Free Fatty Acid Mobilization Research Articles

AN UNLIKELY PRESENTATION OF FAT EMBOLISM SYNDROME

SESSION TITLE: Pathology SESSION TYPE: Med Student/Res Case Report PRESENTED ON: 10/10/2018 03:45 PM - 04:45 PM INTRODUCTION: Fat embolism syndrome (FES) was first clinically described in 1873 as the triad of petechiae, altered mentation, and hypoxemia. Most cases are attributed to traumatic acute pelvic or long bone fractures; there are few reported cases involving smaller bone fractures and a delayed presentation. We present an unusual case of FES, confirmed on lung biopsy, occurring more than one month after initial tissue injury. CASE PRESENTATION: A 63-year-old female with COPD and hypertension presented with vertigo, confusion, right arm and leg weakness, and progressive dyspnea. She suffered a distal left malleolus fracture one month prior. Examination revealed a confused, obese woman in moderate respiratory distress with diffuse wheezing, and tachycardia. She had mild erythema of the left lateral ankle but no other rash, and no focal neurological defects. Admission CXR demonstrated several non-specific multifocal infiltrates. Subsequent chest CT chest showed bilateral hilar lymphadenopathy and diffuse upper lobe patchy infiltrates, but no evidence of pulmonary embolism. Echocardiogram demonstrated a small patent foramen ovale and lower extremity doppler ultrasound with a left soleal deep venous thrombosis. Systemic heparin and prednisone were started, and bronchoscopy with BAL was performed to evaluate pulmonary abnormalities. Findings were unremarkable, and her oxygen requirements continued to increase, necessitating high-flow nasal cannula oxygen. Repeat chest imaging was consistent with ARDS of uncertain etiology and VATS biopsy was completed. Diffuse alveolar damage with intravenous bone marrow fragments consistent with fat embolism were found. No pulmonary emboli seen on biopsy. She gradually improved with supportive measures, and was discharged to a skilled nursing facility after a 21-day hospital stay. DISCUSSION: The pathophysiology of FES is poorly understood, but two theories exist: the mechanical theory suggests that fat droplets physically obstruct pulmonary capillaries while the biochemical theory suggests that a combination of lipid molecules being degraded by pulmonary lipase, and excessive mobilization of free fatty acids from peripheral tissue results in toxic levels of these substances and pneumocyte injury. Most cases occur 24hrs to 2 weeks after exposure to fat droplets. Treatment includes maintenance of adequate oxygenation and supportive care. Evidence supporting the routine use of albumin, steroids, heparin, or other medications is lacking in this population. Mortality ranges from 5-15%. CONCLUSIONS: Definitive diagnosis of FES remains rare and should still be considered in patients who have a delayed presentation. Physicians should suspect fat embolism in patients with a history of orthopedic injury and the appropriate clinical scenario. Classic clinical clues include neurologic manifestations, petechial rash, and hypoxemia with preceding trauma, bone fracture, or injury. Reference #1: Rajoor, Umesh. (2014). Fat Embolism Syndrome: Review. Scholars Journal of Applied Medical Sciences, 2(1D), 466-469. Reference #2: Mellor, A., & Soni, N. (2001). Fat embolism. Anaesthesia, 56(2), 145-154. https://doi.org/10.1046/j.1365-2044.2001.01724.x Reference #3: Shaikh, N. (2009). Emergency management of fat embolism syndrome. Journal of Emergencies, Trauma and Shock, 2(1), 29. https://doi.org/10.4103/0974-2700.44680 DISCLOSURES: No relevant relationships by Kim Jordan, source=Web Response No relevant relationships by Geno Kordic, source=Web Response No relevant relationships by Kevin Swiatek, source=Web Response

Psychological manifestations in post myocardial infraction patients

Background: In the past few years a very important observation that came to light is the increase in prevalence of some psychiatric disorder in chronically ill patients. Symptoms of depression and anxiety are common following myocardial infarction (MI). Both the symptoms have been linked with increased risk of recurrent coronary artery disease (CAD), Severe psychological stress, major life events, and depression causes myocardial infarction (MI) in 15% of case of Coronary Artery Disease (CAD) and are associated with higher rates of morbidity and mortality. Objective: (1) To establish the diagnosis of myocardial infarction in patients. (2) To study and correlate various psychological manifestations in these patients. Methodology: The patients for the present study were taken up from those admitted in ICCU and OPD of department of Medicine G.M.C, Ambikapur, during the study period. 50 patients were studied having CAD (Myocardial infarction). The patients were history taken in detailed & examined (Physical and Psychiatric), investigated with reference to ECG proven myocardial infarction or cardiac enzymes proven MI. Results: We have found 46% of prevalence rate of depression in our study. Majority of patients (20%) have mild depression (score 10-13) on (HAD-Scale), 12% have major depression, 42% had Anxiety. Majority of patients 26% have mild anxiety. Only 6% have severe anxiety (score > 30) in our study. Conclusion: Personality feature of CAD patients are associated with emotional as sympathetic arousal which result in increases in catecholamine as consequent increase in mobilization of free fatty acid from adipose tissue, aggregation of platelets which may precipitate MI. So, a thorough research, prevention and rehabilitation of psychologically oriented care can increase the patients sense of security and is fundamental basis of successful medical care.

