

Muscle Wasting ◽

Clinical Problem ◽

Ubiquitin Proteasome System ◽

Mechanisms Of Action ◽

Loss Of Function ◽

Critical Determinant ◽

Ubiquitin Proteasome

Muscle atrophy complicates many diseases as well as aging, and its presence predicts both decreased quality of life and survival. Much work has been conducted to define the molecular mechanisms involved in maintaining protein homeostasis in muscle. To date, the ubiquitin proteasome system (UPS) has been shown to play an important role in mediating muscle wasting. In this review, we have collated the enzymes in the UPS whose roles in muscle wasting have been confirmed through loss-of-function studies. We have integrated information on their mechanisms of action to create a model of how they work together to produce muscle atrophy. These enzymes are involved in promoting myofibrillar disassembly and degradation, activation of autophagy, inhibition of myogenesis as well as in modulating the signaling pathways that control these processes. Many anabolic and catabolic signaling pathways are involved in regulating these UPS genes, but none appear to coordinately regulate a large number of these genes. A number of catabolic signaling pathways appear to instead function by inhibition of the insulin/IGF-I/protein kinase B anabolic pathway. This pathway is a critical determinant of muscle mass, since it can suppress key ubiquitin ligases and autophagy, activate protein synthesis, and promote myogenesis through its downstream mediators such as forkhead box O, mammalian target of rapamycin, and GSK3β, respectively. Although much progress has been made, a more complete inventory of the UPS genes involved in mediating muscle atrophy, their mechanisms of action, and their regulation will be useful for identifying novel therapeutic approaches to this important clinical problem.

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The new angiotensin II receptor blocker Edarbi® as part of the pathogenetic treatment of arterial hypertension in patients with metabolic disorders

Systemic Hypertension ◽

10.26442/sg29582 ◽

2017 ◽

Vol 14 (3) ◽

pp. 28-35

Author(s):

I Ye Chazova ◽

Yu V Zhernakova ◽

N V Blinova ◽

A N Rogoza

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Angiotensin Receptor Blockers ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Metabolic Effects ◽

Receptor Blocker ◽

Angiotensin Ii Receptor Blocker ◽

Angiotensin Receptor ◽

Stage 1

Relevance. Recently, the proportion of angiotensin receptor blockers has significantly increased among prescribed antihypertensive drugs. High organoprotective properties, additional metabolic effects and tolerability comparable to placebo make them the drugs of choice, especially in patients with stage 1 and stage 2 hypertension having low adherence to antihypertensive therapy, but already burdened by additional metabolic risk factors. Purpose of the study - study of the antihypertensive efficacy of the angiotensin receptor blocker azilsartan medoxomil (Edarbi®), its effect on cardiometabolic risk factors and damage of target organs in patients with stage 2 hypertension. Materials and methods. The study included 32 patients (mean age 47.32±8.4 years), 19 men and 13 women with stage 2 hypertension. All patients were evaluated for clinical blood pressure (BP), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, creatinine, glucose level in a carbohydrate tolerance test, 24-hour blood pressure monitoring, central aortic systolic pressure, сarotid-femoral pulse wave velocity and intima-media thickness was determined initially and after 6 months of therapy. Results. During taking Edarbi® 82% of patients with stage 1 and stage 2 hypertension and metabolic syndrome reached the target level of BP, which was accompanied by a significant improvement in diastolic function of the left ventricle in 56% of patients. Already in the first 6 months the treatment reduced arterial stiffness and improved metabolic control

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Risk factors of arterial hypertension in patients with nonalcoholic fatty liver disease.

