Medicines for Obesity: Appraisal of Clinical Studies with Grading of Recommendations, Assessment, Development, and Evaluation Tool.

We evaluated the quality of evidence from phase III/IV clinical trials of drugs against obesity using the principles of Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. Our systematic review evaluates the quality of clinical evidence from existing clinical trials and not the pharmacological efficacy of anti-obesity therapies. A literature search using select keywords in separate was performed in PubMed and ClinicalTrials.

Adverse Drug Reactions in Relation to Clozapine Plasma Levels: A Systematic Review.

Clozapine is the gold standard for treatment-resistant schizophrenia. Serious and even life-threatening adverse effects, mostly granulocytopenia, myocarditis, and constipation, are of great clinical concern and constitute a barrier to prescribing clozapine, thus depriving many eligible patients of a lifesaving treatment option. Interestingly, clozapine presents variable pharmacokinetics affected by numerous parameters, leading to significant inter- and intra-individual variation.

High density lipoprotein in atherosclerosis and coronary heart disease: Where do we stand today?

Epidemiological studies during the last five years suggest that a relation between high density lipoprotein cholesterol (HDL-C) levels and the risk for cardiovascular disease (CVD) does exist but follows rather a "U-shaped" curve with an optimal range of HDL-C concentration between 40 and 70 mg/dl for men and 50-70 mg/dl for women. Moreover, as research in the field of lipoproteins progresses it becomes increasingly apparent that HDL particles possess different attributes and depending on their structural and functional characteristics, they may be "antiatherogenic" or "proatherogenic". In light of this information, it is highly doubtful that the choice of experimental drugs and the design of respective clinical trials that put the HDL-C raising hypothesis at test, were the most suitable.

Tissue-specific functional interaction between apolipoproteins A1 and E in cold-induced adipose organ mitochondrial energy metabolism.

White (WAT) and brown (BAT) adipose tissue, the two main types of adipose organ, are responsible for lipid storage and non-shivering thermogenesis, respectively. Thermogenesis is a process mediated by mitochondrial uncoupling protein 1 (UCP1) which uncouples oxidative phosphorylation from ATP production, leading to the conversion of free fatty acids to heat. This process can be triggered by exposure to low ambient temperatures, caloric excess, and the immune system.

Isoform and tissue dependent impact of apolipoprotein E on adipose tissue metabolic activation: The role of apolipoprotein A1.

Adipose organ is made of white (WAT) and brown (BAT) adipose tissue which are primarily responsible for lipid storage and energy production (heat and ATP) respectively. Metabolic activation of WAT may ascribe to this tissue characteristics of BAT, namely non-shivering thermogenesis and ATP production. Recent data indicate that apolipoproteins E (APOE) and A1 (APOA1) regulate WAT mitochondrial metabolic activation.

Impact of apolipoprotein A1- or lecithin:cholesterol acyltransferase-deficiency on white adipose tissue metabolic activity and glucose homeostasis in mice.

High density lipoprotein (HDL) has attracted the attention of biomedical community due to its well-documented role in atheroprotection. HDL has also been recently implicated in the regulation of islets of Langerhans secretory function and in the etiology of peripheral insulin sensitivity. Indeed, data from numerous studies strongly indicate that the functions of pancreatic β-cells, skeletal muscles and adipose tissue could benefit from improved HDL functionality.

Western-type diet differentially modulates osteoblast, osteoclast, and lipoblast differentiation and activation in a background of APOE deficiency.

During the past few years, considerable evidence has uncovered a strong relationship between fat and bone metabolism. Consequently, alterations in plasma lipid metabolic pathways strongly affect bone mass and quality. We recently showed that the deficiency of apolipoprotein A-1 (APOA1), a central regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, results in reduced bone mass in C57BL/6 mice.

Pharmacological Management of Dyslipidemia in Atherosclerosis: Limitations, Challenges, and New Therapeutic Opportunities.

