Increased Plasma Triglyceride Concentrations Research Articles

The effect of N-arachidonoylethanolamide administration on energy and fat metabolism of early lactating dairy cows

The aim of the study was to investigate the effect of N-arachidonoylethanolamide (AEA), an endocannabinoid with orexigenic characteristics, on plasma endocannabinoid concentrations, feed intake, energy balance, lipomobilisation, and hepatic lipid metabolism of early-lactating dairy cows. The experiment involved 10 pairs of Holstein half-sibling cows (end of 2nd–3rd pregnancy). Half-sibs of each pair were randomly assigned to either AEA (n = 10) or control (CON) group (n = 10). From day 1 to 30 postpartum, the AEA group received 5 intraperitoneal injections per week of 3 µg/kg body weight AEA and the CON group 0.9% NaCl. In week 1–3 postpartum, AEA administration had no effect on dry matter intake, body weight, or lipomobilisation, but increased plasma triglyceride concentration on d 21 p.p. and mRNA abundances of genes related to hepatic triglyceride synthesis. In week 4 postpartum, the AEA group showed reduced feed intake and whole-body carbohydrate oxidation, but increased whole-body fat oxidation and hepatic lipid accumulation, likely as a result of a counter-regulatory leptin increase. In conclusion, the present study shows a tissue-specific AEA insensitivity and may point to a leptin-controlled regulation of the ECS in early-lactation.

Neuronal ApoE4 in Alzheimer's disease and potential therapeutic targets.

The most prevalent genetic risk factor for Alzheimer's disease (AD) is Apolipoprotein E (ApoE), a gene located on chromosome 19 that encodes three alleles (e2, e3, and e4) that give rise to the ApoE subtypes E2, E3, and E4, respectively. E2 and E4 have been linked to increased plasma triglyceride concentrations and are known to play a critical role in lipoprotein metabolism. The prominent pathological features of AD mainly include senile plaques formed by amyloid β (Aβ42) aggregation and neuronal fibrous tangles (NFTs), and the deposited plaques are mainly composed of Aβ hyperphosphorylation and truncated head. In the central nervous system, the ApoE protein is primarily derived from astrocytes, but ApoE is also produced when neurons are stressed or affected by certain stress, injury, and aging conditions. ApoE4 in neurons induces Aβ and tau protein pathologies, leading to neuroinflammation and neuronal damage, impairing learning and memory functions. However, how neuronal ApoE4 mediates AD pathology remains unclear. Recent studies have shown that neuronal ApoE4 may lead to greater neurotoxicity, which increases the risk of AD development. This review focuses on the pathophysiology of neuronal ApoE4 and explains how neuronal ApoE4 mediates Aβ deposition, pathological mechanisms of tau protein hyperphosphorylation, and potential therapeutic targets.

M6A-Mediated PPARA Translational Suppression Contributes to Corticosterone-Induced Visceral Fat Deposition in Chickens.

Excess fat deposition in broilers leads to great economic losses and is harmful to consumers' health. Chronic stress in the life cycle of chickens could be an important trigger. However, the underlying mechanisms are still unclear. In this study, 30-day-old chickens were subcutaneously injected with 2 mg/kg corticosterone (CORT) twice a day for 14 days to simulate long-term stress. It was shown that chronic CORT exposure significantly increased plasma triglyceride concentrations and enlarged the adipocyte sizes in chickens. Meanwhile, chronic CORT administration significantly enlarged the adipocyte sizes, increased the protein contents of FASN and decreased HSL, ATGL, Beclin1 and PPARA protein levels. Moreover, global m6A methylations were significantly reduced and accompanied by downregulated METTL3 and YTHDF2 protein expression by CORT treatment. Interestingly, the significant differences of site-specific m6A demethylation were observed in exon7 of PPARA mRNA. Additionally, a mutation of the m6A site in the PPARA gene fused GFP and revealed that demethylated RRACH in PPARA CDS impaired protein translation in vitro. In conclusion, these results indicated that m6A-mediated PPARA translational suppression contributes to CORT-induced visceral fat deposition in chickens, which may provide a new target for the treatment of Cushing's syndrome.

Effects of dietary supplementation of different oils and conjugated linoleic acid on the reproductive and metabolic aspects of male mice.

