Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes

BACKGROUND: Both nutritional and genetic factors are involved in the pathogenesis of nonalcoholic fatty liver disease and insulin resistance. OBJECTIVE: The aim was to assess the effects of fructose, a potent stimulator of hepatic de novo lipogenesis, on intrahepatocellular lipids (IHCLs) and insulin sensitivity in healthy offspring of patients with type 2 diabetes (OffT2D)--a subgroup of individuals prone to metabolic disorders. DESIGN: Sixteen male OffT2D and 8 control subjects were studied in a crossover design after either a 7-d isocaloric diet or a hypercaloric high-fructose diet (3.5 g x kg FFM(-1) x d(-1), +35% energy intake). Hepatic and whole-body insulin sensitivity were assessed with a 2-step hyperinsulinemic euglycemic clamp (0.3 and 1.0 mU x kg(-1) x min(-1)), together with 6,6-[2H2]glucose. IHCLs and intramyocellular lipids (IMCLs) were measured by 1H-magnetic resonance spectroscopy. RESULTS: The OffT2D group had significantly (P < 0.05) higher IHCLs (+94%), total triacylglycerols (+35%), and lower whole-body insulin sensitivity (-27%) than did the control group. The high-fructose diet significantly increased IHCLs (control: +76%; OffT2D: +79%), IMCLs (control: +47%; OffT2D: +24%), VLDL-triacylglycerols (control: +51%; OffT2D: +110%), and fasting hepatic glucose output (control: +4%; OffT2D: +5%). Furthermore, the effects of fructose on VLDL-triacylglycerols were higher in the OffT2D group (group x diet interaction: P < 0.05). CONCLUSIONS: A 7-d high-fructose diet increased ectopic lipid deposition in liver and muscle and fasting VLDL-triacylglycerols and decreased hepatic insulin sensitivity. Fructose-induced alterations in VLDL-triacylglycerols appeared to be of greater magnitude in the OffT2D group, which suggests that these individuals may be more prone to developing dyslipidemia when challenged by high fructose intakes. This trial was registered at clinicaltrials.gov as NCT00523562.

Functions of lipid raft membrane microdomains at the blood-brain barrier

The blood-brain barrier (BBB) is a highly specialized structural and functional component of the central nervous system that separates the circulating blood from the brain and spinal cord parenchyma. Brain endothelial cells (BECs) that primarily constitute the BBB are tightly interconnected by multiprotein complexes, the adherens junctions and the tight junctions, thereby creating a highly restrictive cellular barrier. Lipid-enriched membrane microdomain compartmentalization is an inherent property of BECs and allows for the apicobasal polarity of brain endothelium, temporal and spatial coordination of cell signaling events, and actin remodeling. In this manuscript, we review the role of membrane microdomains, in particular lipid rafts, in the BBB under physiological conditions and during leukocyte transmigration/diapedesis. Furthermore, we propose a classification of endothelial membrane microdomains based on their function, or at least on the function ascribed to the molecules included in such heterogeneous rafts: (1) rafts associated with interendothelial junctions and adhesion of BECs to basal lamina (scaffolding rafts); (2) rafts involved in immune cell adhesion and migration across brain endothelium (adhesion rafts); (3) rafts associated with transendothelial transport of nutrients and ions (transporter rafts).

Effects of deflazacort versus prednisone on bone mass, body composition, and lipid profile: a randomized, double blind study in kidney transplant patients

To compare the effects of deflazacort (DEFLA) vs. prednisone (PRED) on bone mineral density (BMD), body composition, and lipids, 24 patients with end-stage renal disease were randomized in a double blind design and followed 78 weeks after kidney transplantation. BMD and body composition were assessed using dual energy x-ray absorptiometry. Seventeen patients completed the study. Glucocorticosteroid doses, cyclosporine levels, rejection episodes, and drop-out rates were similar in both groups. Lumbar BMD decreased more in PRED than in DEFLA (P < 0.05), the difference being particularly marked after 24 weeks (9.1 +/- 1.8% vs. 3.0 +/- 2.4%, respectively). Hip BMD decreased from baseline in both groups (P < 0.01), without intergroup differences. Whole body BMD decreased from baseline in PRED (P < 0.001), but not in DEFLA. Lean body mass decreased by approximately 2.5 kg in both groups after 6-12 weeks (P < 0.001), then remained stable. Fat mass increased more (P < 0.01) in PRED than in DEFLA (7.1 +/- 1.8 vs. 3.5 +/- 1.4 kg). Larger increases in total cholesterol (P < 0.03), low density lipoprotein cholesterol (P < 0.01), lipoprotein B2 (P < 0.03), and triglycerides (P = 0.054) were observed in PRED than in DEFLA. In conclusion, using DEFLA instead of PRED in kidney transplant patients is associated with decreased loss of total skeleton and lumbar spine BMD, but does not alter bone loss at the upper femur. DEFLA also helps to prevent fat accumulation and worsening of the lipid profile.