Clinical and epidemiological studies during the last 7 decades indicated that elevated low-density lipoprotein cholesterol (LDL-C) levels and reduced high-density lipoprotein cholesterol (HDL-C) levels correlate with the pathogenesis and progression of atherosclerotic lesions in the arterial wall. This observation led to the development of LDL-C-lowering drugs for the prevention and treatment of atherosclerosis, some with greater success than others. However, a body of recent clinical evidence shows that a substantial residual cardiovascular risk exists even at very low levels of LDL-C, suggesting that new therapeutic modalities are still needed for reduction of atherosclerosis morbidity and mortality.

Apolipoprotein E in diet-induced obesity: a paradigm shift from conventional perception.

Apolipoprotein E (APOE) is a major protein component of peripheral and brain lipoprotein transport systems. APOE in peripheral circulation does not cross blood brain barrier or blood cerebrospinal fluid barrier. As a result, peripheral APOE expression does not affect brain APOE levels and vice versa.

Strain-specific Differences in the Effects of Lymphocytes on the Development of Insulin Resistance and Obesity in Mice.

Obesity is characterized as a chronic, low-grade inflammatory disease owing to the infiltration of the adipose tissue by macrophages. Although the role of macrophages in this process is well established, the role of lymphocytes in the development of obesity and metabolism remains less well defined. In the current study, we fed WT and Rag1-/- male mice, of C57BL/6J and BALB/c backgrounds, high-fat diet (HFD) or normal diet for 15 wk.

Site-specific effects of apolipoprotein E expression on diet-induced obesity and white adipose tissue metabolic activation.

Apolipoprotein E (APOE) has been strongly implicated in the development of diet induced obesity. In the present study, we investigated the contribution of brain and peripherally expressed human apolipoprotein E3 (APOE3), the most common human isoform, to diet induced obesity. In our studies APOE3 knock-in (Apoe3), Apoe-deficient (apoe) and brain-specific expressing APOE3 (Apoe3) mice were fed western-type diet for 12week and biochemical analyses were performed.

Distinct Roles of Apolipoproteins A1 and E in the Modulation of High-Density Lipoprotein Composition and Function.

In addition to high-density lipoprotein cholesterol (HDL-C) levels, HDL quality also appears to be very important for atheroprotection. Analysis of various clinical paradigms suggests that the lipid and apolipoprotein composition of HDL defines its size, shape, and functions and may determine its beneficial effects on human health. Previously, we reported that like apolipoprotein A-I (Apoa1), apolipoprotein E (Apoe) is also capable of promoting the de novo biogenesis of HDL with the participation of ATP binding cassette A lipid transporter member 1 (Abca1) and plasma enzyme lecithin:cholesterol acyltransferase (Lcat), in a manner independent of a functional Apoa1.

Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice.

Imbalances in lipid metabolism affect bone homeostasis, altering bone mass and quality. A link between bone mass and high-density lipoprotein (HDL) has been proposed. Indeed, it has been recently shown that absence of the HDL receptor scavenger receptor class B type I (SR-B1) causes dense bone mediated by increased adrenocorticotropic hormone (ACTH).

Advances in high-density lipoprotein physiology: surprises, overturns, and promises.

Emerging evidence strongly supports that changes in the HDL metabolic pathway, which result in changes in HDL proteome and function, appear to have a causative impact on a number of metabolic disorders. Here, we provide a critical review of the most recent and novel findings correlating HDL properties and functionality with various pathophysiological processes and disease states, such as obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, inflammation and sepsis, bone and obstructive pulmonary diseases, and brain disorders.

Deficiency in apolipoprotein A-I ablates the pharmacological effects of metformin on plasma glucose homeostasis and hepatic lipid deposition.

Recently, we showed that deficiency in apolipoprotein A-I (ApoA-I) sensitizes mice to diet-induced obesity, glucose intolerance and NAFLD. Here we investigated the potential involvement of ApoA-I in the pharmacological effects of metformin on glucose intolerance and NAFLD development. Groups of apoa1-deficient (apoa1(-/-)) and C57BL/6 mice fed western-type diet were either treated with a daily dose of 300 mg/kg metformin for 18 weeks or left untreated for the same period.

Scavenger Receptor Class B Type I Regulates Plasma Apolipoprotein E Levels and Dietary Lipid Deposition to the Liver.