The present study was carried out to examine first, if diets enriched with 320 g of the base diet with common dietary oils including fish oil, olive oil, hydrogenated sunflower seed (H-SFS) oil, flaxseed oil and sunflower seed oil (SFS) could induce weight gain and alter reproductive and metabolic characteristics of male mice. Second, whether the addition of conjugated linoleic acid (CLA, 10% of the diet) could ameliorate any negative effects. In this cross-sectional study, 90 four-week-old male NMRI mice were used in two consecutive experiments. A high level of dietary oils negatively affected some reproductive and metabolic characteristics of male mice (p < 0.05), specifically, sunflower seed oil enrichment resulted in higher HDL levels and apoptosis of germinal epithelial cells. An olive oil-enriched diet caused an increase in plasma triglyceride concentrations and germinal cell apoptosis, as well as a decrease in sperm concentration and perturbed spermatogenesis. When CLA was fed in conjunction with dietary oils it successfully mitigated some of the negative reproductive and metabolic characteristics. We conclude that male reproductive processes are affected by high dietary oils, even before signs of obesity are evident. Inclusion of dietary CLA may provide some benefit to offset negative effects, although further studies are required.

Thermogenesis is supported by high rates of circulatory fatty acid and triglyceride delivery in highland deer mice.

Highland native deer mice (Peromyscus maniculatus) have greater rates of lipid oxidation during maximal cold challenge in hypoxia (hypoxic cold-induced V̇O2,max) compared with their lowland conspecifics. Lipid oxidation is also increased in deer mice acclimated to simulated high altitude (cold hypoxia), regardless of altitude ancestry. The underlying lipid metabolic pathway traits responsible for sustaining maximal thermogenic demand in deer mice is currently unknown. The objective of this study was to characterize key steps in the lipid oxidation pathway in highland and lowland deer mice acclimated to control (23°C, 21 kPa O2) or cold hypoxic (5°C, 12 kPa O2) conditions. We hypothesized that capacities for lipid delivery and tissue uptake will be greater in highlanders and further increase with cold hypoxia acclimation. With the transition from rest to hypoxic cold-induced V̇O2,max, both highland and lowland deer mice showed increased plasma glycerol concentrations and fatty acid availability. Interestingly, acclimation to cold hypoxia led to increased plasma triglyceride concentrations at cold-induced V̇O2,max, but only in highlanders. Highlanders also had significantly greater delivery rates of circulatory free fatty acids and triglycerides due to higher plasma flow rates at cold-induced V̇O2,max. We found no population or acclimation differences in fatty acid translocase (FAT/CD36) abundance in the gastrocnemius or brown adipose tissue, suggesting that fatty acid uptake across membranes is not limiting during thermogenesis. Our data indicate that circulatory lipid delivery plays a major role in supporting the high thermogenic rates observed in highland versus lowland deer mice.

Imbalanced Activation of Wnt-/β-Catenin-Signaling in Liver Endothelium Alters Normal Sinusoidal Differentiation.

Endothelial wingless-related integration site (Wnt)-/β-catenin signaling is a key regulator of the tightly sealed blood–brain barrier. In the hepatic vascular niche angiokine-mediated Wnt signaling was recently identified as an important regulator of hepatocyte function, including the determination of final adult liver size, liver regeneration, and metabolic liver zonation. Within the hepatic vasculature, the liver sinusoidal endothelial cells (LSECs) are morphologically unique and functionally specialized microvascular endothelial cells (ECs). Pathological changes of LSECs are involved in chronic liver diseases, hepatocarcinogenesis, and liver metastasis. To comprehensively analyze the effects of endothelial Wnt-/β-catenin signaling in the liver, we used endothelial subtype-specific Clec4g-iCre mice to generate hepatic ECs with overexpression of Ctnnb1. In the resultant Clec4g-iCretg/wt;Ctnnb1(Ex3)fl/wt (Ctnnb1OE−EC) mice, activation of endothelial Wnt-/β-catenin signaling resulted in sinusoidal transdifferentiation with disturbed endothelial zonation, that is, loss of midzonal LSEC marker lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve1) and enrichment of continuous EC genes, such as cluster of differentiation (CD)34 and Apln. Notably, gene set enrichment analysis revealed overrepresentation of brain endothelial transcripts. Activation of endothelial Wnt-/β-catenin signaling did not induce liver fibrosis or alter metabolic liver zonation, but Ctnnb1OE−EC mice exhibited significantly increased plasma triglyceride concentrations, while liver lipid content was slightly reduced. Ctnnb1 overexpression in arterial ECs of the heart has been reported previously to cause cardiomyopathy. As Clec4g-iCre is active in a subset of cardiac ECs, it was not unexpected that Ctnnb1OE−EC mice showed reduced overall survival and cardiac dysfunction. Altogether, balanced endothelial Wnt-/β-catenin signaling in the liver is required for normal LSEC differentiation and for maintenance of normal plasma triglyceride levels.