[Dyslipidemia - when are lipid lowering medications useful in clinical practice?]

Dyslipidemia is one of the main modifiable cardiovascular risk factors. There is strong evidence for the efficacy of lipid-lowering drugs in secondary prevention, as well as in primary prevention for patients at high cardiovascular risk. In primary prevention, indication for lipid-lowering interventions should be based on an individual assessment of the cardiovascular risk and on the LDL cholesterol level, despite less strong evidence for the efficacy of drug-based interventions in low risk patients. Treatment consists of statins, as well as lifestyle modifications such as body weight control and increased physical exercise. The latter constitute the primary intervention in patients at low cardiovascular risk. Secondary dyslipidemias due to an underlying medical condition and familial dyslipidemias such as Familial Hypercholesterolemia and Familial Combined Hyperlipidemia should be identified and treated accordingly, taking into account that the risk scoring systems are not appropriate in these situations.

Lipid synthesis in protozoan parasites: a comparison between kinetoplastids and apicomplexans.

Lipid metabolism is of crucial importance for pathogens. Lipids serve as cellular building blocks, signalling molecules, energy stores, posttranslational modifiers, and pathogenesis factors. Parasites rely on a complex system of uptake and synthesis mechanisms to satisfy their lipid needs. The parameters of this system change dramatically as the parasite transits through the various stages of its life cycle. Here we discuss the tremendous recent advances that have been made in the understanding of the synthesis and uptake pathways for fatty acids and phospholipids in apicomplexan and kinetoplastid parasites, including Plasmodium, Toxoplasma, Cryptosporidium, Trypanosoma and Leishmania. Lipid synthesis differs in significant ways between parasites from both phyla and the human host. Parasites have acquired novel pathways through endosymbiosis, as in the case of the apicoplast, have dramatically reshaped substrate and product profiles, and have evolved specialized lipids to interact with or manipulate the host. These differences potentially provide opportunities for drug development. We outline the lipid pathways for key species in detail as they progress through the developmental cycle and highlight those that are of particular importance to the biology of the pathogens and/or are the most promising targets for parasite-specific treatment.

Aerobic exercise but not resistance exercise reduces intrahepatic lipid content and visceral fat and improves insulin sensitivity in obese adolescent girls: a randomized controlled trial

It is unclear whether regular exercise alone (no caloric restriction) is a useful strategy to reduce adiposity and obesity-related metabolic risk factors in obese girls. We examined the effects of aerobic (AE) vs. resistance exercise (RE) alone on visceral adipose tissue (VAT), intrahepatic lipid, and insulin sensitivity in obese girls. Forty-four obese adolescent girls (BMI ≥95th percentile, 12-18 yr) with abdominal obesity (waist circumference 106.5 ± 11.1 cm) were randomized to 3 mo of 180 min/wk AE (n = 16) or RE (n = 16) or a nonexercising control group (n = 12). Total fat and VAT were assessed by MRI and intrahepatic lipid by proton magnetic resonance spectroscopy. Intermuscular AT (IMAT) was measured by CT. Insulin sensitivity was evaluated by a 3-h hyperinsulinemic (80 mU·m(2)·min(-1)) euglycemic clamp. Compared with controls (0.13 ± 1.10 kg), body weight did not change (P > 0.1) in the AE (-1.31 ± 1.43 kg) and RE (-0.31 ± 1.38 kg) groups. Despite the absence of weight loss, total body fat (%) and IMAT decreased (P < 0.05) in both exercise groups compared with control. Compared with control, significant (P < 0.05) reductions in VAT (Δ-15.68 ± 7.64 cm(2)) and intrahepatic lipid (Δ-1.70 ± 0.74%) and improvement in insulin sensitivity (Δ0.92 ± 0.27 mg·kg(-1)·min(-1) per μU/ml) were observed in the AE group but not the RE group. Improvements in insulin sensitivity in the AE group were associated with the reductions in total AT mass (r = -0.65, P = 0.02). In obese adolescent girls, AE but not RE is effective in reducing liver fat and visceral adiposity and improving insulin sensitivity independent of weight loss or calorie restriction.