Clinical Medicine (Russian Journal) ◽

10.18821/0023-2149-2018-96-6-537-543 ◽

2018 ◽

Vol 96 (6) ◽

pp. 537-543

Author(s):

E. V. Sevostyanova ◽

V. Ya. Polyakov ◽

Yu. A. Nikolaev ◽

I. M. Mitrofanov

Keyword(s):

Risk Factors ◽

Liver Disease ◽

Cardiovascular Diseases ◽

Arterial Hypertension ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Density Lipoprotein ◽

Modifiable Risk Factors ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Purpose of the study. To study frequency of occurrence and values ofparameters of the main risk factors for cardiovascular diseases in patients with hypertension in combination with non-alcoholic fatty liver disease. Material and methods. The analysis of 17,202 medical cards of patients (6,730 men, 10,472 women), which were examined and treated in the clinic of the Scientific Research Institute of Experimental and Clinical Medicine, Novosibirsk, was carried out. Of them - 3,087patients with arterial hypertension (AH), combined with non-alcoholic fatty liver disease (NAFLD) (main group); 13,384 patients with isolated arterial hypertension; 731 patients with NAFLD (comparison groups). According to the clinical and laboratory examination, the following risk factors were assessed: high blood pressure, obesity, elevated blood levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, uric acid, a low content of high-density lipoprotein cholesterol in the blood. Results. In patients with hypertension combined with NAFLD, in comparison with patients with isolated diseases, an increase in the values of the indices determining the main modifiable risk factors for cardiovascular diseases (hypertension, obesity, hyperglycemia, hypercholesterolemia, hyperuricemia) was revealed. Similar changes were detected in both men and women. Conclusion. An important role of risk factors for cardiovascular diseases, which together represent the clinical manifestations of the metabolic syndrome, has been identified in the development of comorbid pathology - AH and NAFLD. The data obtained indicate the need for differentiated, personified prevention and treatment of patients with this comorbid pathology with mandatory identification and correction of modifiable risk factors for cardiovascular diseases.

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The Association Between Risk Factors And Ultrasound-Based Grades Of Non-Alcoholic Fatty Liver Disease In Type-2 Diabetes Patients

Jurnal Widya Medika ◽

10.33508/jwm.v5i1.1998 ◽

2019 ◽

Vol 5 (1) ◽

pp. 47-59

Author(s):

FX Himawan Haryanto Jong ◽

Prettysun Ang Mellow

Keyword(s):

Risk Factors ◽

Type 2 Diabetes ◽

Body Mass Index ◽

Liver Disease ◽

Total Cholesterol ◽

Fatty Liver Disease ◽

Density Lipoprotein ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Background: Non-alcoholic fatty liver disease (NAFLD) has become more common as the cause of cirrhosis and liver cancer. The liver disease is highly prevalent in people with type-2 diabetes. Indonesia is not spared from the global epidemic of type-2 diabetes. The ultrasound examination is clinically easy-to-use, economical and non-invasive as a tool to detect NAFLD, compared to the gold standard, liver biopsy. To date, there has been no study in Indonesia to link risk factors and ultrasound-based severity grading of NAFLD. Aim: To understand the association between risk factors and ultrasound-based grades of NAFLD in patients with type-2 diabetes. Method: The present study was an observational study with a cross-sectional design (May-October 2018) that involved 82 type-2 diabetes outpatients of the internal medicine clinic in the Gotong Royong Hospital (Surabaya, Indonesia). The risk factors assessed were gender, age, diabetes duration, obesity (anthropometric measurement: body mass index/ BMI, waist circumference and waist-to-hip ratio), glycemic control (hemoglobin A1c/ HbA1c level) and dyslipidemia (lipid profile: total cholesterol, low-density lipoprotein/ LDL, high-density lipoprotein/ HDL and triglyceride). The ultrasound-based grades of NAFLD consisted of grade 0 (no NAFLD), grade 1 (increased liver echogenicity with normal images of intrahepatic vessel lines and diaphragm), grade 2 (blurred image of intrahepatic vessel lines) and grade 3 (blurred images of intrahepatic vessel lines and diaphragm). Statistical p-value was significant at ≤ 0.05. Results: Seventy-eight subjects (95,1%) had NAFLD. The ultrasound-based NAFLD grades were significantly different across age groups (Kruskal-Wallis) but the Spearman’s rank correlation test result was not significant. Body mass index and total cholesterol were positively correlated (r = 0.390 and 0.237, respectively) with the NAFLD grades. Conclusion: Higher BMI and total cholesterol are associated with increased ultrasound-based NAFLD grades.

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