Physiological Responses to Hypoxia on Triglyceride Levels.

Hypoxia is a condition during which the body or specific tissues are deprived of oxygen. This phenomenon can occur in response to exposure to hypoxic environmental conditions such as high-altitude, or because of pathophysiological conditions such as obstructive sleep apnea. Circumstances such as these can restrict supply or increase consumption of oxygen, leading to oxyhemoglobin desaturation and tissue hypoxia. In certain cases, hypoxia may lead to severe health consequences such as an increased risk of developing cardiovascular diseases and type 2 diabetes. A potential explanation for the link between hypoxia and an increased risk of developing cardiovascular diseases lies in the disturbing effect of hypoxia on circulating blood lipids, specifically its capacity to increase plasma triglyceride concentrations. Increased circulating triglyceride levels result from the production of triglyceride-rich lipoproteins, such as very-low-density lipoproteins and chylomicrons, exceeding their clearance rate. Considerable research in murine models reports that hypoxia may have detrimental effects on several aspects of triglyceride metabolism. However, in humans, the mechanisms underlying the disturbing effect of hypoxia on triglyceride levels remain unclear. In this mini-review, we outline the available evidence on the physiological responses to hypoxia and their impact on circulating triglyceride levels. We also discuss mechanisms by which hypoxia affects various organs involved in the metabolism of triglyceride-rich lipoproteins. This information will benefit scientists and clinicians interested in the mechanistic of the regulatory cascade responsible for the response to hypoxia and how this response could lead to a deteriorated lipid profile and an increased risk of developing hypoxia-related health consequences.

Olanzapine leads to nonalcoholic fatty liver disease through the apolipoprotein A5 pathway

The antipsychotic drug olanzapine was reported to induce nonalcoholic fatty liver disease (NAFLD), whereas the underlying mechanism remains incompletely understood. This study investigated whether apolipoprotein A5 (apoA5) and sortilin, two interactive factors involved in NAFLD pathogenesis, are implicated in olanzapine-induced NAFLD. In our study, at week 8, olanzapine treatment successfully induced hepatic steatosis in female C57 BL/6 J mice, which was independent of body weight gain. Likewise, olanzapine effectively mediated hepatocyte steatosis in HepG2 cells characterized by substantially elevated intracellular lipid droplets. Increased plasma triglyceride concentration and decreased plasma apoA5 levels were observed in mice treated with 8-week olanzapine. Surprisingly, olanzapine markedly enhanced hepatic apoA5 protein levels in mice, without a significant effect on rodent hepatic ApoA5 mRNA. Our in vitro study showed that olanzapine reduced apoA5 protein levels in the medium and enhanced apoA5 protein levels in hepatocytes, whereas this drug exerted no effect on hepatocyte APOA5 mRNA. By transfecting APOA5 siRNA into HepG2 cells, it was demonstrated that APOA5 knockdown effectively reversed olanzapine-induced hepatocyte steatosis in vitro. In addition, olanzapine drastically increased sortilin mRNA and protein levels in vivo and in vitro. Interestingly, SORT1 knockdown reduced intracellular apoA5 protein levels and increased medium apoA5 protein levels in vitro, without affecting intracellular APOA5 mRNA levels. Furthermore, SORT1 knockdown greatly ameliorated hepatocyte steatosis in vitro. This study provides the first evidence that sortilin inhibits the hepatic apoA5 secretion that is attributable to olanzapine-induced NAFLD, which provides new insight into effective strategies against NAFLD for patients with schizophrenia administered olanzapine.

