Apolipoprotein C-I plays a role in the pathogenesis of glomerulosclerosis.

Diabetic nephropathy is the leading cause of end-stage renal disease. Diabetic patients have increased plasma concentrations of apolipoprotein C-I (apoCI), and meta-analyses found that a polymorphism in APOC1 is associated with an increased risk of developing nephropathy. To investigate whether overexpressing apoCI contributes to the development of kidney damage, we studied renal tissue and peritoneal macrophages from APOC1 transgenic (APOC1-tg) mice and wild-type littermates.

HDL functionality in South Asians as compared to white Caucasians.

Background And Aims: South Asians have an exceptionally high risk of developing cardiovascular disease compared to white Caucasians. A contributing factor might be dysfunction of high density lipoprotein (HDL). We aimed to compare HDL function in different age groups of both ethnicities.

Anacetrapib reduces (V)LDL cholesterol by inhibition of CETP activity and reduction of plasma PCSK9.

Recently, we showed in APOE*3-Leiden cholesteryl ester transfer protein (E3L.CETP) mice that anacetrapib attenuated atherosclerosis development by reducing (V)LDL cholesterol [(V)LDL-C] rather than by raising HDL cholesterol. Here, we investigated the mechanism by which anacetrapib reduces (V)LDL-C and whether this effect was dependent on the inhibition of CETP.

Salsalate attenuates diet induced non-alcoholic steatohepatitis in mice by decreasing lipogenic and inflammatory processes.

Background And Purpose: Salsalate (salicylsalicylic acid) is an anti-inflammatory drug that was recently found to exert beneficial metabolic effects on glucose and lipid metabolism. Although its utility in the prevention and management of a wide range of vascular disorders, including type 2 diabetes and metabolic syndrome has been suggested before, the potential of salsalate to protect against non-alcoholic steatohepatitis (NASH) remains unclear. The aim of the present study was therefore to ascertain the effects of salsalate on the development of NASH.

Plasma cholesteryl ester transfer protein is predominantly derived from Kupffer cells.

Unlabelled: The role of Kupffer cells (KCs) in the pathophysiology of the liver has been firmly established. Nevertheless, KCs have been underexplored as a target for diagnosis and treatment of liver diseases owing to the lack of noninvasive diagnostic tests. We addressed the hypothesis that cholesteryl ester transfer protein (CETP) is mainly derived from KCs and may predict KC content.

Establishment of a general NAFLD scoring system for rodent models and comparison to human liver pathology.

Background And Aims: The recently developed histological scoring system for non-alcoholic fatty liver disease (NAFLD) by the NASH Clinical Research Network (NASH-CRN) has been widely used in clinical settings, but is increasingly employed in preclinical research as well. However, it has not been systematically analyzed whether the human scoring system can directly be converted to preclinical rodent models. To analyze this, we systematically compared human NAFLD liver pathology, using human liver biopsies, with liver pathology of several NAFLD mouse models.

Brown adipose tissue takes up plasma triglycerides mostly after lipolysis.

Brown adipose tissue (BAT) produces heat by burning TGs that are stored within intracellular lipid droplets and need to be replenished by the uptake of TG-derived FA from plasma. It is currently unclear whether BAT takes up FA via uptake of TG-rich lipoproteins (TRLs), after lipolysis-mediated liberation of FA, or via a combination of both. Therefore, we generated glycerol tri[(3)H]oleate and [(14)C]cholesteryl oleate double-labeled TRL-mimicking particles with an average diameter of 45, 80, and 150 nm (representing small VLDL to chylomicrons) and injected these intravenously into male C57Bl/6J mice.

Hematopoietic α7 nicotinic acetylcholine receptor deficiency increases inflammation and platelet activation status, but does not aggravate atherosclerosis.

Background: The autonomic nervous system attenuates inflammation through activation of the α7 nicotinic acetylcholine receptor (α7nAChR), a pathway termed the cholinergic anti-inflammatory reflex. Interestingly, α7nAChR is expressed on immune cells and platelets, both of which play a crucial role in the development of atherosclerosis.

Objective: To investigate the role of hematopoietic α7nAChR in inflammation and platelet function in atherosclerotic ldlr(-/-) mice and to identify its consequences for atherosclerotic lesion development.

Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity.

The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis, and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintenance of weight loss and reduction of dyslipidemia in experimental and human obesity. The molecular mechanism by which CB1R blockade reverses dyslipidemia in obesity has not yet been clarified.

Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin.

Background: The residual risk that remains after statin treatment supports the addition of other LDL-C-lowering agents and has stimulated the search for secondary treatment targets. Epidemiological studies propose HDL-C as a possible candidate. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from atheroprotective HDL to atherogenic (V)LDL.

Inhibition of the central melanocortin system decreases brown adipose tissue activity.

The melanocortin system is an important regulator of energy balance, and melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity. We investigated whether the relationship between melanocortin system activity and energy expenditure (EE) is mediated by brown adipose tissue (BAT) activity. Therefore, female APOE*3-Leiden.

Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and type 2 diabetes susceptibility.

Aims: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic β-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to type 2 diabetes in humans.

Methods: Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for type 2 diabetes susceptibility in up to 25 000 people (8148 with type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort.

Brown adipose tissue volume in healthy lean south Asian adults compared with white Caucasians: a prospective, case-controlled observational study.

Background: Individuals of south Asian origin have a very high risk of developing type 2 diabetes compared with white Caucasians. We aimed to assess volume and activity of brown adipose tissue (BAT), which is thought to have a role in energy metabolism by combusting fatty acids and glucose to produce heat and might contribute to the difference in incidence of type 2 diabetes between ethnic groups.

