Altered Peroxisome-Proliferator Activated Receptors Expression in Human Endometrial Cancer

Peroxisome proliferator-activated receptors (PPARs) belong to a family of nuclear hormone receptors acting as transcriptional factors, recently involved also in carcinogenesis. Present study was undertaken to evaluate the presence and subcellular localization of different PPAR isoforms (α, β, γ) in healthy endometrial tissue (n = 10) and endometrial carcinoma (FIGO I, endometrioides type, G1, n = 35). We sought to analyze PPARs mRNA content as well as protein immunohistochemical expression that was further quantified by Western Blot technique. For both PPARα and PPARβ, protein expression was significantly higher in endometrial cancers compared to normal endometrial mucosa. In opposite, PPARγ protein expression was lower in endometrial cancer cells. In each case, immunohistochemical reaction was confined to the perinuclear and/or nuclear region. At the transcriptional level, the content of mRNA of all PPAR subunits did not follow the protein pattern of changes. These results provide evidence for altered PPAR's protein expression and disregulation of posttranslational processes in endometrial cancers

Hypoxia-induced fatty acid transporter translocation increases fatty acid transport and contributes to lipid accumulation in the heart

AbstractProtein-mediated LCFA transport across plasma membranes is highly regulated by the fatty acid transporters FAT/CD36 and FABPpm. Physiologic stimuli (insulin stimulation, AMP kinase activation) induce the translocation of one or both transporters to the plasma membrane and increase the rate of LCFA transport. In the hypoxic/ischemic heart, intramyocardial lipid accumulation has been attributed to a reduced rate of fatty acid oxidation. However, since acute hypoxia (15min) activates AMPK, we examined whether an increased accumulation of intramyocardial lipid during hypoxia was also attributable to an increased rate of LCFA uptake as a result AMPK-induced translocation of FAT/CD36 and FABPpm. In cardiac myocytes, hypoxia (15min) induced the redistribution of FAT/CD36 from an intracellular pool (LDM) (−25%, P<0.05) to the plasma membranes (PM) (+54%, P<0.05). Hypoxia also induced an increase in FABPpm at the PM (+56%, P<0.05) and a concomitant FABPpm reduction in the LDM (−24%, P<0.05). Similarly, in intact, Langendorff perfused hearts, hypoxia induced the translocation of a both FAT/CD36 and FABPpm to the PM (+66% and +61%, respectively, P<0.05), with a concomitant decline in FAT/CD36 and FABPpm in the LDM (−24% and −23%, respectively, P<0.05). Importantly, the increased plasmalemmal content of these transporters was associated with increases in the initial rates of palmitate uptake into cardiac myocytes (+40%, P<0.05). Acute hypoxia also redirected palmitate into intracellular lipid pools, mainly to PL and TG (+48% and +28%, respectively, P<0.05), while fatty acid oxidation was reduced (−35%, P<0.05). Thus, our data indicate that the increased intracellular lipid accumulation in hypoxic hearts is attributable to both: (a) a reduced rate of fatty acid oxidation and (b) an increased rate of fatty acid transport into the heart, the latter being attributable to a hypoxia-induced translocation of fatty acid transporters

Protein-mediated Fatty Acid Uptake in the Heart

Long chain fatty acids (LCFAs) provide 70-80% of the energy for cardiac contractile activity. LCFAs are also essential for many other cellular functions, such as transcriptional regulation of proteins involved in lipid metabolism, modulation of intracellular signalling pathways, and as substrates for membrane constituents. When LCFA uptake exceeds the capacity for their cardiac utilization, the intracellular lipids accumulate and are thought to contribute to contractile dysfunction, arrhythmias, cardiac myocyte apoptosis and congestive heart failure. Moreover, increased cardiac myocyte triacylglycerol, diacylglycerol and ceramide depots are cardinal features associated with obesity and type 2 diabetes. In recent years considerable evidence has accumulated to suggest that, the rate of entry of long chain fatty acids (LCFAs) into the cardiac myocyte is a key factor contributing to a) regulating cardiac LCFA metabolism and b) lipotoxicity in the obese and diabetic heart. In the present review we i) examine the evidence indicating that LCFA transport into the heart involves a protein-mediated mechanism, ii) discuss the proteins involved in this process, including FAT/CD36, FABPpm and FATP1, iii) discuss the mechanisms involved in regulating LCFA transport by some of these proteins (including signaling pathways), as well as iv) the possible interactions of these proteins in regulating LCFA transport into the heart. In addition, v) we discuss how LCFA transport and transporters are altered in the obese/diabetic heart

Heart Failure Disturbs Gut–Blood Barrier and Increases Plasma Trimethylamine, a Toxic Bacterial Metabolite

Trimethylamine (TMA) is a gut bacteria product oxidized by the liver to trimethylamine-N-oxide (TMAO). Clinical evidence suggests that cardiovascular disease is associated with increased plasma TMAO. However, little headway has been made in understanding this relationship on a mechanistic and molecular level. We investigated the mechanisms affecting plasma levels of TMAO in Spontaneously Hypertensive Heart Failure (SHHF) rats. Healthy Wistar Kyoto (WKY) and SHHF rats underwent metabolic, hemodynamic, histopathological and biochemical measurements, including tight junction proteins analysis. Stool, plasma and urine samples were evaluated for TMA and TMAO using ultra performance liquid chromatography-mass spectrometry. SHHF presented disturbances of the gut&ndash;blood barrier including reduced intestinal blood flow, decreased thickness of the colonic mucosa and alterations in tight junctions, such as claudin 1 and 3, and zonula occludens-1. This was associated with significantly higher plasma levels of TMA and TMAO and increased gut-to-blood penetration of TMA in SHHF compared to WKY. There was no difference in kidney function or liver oxidation of TMA to TMAO between WKY and SHHF. In conclusion, increased plasma TMAO in heart failure rats results from a perturbed gut&ndash;blood barrier and increased gut-to-blood passage of TMAO precursor, i.e., TMA. Increased gut-to-blood penetration of bacterial metabolites may be a marker and a mediator of cardiovascular pathology