FC 060METABOLIC PROFILING AS A MARKER OF CARDIOVASCULAR DISEASE AND ARTERIAL CALCIFICATION IN THE COPENHAGEN CHRONIC KIDNEY DISEASE COHORT

Abstract Background and Aims The relation between chronic kidney disease and adverse cardiovascular events is well-established. It is also known that traditional risk factors of cardiovascular disease such as smoking, low-density lipoprotein (LDL) cholesterol and increased blood pressure, cannot fully explain the increased cardiovascular burden observed in patients with chronic kidney disease. In addition, patients with chronic kidney disease do not demonstrate typical clinical symptoms of cardiovascular disease. Thus, good biomarkers for identifying patients at risk and a better understanding of the pathophysiology leading to cardiovascular disease in patients with chronic kidney disease are needed. The objective of the present study was to investigate associations between plasma metabolites and prevalent cardiovascular disease, as well as subclinical cardiovascular disease measured as coronary artery calcification score (CACS), in patients with chronic kidney disease. Method More than 200 metabolic biomarkers, including subclasses of lipoproteins as well as the lipid composition of these, were quantified using nuclear magnetic resonance spectroscopy in 725 patients and 174 controls from the Copenhagen Chronic Kidney Disease Cohort, a single-centre prospective, observational study of non-dialysis patients with stage 1-5 chronic kidney disease. Associations between metabolites and prevalent cardiovascular disease and between metabolites and CACS were determined using multivariable logistic regression and linear regression, respectively. The statistical models were adjusted for traditional cardiovascular risk factors and multiple testing. CACS was determined by CT-scannning and calcium scores were subsequently divided into categories of 0 (no calcification), 1-100, 101-400 and &amp;gt; 400. Results When comparing metabolite concentrations in patients with controls, patients presented with the expected pattern of dyslipidaemia in CKD. We found that they had increased plasma triglyceride concentrations, mainly due to an increase in the triglyceride concentration in very low-density lipoprotein (VLDL) particles, while the concentration of cholesterol in high-density lipoprotein (HDL) particles was decreased. Overall, 85 metabolites were significantly associated with prevalent cardiovascular disease in a model adjusted for eGFR, age and sex (p &amp;lt; 0.001). After further adjusting for diabetes, body mass index, smoking and cholesterol-lowering medication, the significance was lost for all but six metabolites (p &amp;lt; 0.001). The consistent inverse associations with metabolites were primarily involved in HDL metabolism (e.g. ApoA-1, HDL-C and HDL-2). This also applied to the concentration of total lipids in large HDL particles, the concentration of phospholipids in large HDL particles and the the ratio of phospholipids to total lipids in very small VLDL particles. Of the 84 metabolites associated with prevalent cardiovascular disease, 71 were also associated with CACS in a similar pattern. Yet, in the model adjusted for all seven cardiovascular risk factors, only plasma glucose levels as well as the triglyceride content of larger LDL particles remained significant. Conclusion In this study we identified metabolites associated with prevalent cardiovascular disease and subclinical cardiovascular disease (CACS) in patients with CKD. For prevalent cardiovascular disease associations were mainly found for HDL associated metabolites, while CACS was associated with an increase in the triglyceride content of LDL particles and glucose. Further work needs to be done to establish whether these associations are merely a consequence of the cardiovascular burden or whether there is a causal relation.

ABCA1 gene R1587K polymorphism could be associated with metabolic syndrome and increased plasma triglyceride concentration in adults from northern Mexico.