Scavenger receptor class B type I (SR-BI) is primarily responsible for the selective uptake of cholesteryl esters (CE) of high-density lipoprotein (HDL) by the liver and other tissues. In the present study, we show that SR-BI-deficient (scarb1(-/-)) mice are resistant to diet-induced obesity, hepatic lipid deposition, and glucose intolerance after 24 weeks of being fed a western-type diet. No differences in energy expenditure or mitochondrial function could account for the observed phenotype.

Lack of LCAT reduces the LPS-neutralizing capacity of HDL and enhances LPS-induced inflammation in mice.

HDL has important immunomodulatory properties, including the attenuation of lipopolysaccharide (LPS)-induced inflammatory response. As lecithin-cholesterol acyltransferase (LCAT) is a critical enzyme in the maturation of HDL we investigated whether LCAT-deficient (Lcat(-/-)) mice present an increased LPS-induced inflammatory response. LPS (100μg/kg body weight)-induced cytokine response in Lcat(-/-) mice was markedly enhanced and prolonged compared to wild-type mice.

HDL quality and functionality: what can proteins and genes predict?

Epidemiological and clinical studies have over the years established that dyslipidemia constitutes the main risk factor for atherosclerosis. The inverse correlation between HDL cholesterol (HDL-C) levels and coronary heart disease morbidity and mortality identified HDL-C as an alternative pharmacological target to LDL-C and a potential anti-atherosclerosis marker. However, more recent data reinforced the principle of 'HDL quality' in atherosclerosis that refers to the functionality of HDL particle, as defined by its protein and lipid content, rather than HDL-C levels in plasma.

Perturbations in the HDL metabolic pathway predispose to the development of osteoarthritis in mice following long-term exposure to western-type diet.

Objective: Recent data suggest that obesity and related metabolic aberrations are associated with osteoarthritis (OA) development, a phenomenon that is attributed at least in part to the consumption of lipid-rich diets. To date, the molecular mechanisms that govern the lipid-OA connection remain largely unknown. Given the important role of high-density lipoprotein (HDL) in plasma and tissue lipid metabolism, the main purpose of the present study was to investigate the role of HDL metabolism in the pathobiology of OA.

Lecithin/cholesterol acyltransferase modulates diet-induced hepatic deposition of triglycerides in mice.

Lecithin/cholesterol acyltransferase (LCAT) is responsible for the esterification of the free cholesterol of plasma lipoproteins. Here, we investigated the involvement of LCAT in mechanisms associated with diet-induced hepatic triglyceride accumulation in mice. LCAT-deficient (LCAT(-/-)) and control C57BL/6 mice were placed on a Western-type diet (17.

Apolipoprotein A-I modulates processes associated with diet-induced nonalcoholic fatty liver disease in mice.

Apolipoprotein A-I (apoA-I) is the main protein of high-density lipoprotein (HDL). We investigated the involvement of apoA-I in diet-induced accumulation of triglycerides in hepatocytes and its potential role in the treatment of nonalcoholic fatty liver disease (NAFLD). ApoA-I-deficient (apoA-I(-/-)) mice showed increased diet-induced hepatic triglyceride deposition and disturbed hepatic histology while they exhibited reduced glucose tolerance and insulin sensitivity.

Deficiency in apolipoprotein E has a protective effect on diet-induced nonalcoholic fatty liver disease in mice.

Apolipoprotein E (apoE) mediates the efficient catabolism of the chylomicron remnants very low-density lipoprotein and low-density lipoprotein from the circulation, and the de novo biogenesis of high-density lipoprotein. Lipid-bound apoE is the natural ligand for the low-density lipoprotein receptor (LDLr), LDLr-related protein 1 and other scavenger receptors. Recently, we have established that deficiency in apoE renders mice resistant to diet-induced obesity.

Mechanisms of obesity and related pathologies: role of apolipoprotein E in the development of obesity.

Apolipoprotein E is a polymorphic glycoprotein in humans with a molecular mass of 34.5 kDa. It is a component of chylomicron remnants, very low density lipoprotein, low density lipoprotein and high density lipoprotein, and is primarily responsible for maintaining plasma lipid homeostasis.