How Hypertension Affects Heart Metabolism

Hypertension is one of the most frequently observed cardiovascular diseases, which precedes heart failure in 75% of its cases. It is well-established that hypertensive patients have whole body metabolic complications such as hyperlipidemia, hyperglycemia, decreased insulin sensitivity or diabetes mellitus. Since myocardial metabolism is strictly dependent on hormonal status as well as substrate milieu, the above mentioned disturbances may affect energy generation status in the heart. Interestingly, it was found that hypertension induces a shift in substrate preference toward increased glucose utilization in cardiac muscle, prior to structural changes development. The present work reports advances in the aspect of heart metabolism under high blood pressure conditions, including human and the most common animal models of hypertension

A multi-ingredient nutritional supplement enhances exercise training-related reductions in markers of systemic inflammation in healthy older men

We evaluated whether twice daily consumption of a multi-ingredient nutritional supplement (SUPP) would reduce systemic inflammatory markers following 6wk of supplementation alone (Phase 1), and the subsequent addition of 12wk exercise training (Phase 2) in healthy older men, in comparison to a carbohydrate-based control (CON). Tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) concentrations were progressively reduced (P-time<0.05) SUPP group. No change in TNF-α or IL-6 concentrations was observed in the CON group

One week of bed rest leads to substantial muscle atrophy and induces whole-body insulin resistance in the absence of skeletal muscle lipid accumulation

Short ( < 10 days) periods of muscle disuse, often necessary for recovery from illness or injury, lead to various negative health consequences. The current study investigated mechanisms underlying disuse-induced insulin resistance, taking into account muscle atrophy. Ten healthy, young males (age: 23 ± 1 years; BMI: 23.0 ± 0.9 kg · m−2) were subjected to 1 week of strict bed rest. Prior to and after bed rest, lean body mass (dual-energy X-ray absorptiometry) and quadriceps cross-sectional area (CSA; computed tomography) were assessed, and peak oxygen uptake (VO2peak) and leg strength were determined. Whole-body insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Additionally, muscle biopsies were collected to assess muscle lipid (fraction) content and various markers of mitochondrial and vascular content. Bed rest resulted in 1.4 ± 0.2 kg lean tissue loss and a 3.2 ± 0.9% decline in quadriceps CSA (both P < 0.01). VO2peak and one-repetition maximum declined by 6.4 ± 2.3 (P < 0.05) and 6.9 ± 1.4% (P < 0.01), respectively. Bed rest induced a 29 ± 5% decrease in whole-body insulin sensitivity (P < 0.01). This was accompanied by a decline in muscle oxidative capacity, without alterations in skeletal muscle lipid content or saturation level, markers of oxidative stress, or capillary density. In conclusion, 1 week of bed rest substantially reduces skeletal muscle mass and lowers whole-body insulin sensitivity, without affecting mechanisms implicated in high-fat diet–induced insulin resistance

In Vivo, Fatty Acid Translocase (CD36) Critically Regulates Skeletal Muscle Fuel Selection, Exercise Performance, and Training-induced Adaptation of Fatty Acid Oxidation

For ∼40 years it has been widely accepted that (i) the exercise-induced increase in muscle fatty acid oxidation (FAO) is dependent on the increased delivery of circulating fatty acids, and (ii) exercise training-induced FAO up-regulation is largely attributable to muscle mitochondrial biogenesis. These long standing concepts were developed prior to the recent recognition that fatty acid entry into muscle occurs via a regulatable sarcolemmal CD36-mediated mechanism. We examined the role of CD36 in muscle fuel selection under basal conditions, during a metabolic challenge (exercise), and after exercise training. We also investigated whether CD36 overexpression, independent of mitochondrial changes, mimicked exercise training-induced FAO up-regulation. Under basal conditions CD36-KO versus WT mice displayed reduced fatty acid transport (−21%) and oxidation (−25%), intramuscular lipids (less than or equal to −31%), and hepatic glycogen (−20%); but muscle glycogen, VO(2max), and mitochondrial content and enzymes did not differ. In acutely exercised (78% VO(2max)) CD36-KO mice, fatty acid transport (−41%), oxidation (−37%), and exercise duration (−44%) were reduced, whereas muscle and hepatic glycogen depletions were accelerated by 27–55%, revealing 2-fold greater carbohydrate use. Exercise training increased mtDNA and β-hydroxyacyl-CoA dehydrogenase similarly in WT and CD36-KO muscles, but FAO was increased only in WT muscle (+90%). Comparable CD36 increases, induced by exercise training (+44%) or by CD36 overexpression (+41%), increased FAO similarly (84–90%), either when mitochondrial biogenesis and FAO enzymes were up-regulated (exercise training) or when these were unaltered (CD36 overexpression). Thus, sarcolemmal CD36 has a key role in muscle fuel selection, exercise performance, and training-induced muscle FAO adaptation, challenging long held views of mechanisms involved in acute and adaptive regulation of muscle FAO