Objectives: to investigate the relationship of R1587K genotypes with cardiovascular (CV) risk, metabolic syndrome (MetS), lipid profile, paraoxonase-1 (PON1) activity, and anti-oxLDL titers. Methods: we performed a cross-sectional study in 57 northern Mexican adults with no reported diseases. The ABCA1 R1587K SNP was detected by real-time polymerase chain reaction (qPCR) using TaqMan allelic discrimination probes. We evaluated the relationship of R1587K with metabolic syndrome and clinical parameters including lipid profile, glucose and insulin, PON1 activity and concentration, anti-oxLDL antibodies, anthropometry and body-composition parameters, and the atherogenic index of plasma calculation. Results: our results show higher triglyceride levels in the RK + KK carriers as compared to RR carriers (p = 0.031). An association between the RK + KK genotype and the presence of MetS (OR = 4.566, 95% CI = 1.386-14.92, p = 0.010) and a tendency towards high CV risk (OR = 3.317, 95% CI = 0.910-8.611, p = 0.069) was observed in comparison to RR carriers; however, there were no differences in HDL-C levels, PON1 activity and concentration, and anti-oxLDL titers among the R1587K genotypes. Conclusions: in the northern Mexican population, the ABCA1 gene R1587K SNP is present and the RK + KK genotypes are associated with MetS and increased triglyceride concentrations; therefore, it could be a CV risk biomarker. Nevertheless there is a need for further confirmation in longitudinal studies.

Effect of crude Moringa oleifera Lam. seed extract on the blood markers of metabolic syndrome in high-fructose diet-fed growing Sprague-Dawley rats.

Background Moringa oleifera seed has anti-diabetic and anti-obesogenic properties. This study interrogated the effect of crude hydroethanolic M. oleifera seed extract on the blood markers of metabolic syndrome (MetS) in high-fructose diet fed growing Sprague-Dawley rats. Methods Sixty 21-day old female and male Sprague-Dawley rat pups were randomly allocated to and administered one of the following treatment regimens daily for twelve weeks: group I - plain drinking water (PW)+plain gelatine cube (PC), group II - 20% (w/v) fructose solution (FS)+PC, group III - FS+100 mg/kg body mass fenofibrate in gelatine cube (FN), group IV - FS+low dose (50 mg/kg body mass) of M. oleifera in gelatine cube (LMol) and group V - FS+high dose (500 mg/kg body mass) of M. oleifera in gelatine cube (HMol). The rats in each treatment regimen had ad libitum access to a standard rat chow. After the 12-week trial, the rats were subjected to an oral glucose tolerance test and then euthanised 48 h later. Blood was collected. Plasma triglyceride, cholesterol and insulin concentration were determined. HOMA-IR was then computed. Results The high-fructose diet increased (p<0.05) plasma insulin concentration and HOMA-IR in female rats only. It increased plasma triglyceride concentration in both female and male rats and plasma cholesterol concentration in male rats only. The crude hydroethanolic M. oleifera seed extract prevented the high-fructose diet-induced metabolic derangements in male and female rats. Conclusion Crude hydroethanolic M. oleifera seed extract can potentially be used as a prophylactic intervention for diet-induced MetS in children.

Immunoreactivity of glucose transporter 8 is localized in the epithelial cells of the choroid plexus and in ependymal cells

High fructose intake is known to be associated with increased plasma triglyceride concentration, impaired glucose tolerance, insulin resistance, and high blood pressure. In addition, excess fructose intake is also thought to be a risk factor for dementia. Previous immunohistochemical studies have shown the presence of glucose transporter 5 (GLUT5), a major transporter of fructose, in the epithelial cells of the choroid plexus and ependymal cells in the brains of humans, rats, and mice, while GLUT2, a minor transporter of fructose, was localized in the ependymal cells of rat brain. In this study, immunoreactivity for the fructose transporter GLUT8 was observed in the cytoplasm of the epithelial cells in the choroid plexus and in the ependymal cells of the brains of humans and mice. These structures were not immunoreactive for GLUT7, GLUT11, and GLUT12. Our findings support the hypothesis of the transport of intravascular fructose through the epithelial cells of the choroid plexus and the ependymal cells.