Variation in fat mobilization during early lactation differently affects feed intake, body condition, and lipid and glucose metabolism in high-yielding dairy cows.

Fat mobilization to meet energy requirements during early lactation is inevitable because of insufficient feed intake, but differs greatly among high-yielding dairy cows. Therefore, we studied milk production, feed intake, and body condition as well as metabolic and endocrine changes in high-yielding dairy cows to identify variable strategies in metabolic and endocrine adaptation to overcome postpartum metabolic load attributable to milk production. Cows used in this study varied in fat mobilization around calving, as classified by mean total liver fat concentrations (LFC) postpartum. German Holstein cows (n=27) were studied from dry off until d 63 postpartum in their third lactation. All cows were fed the same total mixed rations ad libitum during the dry period and lactation. Plasma concentrations of metabolites and hormones were measured in blood samples taken at d 56, 28, 15, and 5 before expected calving and at d 1 and once weekly up to d 63 postpartum. Liver biopsies were taken on d 56 and 15 before calving, and on d 1, 14, 28, and 49 postpartum to measure LFC and glycogen concentrations. Cows were grouped accordingly to mean total LFC on d 1, 14, and 28 in high, medium, and low fat-mobilizing cows. Mean LFC (±SEM) differed among groups and were 351±14, 250±10, and 159±9 mg/g of dry matter for high, medium, and low fat-mobilizing cows, respectively, whereas hepatic glycogen concentrations postpartum were the highest in low fat-mobilizing cows. Cows in the low group showed the highest dry matter intake and the least negative energy balance postpartum, but energy-corrected milk yield was similar among groups. The decrease in body weight postpartum was greatest in high fat-mobilizing cows, but the decrease in backfat thickness was greatest in medium fat-mobilizing cows. Plasma concentrations of nonesterified fatty acids and β-hydroxybutyrate were highest around calving in high fat-mobilizing cows. Plasma triglycerides were highest in the medium group and plasma cholesterol concentrations were lowest in the high group at calving. During early lactation, the decrease in plasma glucose concentrations was greatest in the high group, and plasma insulin concentrations postpartum were highest in the low group. The revised quantitative insulin sensitivity check index values decreased during the transition period and postpartum, and were highest in the medium group. Plasma cortisol concentrations during the transition period and postpartum period and plasma leptin concentrations were highest in the medium group. In conclusion, cows adapted differently to the metabolic load and used variable strategies for homeorhetic regulation of milk production. Differences in fat mobilization were part of these strategies and contributed to the individual adaptation of energy metabolism to milk production.

Liver fat content and lipid metabolism in dairy cows during early lactation and during a mid-lactation feed restriction.

During the transition period, the lipid metabolism of dairy cows is markedly affected by energy status. Fatty liver is one of the main health disorders after parturition. The aim of this study was to evaluate the effects of a negative energy balance (NEB) at 2 stages in lactation [NEB at the onset of lactation postpartum (p.p.) and a deliberately induced NEB by feed restriction near 100 d in milk] on liver triglyceride content and parameters of lipid metabolism in plasma and liver based on mRNA abundance of associated genes. Fifty multiparous dairy cows were studied from wk 3 antepartum to approximately wk 17 p.p. in 2 periods. According to their energy balance in period 1 (parturition to wk 12 p.p.), cows were allocated to a control (CON; n=25) or a restriction group (RES; 70% of energy requirements; n=25) for 3 wk in mid lactation starting at around 100 d in milk (period 2). Liver triglyceride (TG) content, plasma nonesterified fatty acids (NEFA), and β-hydroxybutyrate were highest in wk 1 p.p. and decreased thereafter. During period 2, feed restriction did not affect liver TG and β-hydroxybutyrate concentration, whereas NEFA concentration was increased in RES cows as compared with CON cows. Hepatic mRNA abundances of tumor necrosis factor α, ATP citrate lyase, mitochondrial glycerol-3-phosphate acyltransferase, and glycerol-3-phosphate dehydrogenase 2 were not altered by lactational and energy status during both experimental periods. The expression of fatty acid synthase was higher in period 2 compared with period 1, but did not differ between RES and CON groups. The mRNA abundance of acetyl-coenzyme A-carboxylase showed a tendency toward higher expression during period 2 compared with period 1. The solute carrier family 27 (fatty acid transporter), member 1 (SLC27A1) was upregulated in wk 1 p.p. and also during feed restriction in RES cows. In conclusion, the present study shows that a NEB has different effects on hepatic lipid metabolism and TG concentration in the liver of dairy cows at early and later lactation. Therefore, the homeorhetic adaptations during the periparturient period trigger excessive responses in metabolism, whereas during the homeostatic control of endocrine and metabolic systems after established lactation, as during the period of feed restriction in the present study, organs are well adapted to metabolic and environmental changes.