Methods: We enrolled Dutch nationals with south Asian ancestry and matched Caucasian participants at The Rijnland Hospital (Leiderdorp, Netherlands).

Metabolically induced liver inflammation leads to NASH and differs from LPS- or IL-1β-induced chronic inflammation.

The nature of the chronic inflammatory component that drives the development of non-alcoholic steatohepatitis (NASH) is unclear and possible inflammatory triggers have not been investigated systematically. We examined the effect of non-metabolic triggers (lipopolysaccharide (LPS), interleukin-1β (IL-1β), administered by slow-release minipumps) and metabolic dietary triggers (carbohydrate, cholesterol) of inflammation on the progression of bland liver steatosis (BS) to NASH. Transgenic APOE3*Leiden.

Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration.

Background And Purpose: The aetiology of inflammation in the liver and vessel wall, leading to non-alcoholic steatohepatitis (NASH) and atherosclerosis, respectively, shares common mechanisms including macrophage infiltration. To treat both disorders simultaneously, it is highly important to tackle the inflammatory status. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces hepatic steatosis and has been suggested to reduce atherosclerosis; however, its effects on liver inflammation are underexplored.

Long-term niacin treatment induces insulin resistance and adrenergic responsiveness in adipocytes by adaptive downregulation of phosphodiesterase 3B.

The lipid-lowering effect of niacin has been attributed to the inhibition of cAMP production in adipocytes, thereby inhibiting intracellular lipolysis and release of nonesterified fatty acids (NEFA) to the circulation. However, long-term niacin treatment leads to a normalization of plasma NEFA levels and induces insulin resistance, for which the underlying mechanisms are poorly understood. The current study addressed the effects of long-term niacin treatment on insulin-mediated inhibition of adipocyte lipolysis and focused on the regulation of cAMP levels.

APOE*3Leiden.CETP transgenic mice as model for pharmaceutical treatment of the metabolic syndrome.

Aims: This study aimed to investigate systematically (i) the appropriate dietary conditions to induce the features of the MetS in APOE*3Leiden.humanCholesteryl Ester Transfer Protein (E3L.CETP) mice and (ii) whether the response of this model to different antidiabetic and hypolipidemic drugs is similar as in humans.

Glucocorticoid excess induces long-lasting changes in body composition in male C57Bl/6J mice only with high-fat diet.

Glucocorticoid (GC) overexposure period as observed in Cushing's syndrome (CS) is associated with the metabolic syndrome and cardiovascular disease, which persist after long-term correction of GC excess. We performed a mouse study to identify factors that modulate metabolic recovery from a GC overexposure period. Male C57Bl/6J mice, fed a low-fat diet (LFD) or a high-fat diet (HFD), received corticosterone (CORT) (50 μg/mL) or vehicle in the drinking water for 4 weeks, followed by an 8-week washout period.

The effect of PPE-induced emphysema and chronic LPS-induced pulmonary inflammation on atherosclerosis development in APOE*3-LEIDEN mice.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary inflammation, airways obstruction and emphysema, and is a risk factor for cardiovascular disease (CVD). However, the contribution of these individual COPD components to this increased risk is unknown. Therefore, the aim of this study was to determine the contribution of emphysema in the presence or absence of pulmonary inflammation to the increased risk of CVD, using a mouse model for atherosclerosis.

Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies.

Important players in triglyceride (TG) metabolism include the liver (production), white adipose tissue (WAT) (storage), heart and skeletal muscle (combustion to generate ATP), and brown adipose tissue (BAT) (combustion toward heat), the collective action of which determine plasma TG levels. Interestingly, recent evidence points to a prominent role of the hypothalamus in TG metabolism through innervating the liver, WAT, and BAT mainly via sympathetic branches of the autonomic nervous system. Here, we review the recent findings in the area of sympathetic control of TG metabolism.

Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice.

Metformin is the first-line drug for the treatment of type 2 diabetes. Besides its well-characterized antihyperglycemic properties, metformin also lowers plasma VLDL triglyceride (TG). In this study, we investigated the underlying mechanisms in APOE*3-Leiden.

BMP7 activates brown adipose tissue and reduces diet-induced obesity only at subthermoneutrality.

Background/aims: Brown adipose tissue (BAT) dissipates energy stored in triglycerides as heat via the uncoupling protein UCP-1 and is a promising target to combat hyperlipidemia and obesity. BAT is densely innervated by the sympathetic nervous system, which increases BAT differentiation and activity upon cold exposure. Recently, Bone Morphogenetic Protein 7 (BMP7) was identified as an inducer of BAT differentiation.

The insulin sensitizing effect of topiramate involves KATP channel activation in the central nervous system.

Background And Purpose: Topiramate improves insulin sensitivity, in addition to its antiepileptic action. However, the underlying mechanism is unknown. Therefore, the present study was aimed at investigating the mechanism of the insulin-sensitizing effect of topiramate both in vivo and in vitro.

Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol.

Objective: Niacin potently lowers triglycerides, mildly decreases LDL-cholesterol, and largely increases HDL-cholesterol. Despite evidence for an atheroprotective effect of niacin from previous small clinical studies, the large outcome trials, AIM-HIGH and HPS2-THRIVE did not reveal additional beneficial effects of niacin (alone or in combination with laropiprant) on top of statin treatment. We aimed to address this apparent discrepancy by investigating the effects of niacin without and with simvastatin on atherosclerosis development and determine the underlying mechanisms, in APOE*3Leiden.