Abstract 50: Procollagen C-endopeptidase Enhancer protein 2 (PCPE2) Deficiency Profoundly Affects Adipose Distribution in Mice and Humans and Links HDL Metabolism to Adipocyte Biology

Procollagen C-endopeptidase enhancer protein 2 (PCPE2) modulates selective HDL cholesterol ester uptake by SR-BI. Ldlr-/-,Pcpe2-/- mice develop greater aortic atherosclerosis despite increased concentrations of enlarged plasma HDL, suggesting PCPE2 confers functionality to HDL for reverse cholesterol transport. PCPE2 is a 52 kDa glycoprotein encoded by PCOLCE2 gene most highly expressed in adipose tissue, heart and aorta. PCPE2 has 2 CUB domains separated by a short linker, with each CUB domain containing a beta-sandwich fold, mediating a variety of protein-protein interactions. PCPE2 also contains a C-terminal netrin-like domain that binds tightly to cell surface glycosaminoglycans accounting for its location in the extracellular matrix. Because of the strong inverse correlation between HDL and triglyceride levels, and the potential role of SR-BI in triglyceride-rich lipoprotein uptake we examined Ldlr-/-,Pcpe2-/-mice fed a Western diet for 25 weeks. Ldlr-/-,Pcpe2-/- mice showed 1.7 fold increase in plasma triglyceride concentrations when compared to age and gender matched Ldlr-/- mice. We also noted that despite similar body weights, Ldlr-/-,Pcpe2-/- visceral fat pad weight was reduced 60% (p&lt;0.001, n=9 per genotype) compared to Ldlr-/- mice, while subcutaneous fat pad weight was not significantly different. This maldistribution of adipose in Ldlr-/-,Pcpe2-/- was associated with increased fasting plasma glucose levels, elevated 25% (p&lt;0.02) over Ldlr-/- mice. In humans, analyses showed significant correlations of subcutaneous fat PCPE2 RNA expression with DEXA traits from the TwinsUK cohort; % android fat (p&lt;0.0002), % trunk fat (p&lt;0.0001) and % gynoid fat (p&lt;0.04). Additional correlations between PCPE2 mRNA abundance and candidate marker expression will also be presented using 53 human visceral fat samples. Overall these data suggest that PCPE2 plays an important role in regional fat deposition linking SR-BI mediated cholesterol ester uptake to adipose cell biology.

Nutritional management of hyperlipaemia

SummaryHyperlipaemia is a disease resulting from excessive mobilisation of triglyceride stores such that plasma clearance processes become overwhelmed. Consequently increased plasma triglyceride concentrations (&gt;5.6 mmol/l), visibly cloudy plasma and a sick, anorexic or hypophagic subject follow. Epidemiological studies have identified many predisposing and triggering factors and the attentive carer or veterinary surgeon should be alert to such risk factors so that the disease can be prevented, or at least identified and treated at an early stage. Hyperlipaemic subjects are invariably in a negative energy balance, and nutritional management therefore plays a central role in both the prevention and resolution of the disease.

Prevalence of plasma small dense LDL is increased in obesity in a Thai population.

BackgroundPlasma low density lipoprotein (LDL) particles vary in size, density, electrical charge and chemical composition. An increased presence of small dense LDL (sdLDL), along with raised triglyceride concentrations and decreased high density lipoprotein (HDL) cholesterol concentrations is commonly known as the atherogenic triad and has been observed in some cases of obesity, principally in Europe and America. This study examines the prevalence of sdLDL in the plasma of an obese (BMI ≥ 25 kg/m2) Thai population.MethodsPlasma from fasted obese (n = 48) and non-obese (n = 16) Thai participants was subjected to density gradient ultracentrifugation in iodixanol to separate lipoproteins. Gradients were unloaded top-to-bottom into 20 fractions which were assayed for cholesterol, triglyceride, apo B and apo A-1 to identify lipoprotein types and subtypes.ResultsLDL cholesterol was subfractionated into LDL I + II (fractions 3–6, ρ = 1.021-1.033 g/ml) which was considered to represent large buoyant LDL (lbLDL), LDL III (fractions 7–9, ρ = 1.036-1.039 g/ml) which was considered to represent sdLDL, and, LDL IV (fractions 10–12, ρ = 1.044-1.051 g/ml) which was considered to represent very sdLDL. Concentrations of LDL III and IV were increased by 15-20% in obese participants whilst that of LDL I + II was concomitantly decreased by 10%. This was accompanied by a 50% increase in plasma triglyceride concentrations and 15% decrease in HDL cholesterol concentrations. Only 3/16 (19%) non-obese participants had a pattern B LDL cholesterol profile (peak density of >1.033 g/ml), whilst 28/48 (58%) obese participants were pattern B. When expressed as a fraction of the LDL concentration, total sdLDL (i.e. LDL III + IV) showed highly significant correlations to plasma triglyceride concentrations and the triglyceride/HDL cholesterol ratio.ConclusionsThe prevalence of sdLDL is increased in obesity in a Thai population such that they demonstrate a similar atherogenic triad to that previously observed in European and American populations.