Hepatic gene expression involved in glucose and lipid metabolism in transition cows: effects of fat mobilization during early lactation in relation to milk performance and metabolic changes.

Insufficient feed intake during early lactation results in elevated body fat mobilization to meet energy demands for milk production. Hepatic energy metabolism is involved by increasing endogenous glucose production and hepatic glucose output for milk synthesis and by adaptation of postcalving fuel oxidation. Given that cows differ in their degree of fat mobilization around parturition, indicated by variable total liver fat concentration (LFC), the study investigated the influence of peripartum fat mobilization on hepatic gene expression involved in gluconeogenesis, fatty acid oxidation, ketogenesis, and cholesterol synthesis, as well as transcriptional factors referring to energy metabolism. German Holstein cows were grouped according to mean total LFC on d 1, 14, and 28 after parturition as low [<200mg of total fat/g of dry matter (DM); n=10], medium (200-300 mg of total fat/g of DM; n=10), and high (>300 mg of total fat/g of DM; n=7), indicating fat mobilization during early lactation. Cows were fed total mixed rations ad libitum and held under equal conditions. Liver biopsies were taken at d 56 and 15 before and d 1, 14, 28, and 49 after parturition to measure mRNA abundances of pyruvate carboxylase (PC); phosphoenolpyruvate carboxykinase; glucose-6-phosphatase; propionyl-coenzyme A (CoA) carboxylase α; carnitine palmitoyl-transferase 1A (CPT1A); acyl-CoA synthetase, long chain 1 (ASCL1); acyl-CoA dehydrogenase, very long chain; 3-hydroxy-3-methylglutaryl-CoA synthase 1 and 2; sterol regulatory element-binding factor 1; and peroxisome proliferator-activated factor α. Total LFC postpartum differed greatly among cows, and the mRNA abundance of most enzymes and transcription factors changed with time during the experimental period. Abundance of PC mRNA increased at parturition to a greater extent in high- and medium-LFC groups than in the low-LFC group. Significant LFC × time interactions for ACSL1 and CPT1A during the experimental period indicated variable gene expression depending on LFC after parturition. Correlations between hepatic gene expression and performance data and plasma concentrations of metabolites and hormones showed time-specific relations during the transition period. Elevated body fat mobilization during early lactation affected gene expression involved in gluconeogenesis to a greater extent than gene expression involved in lipid metabolism, indicating the dependence of hepatic glucose metabolism on hepatic lipid status and fat mobilization during early lactation.

Lipid biomarkers in Holocene and glacial sediments from ancient Lake Ohrid (Macedonia, Albania)