The hepatoselective glucokinase activator PF-04991532 ameliorates hyperglycemia without causing hepatic steatosis in diabetic rats.

Hyperglycemia resulting from type 2 diabetes mellitus (T2DM) is the main cause of diabetic complications such as retinopathy and neuropathy. A reduction in hyperglycemia has been shown to prevent these associated complications supporting the importance of glucose control. Glucokinase converts glucose to glucose-6-phosphate and determines glucose flux into the β-cells and hepatocytes. Since activation of glucokinase in β-cells is associated with increased risk of hypoglycemia, we hypothesized that selectively activating hepatic glucokinase would reduce fasting and postprandial glucose with minimal risk of hypoglycemia. Previous studies have shown that hepatic glucokinase overexpression is able to restore glucose homeostasis in diabetic models; however, these overexpression experiments have also revealed that excessive increases in hepatic glucokinase activity may also cause hepatosteatosis. Herein we sought to evaluate whether liver specific pharmacological activation of hepatic glucokinase is an effective strategy to reduce hyperglycemia without causing adverse hepatic lipids changes. To test this hypothesis, we evaluated a hepatoselective glucokinase activator, PF-04991532, in Goto-Kakizaki rats. In these studies, PF-04991532 reduced plasma glucose concentrations independent of changes in insulin concentrations in a dose-dependent manner both acutely and after 28 days of sub-chronic treatment. During a hyperglycemic clamp in Goto-Kakizaki rats, the glucose infusion rate was increased approximately 5-fold with PF-04991532. This increase in glucose infusion can be partially attributed to the 60% reduction in endogenous glucose production. While PF-04991532 induced dose-dependent increases in plasma triglyceride concentrations it had no effect on hepatic triglyceride concentrations in Goto-Kakizaki rats. Interestingly, PF-04991532 decreased intracellular AMP concentrations and increased hepatic futile cycling. These data suggest that hepatoselective glucokinase activation may offer glycemic control without inducing hepatic steatosis supporting the evaluation of tissue specific activators in clinical trials.

Immunoreactivity of glucose transporter 5 is located in epithelial cells of the choroid plexus and ependymal cells

High fructose intake is associated with increased plasma triglyceride concentration, hepatic steatosis, impaired glucose tolerance, insulin resistance, and high blood pressure. In addition, increased fructose intake has recently been supposed to be a risk factor for dementia. However, direct effects of fructose on the brain function remain to be clarified. The localization of glucose transporter 5 (Glut5), a representative transporter of fructose, was immunohistochemically examined in the brains of humans, rats, and mice to clarify whether fructose was transported from the blood into the brain. Glut5 immunoreactivity was demonstrated to be located in the epithelial cells of the choroid plexus and the ependymal cells in the brains of humans and rats using commercial antibodies for Glut5. In addition, mRNA expression of mouse Glut5 was confirmed in the brains of mice. Immunohistochemical examination using a custom-made antibody against two regions of amino acid sequences of mouse Glut5 revealed that Glut5 immunoreactivity was also seen in the epithelial cells of the choroid plexus and the ependymal cells in the brains of mice. These findings show that Glut5 immunoreactivity is located in the epithelial cells of the choroid plexus and the ependymal cells, suggesting the possibility of the direct transportation of intravascular fructose into the brain parenchyma.

Energy and fructose from beverages sweetened with sugar or high-fructose corn syrup pose a health risk for some people.

Sugar intake in the United States has increased by >40 fold since the American Revolution. The health concerns that have been raised about the amounts of sugar that are in the current diet, primarily as beverages, are the subject of this review. Just less than 50% of the added sugars (sugar and high-fructose corn syrup) are found in soft drinks and fruit drinks. The intake of soft drinks has increased 5-fold between 1950 and 2000. Most meta-analyses have shown that the risk of obesity, diabetes, cardiovascular disease, and metabolic syndrome are related to consumption of beverages sweetened with sugar or high-fructose corn syrup. Calorically sweetened beverage intake has also been related to the risk of nonalcoholic fatty liver disease, and, in men, gout. Calorically sweetened beverages contribute to obesity through their caloric load, and the intake of beverages does not produce a corresponding reduction in the intake of other food, suggesting that beverage calories are “add-on” calories. The increase in plasma triglyceride concentrations by sugar-sweetened beverages can be attributed to fructose rather than glucose in sugar. Several randomized trials of sugar-containing soft drinks versus low-calorie or calorie-free beverages show that either sugar, 50% of which is fructose, or fructose alone increases triglycerides, body weight, visceral adipose tissue, muscle fat, and liver fat. Fructose is metabolized primarily in the liver. When it is taken up by the liver, ATP decreases rapidly as the phosphate is transferred to fructose in a form that makes it easy to convert to lipid precursors. Fructose intake enhances lipogenesis and the production of uric acid. By worsening blood lipids, contributing to obesity, diabetes, fatty liver, and gout, fructose in the amounts currently consumed is hazardous to the health of some people.

Maternal Obesity Is Associated With the Formation of Small Dense LDL and Hypoadiponectinemia in the Third Trimester

Maternal obesity is associated with high plasma triglyceride, poor vascular function, and an increased risk for pregnancy complications. In normal-weight pregnant women, higher triglyceride is associated with increased small, dense low-density lipoprotein (LDL). In obese pregnancy, increased plasma triglyceride concentrations result in triglyceride enrichment of very low-density lipoprotein-1 particles and formation of small dense LDL via lipoprotein lipase. Women (n = 55) of body mass index of 18-46 kg/m(2) were sampled longitudinally at 12, 26, and 35 weeks' gestation and 4 months postnatally. Women were recruited at hospital antenatal appointments, and study visits were in a clinical research suite. Plasma concentrations of lipids, triglyceride-rich lipoproteins, lipoprotein lipase mass, estradiol, steroid hormone binding globulin, insulin, glucose, leptin, and adiponectin were determined. Obese women commenced pregnancy with higher plasma triglyceride, reached the same maximum, and then returned to higher postnatal levels than normal-weight women. Estradiol response to pregnancy (trimester 1-3 incremental area under the curve) was positively associated with plasma triglyceride response (r(2) adjusted 25%, P < .001). In the third trimester, the proportion of small, dense LDL was 2-fold higher in obese women than normal-weight women [mean (SD) 40.7 (18.8) vs 21.9 (10.9)%, P = .014], and 35% of obese, 14% of overweight, and none of the normal-weight women displayed an atherogenic LDL subfraction phenotype. The small, dense LDL mass response to pregnancy was inversely associated with adiponectin response (17%, P = .013). Maternal obesity is associated with an atherogenic LDL subfraction phenotype and may provide a mechanistic link to poor vascular function and adverse pregnancy outcome.

Does fructose play a role in metabolic disorders?

There is evidence that high fructose diets can lead to the development of obesity, insulin resistance, and dyslipidemia in rodents model. In humans, however, the role of fructose in the recent increase in the prevalence of metabolic diseases remains much debated. Several epidemiological studies show a positive relationship between consumption of added sugar, fructose, or sweetened beverages on one hand, and metabolic disorders on the other hand, but fail to conclusively prove a causal relationship. Several short term overfeeding studies show that a high fructose diet can, over a short period of time, increase plasma triglyceride concentrations and in intra-hepatocellular lipid concentrations, stimulate hepatic de novo lipogenesis, modestly increase endogenous glucose production, and enhance post-glucose glycemic responses. Whether these studies are relevant to the pathophysiology of the metabolic syndrome is however not known, and several important issues remain however to be addressed. More specifically, whether consumption of fructose causes metabolic disorders when consumedas part of an energy-balanced diet is not known. The interactions between fructose intake and other environmental factors such as other macronutrients or physical activity have also not been addressed. This presentation will summarize the present knowledge regarding the metabolic effects of short term high fructose diets in humans. Novel data will be presented to support that a high fructose diet increases plasma triglycerides independently of energy balance. Finally, the influence of other environmental factors (dietary protein intake, exercise) on the metabolic effects of fructose will be presented.