Abstract. Organic matter preserved in Lake Ohrid sediments originates from aquatic and terrestrial sources. Its variable composition reflects climate-controlled changes in the lake basin’s hydrology and related organic matter export, i.e. changes in primary productivity, terrestrial plant matter input and soil erosion. Here, we present first results from lipid biomarker investigations of Lake Ohrid sediments from two near-shore settings: site Lz1120 near the southern shore, with low-lying lands nearby and probably influenced by river discharge, and site Co1202 which is close to the steep eastern slopes. Variable proportions of terrestrial n-alkanoic acids and n-alkanols as well as compositional changes of !- hydroxy acids document differences in soil organic matter supply between the sites and during different climate stages (glacial, Holocene, 8.2 ka cooling event). Changes in the vegetation cover are suggested by changes in the dominant chain length of terrestrial n-alkanols. Effective microbial degradation of labile organic matter and in situ contribution of organic matter derived from the microbes themselves are both evident in the sediments. We found evidence for anoxic conditions within the photic zone by detecting epicholestanol and tetrahymanol from sulphur-oxidising phototrophic bacteria and bacterivorous ciliates and for the influence of a settled human community from the occurrence of coprostanol, a biomarker for human and animal faeces (pigs, sheep, goats), in an early Holocene sample. This study illustrates the potential of lipid biomarkers for future environmental reconstructions using one of Europe’s oldest continental climate archives, Lake Ohrid.

Association of biomarkers of lipid modification with functional and morphological indices of coronary stenosis severity in stable coronary artery disease

Biomarkers of blood lipid modification and oxidative stress have been associated with increased cardiovascular morbidity. We sought to determine whether these biomarkers were related to functional indices of stenosis severity among patients with stable coronary artery disease. We studied 197 consecutive patients with stable coronary artery disease due to single vessel disease. Fractional flow reserve (FFR) ≤ 0.80 was assessed as index of a functionally significant lesion. Serum levels of secretory phospholipase A2 (sPLA2) activity, secretory phospholipase A2 type IIA (sPLA2-IIA), myeloperoxydase (MPO), lipoprotein-associated phospholipase A2 (Lp-PLA2), and oxidized low-density lipoprotein (OxLDL) were assessed using commercially available assays. Patients with FFR > 0.8 had higher sPLA2 activity, sPLA2 IIA, and OxLDL levels than patients with FFR ≤ 0.8 (21.25 [16.03-27.28] vs 25.85 [20.58-34.63] U/mL, p < 0.001, 2.0 [1.5-3.4] vs 2.6 [2.0-3.4] ng/mL, p < 0.01; and 53.0 [36.0-71.0] vs 64.5 [50-89.25], p < 0.001 respectively). Patients with FFR > 0.80 had similar Lp-PLA2 and MPO levels versus those with FFR ≤ 0.8. sPLA2 activity, sPLA2 IIA significantly increased area under the curve over baseline characteristics to predict FFR ≤ 0.8 (0.67 to 0.77 (95 % confidence interval [CI]: 0.69-0.85) p < 0.01 and 0.67 to 0.77 (95 % CI: 0.69-0.84) p < 0.01, respectively). Serum sPLA2 activity as well as sPLA2-IIA level is related to functional characteristics of coronary stenoses in patients with stable coronary artery disease.

The impact of antioxidant supplements and endurance exercise on genes of the carbohydrate and lipid metabolism in skeletal muscle of mice

To ascertain whether reactive oxygen species (ROS) contribute to training-induced adaptation of skeletal muscle, we administered ROS-scavenging antioxidants (AOX; 140 mg/l of ascorbic acid, 12 mg/l of coenzyme Q10 and 1% N-acetyl-cysteine) via drinking water to 16 C57BL/6 mice. Sixteen other mice received unadulterated tap water (CON). One cohort of both groups (CON(EXE) and AOX(EXE) ) was subjected to treadmill exercise for 4 weeks (16-26 m/min, incline of 5°-10°). The other two cohorts (CON(SED) and AOX(SED) ) remained sedentary. In skeletal muscles of the AOX(EXE) mice, GSSG and the expression levels of SOD-1 and PRDX-6 were significantly lower than those in the CON(EXE) mice after training, suggesting disturbance of ROS levels. The peak power related to the body weight and citrate synthase activity was not significantly influenced in mice receiving AOX. Supplementation with AOX significantly altered the mRNA levels of the exercise-sensitive genes HK-II, GLUT-4 and SREBF-1c and the regulator gene PGC-1alpha but not G6PDH, glycogenin, FABP-3, MCAD and CD36 in skeletal muscle. Although the administration of AOX during endurance exercise alters the expression of particular genes of the ROS metabolism, it does not influence peak power or generally shift the metabolism, but it modulates the expression of specific genes of the carbohydrate and lipid metabolism and PGC-1alpha within murine skeletal muscle.