Early Effects of Sleeve Gastrectomy (SG) on Systemic and Organ-Specific Dietary Fatty Acid Uptake, Postprandial Free Fatty Acids (FFA), and Glucose Metabolism in Type 2 Diabetes (T2D)

Postprandial dietary fatty acid (FA) biodistribution is impaired in subjects with glucose intolerance, with decreased FA storage in adipose tissues (AT) and increased FA uptake by the myocardium. These abnormalities are improved after 1 year of lifestyle-induced weight loss. Bariatric surgery leads to early metabolic improvements before weight loss, but the early effects on dietary FA metabolism and biodistribution have never been studied. 9 subjects with T2D underwent a 6-hour postprandial metabolic protocol before and 12 days after SG. A liquid meal containing [U-13C]-palmitate and [2H]-glucose was ingested at time 0, with an IV perfusion of [3H]-glucose and [7,7,8,8-2H]-palmitate, allowing quantification of glucose absorption, endogenous glucose production (EGP), lipolysis and dietary FA spillover. A capsule containing a positron-emitting long-chain FA analog (18FTHA) was taken with the meal for the quantification of organ-specific dietary FA uptake using PET/CT (n=6). Twelve days after SG, whole body and hepatic insulin sensitivity increased significantly whereas fasting and postprandial EGP decreased. Postprandial GLP-1, GIP, PYY and glucagon were higher after vs. before SG. Postprandial AUC of FFA (175 vs. 228 mmol/Lx min; p< 0.05) and total FA oxidation were higher (p< 0.02 from 180 min to 360 min), but dietary FA oxidation was reduced after SG (p< 0.002 from 180 min to 360 min). After SG, uptake of dietary FA 6 hours after the meal was reduced in the myocardium (mean SUV 2.07± 0.66 vs. 1.36± 0.44; p=0.06) and was increased in visceral AT (mean SUV 0.24± 0.2 vs. 0.42± 0.2; p=0.03), without changes in other organs. In conclusion, there is reduced myocardial and increased visceral AT uptake of dietary FA associated with reduced dietary FA oxidation and increased FFA mobilization and oxidation, concomitant with reduced EGP and insulin sensitization in patients with T2D early after SG. Disclosure A. Carreau: None. C. Noll: None. B. Guerin: None. L. Biertho: Advisory Panel; Self; Novo Nordisk Inc.. Consultant; Self; Johnson & Johnson Services, Inc., Valeant Pharmaceuticals International, Inc.. E.E. Turcotte: None. A. Tchernof: Research Support; Self; Johnson & Johnson Services, Inc., Medtronic. A. Carpentier: Consultant; Self; UniQure, Janssen Pharmaceuticals, Inc., Siemens. Research Support; Self; Caprion, Merck Sharp & Dohme Corp., GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, AstraZeneca, Bristol-Myers Squibb Company, Sanofi-Aventis, Pfizer Inc., Novo Nordisk Inc., Exelixis, Amgen Inc..

Lipid droplet autophagy during energy mobilization, lipid homeostasis and protein quality control.

Lipid droplets (LDs) have well-established functions as sites for lipid storage and energy mobilization to meet the metabolic demands of cells. However, recent studies have expanded the roles of LDs to protein quality control. Lipophagy, or LD degradation by autophagy, plays a vital role not only in the mobilization of free fatty acids (FFAs) and lipid homeostasis at LDs, but also in the adaptation of cells to certain forms of stress including lipid imbalance. Recent studies have provided new mechanistic insights about the diverse types of lipophagy, in particular microlipophagy. This review summarizes key findings about the mechanisms and functions of lipophagy and highlights a novel function of LD microlipophagy as a mechanism to maintain endoplasmic reticulum (ER) proteostasis under conditions of lipid imbalance.

Metabolic Complications of Acromegaly.

Diabetes is recognized as one of the most common acromegaly co-morbidities with a prevalence ranging 20-53%, while over one-third of these patients have an altered lipid profile. In fact, as in the non-acromegalic population, carbohydrate and lipid metabolism abnormalities are closely linked. Long term exposure to an excess of growth hormone (GH) and Insulin-like growth factor-1 concentrations results in insulin resistance and an increased hepatic glucose production. The lipolytic effect of GH results in the mobilization of free fatty acids that further contributes to the decreased insulin sensitivity found in these patients. Some studies suggest that the presence of diabetes contributes to the increased mortality of acromegaly, although this remains controversial. Successful treatment of acromegaly usually results in significant, albeit incomplete improvements of the abnormal metabolic profile.

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing.

Catecholamine-induced lipolysis, the first step in generation of energy substrates through hydrolysis of triglycerides (TGs) 1, declines with age 2,3. The defect in mobilization of free fatty acids (FFA) in elderly is accompanied with increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. While catecholamine signaling in adipocytes is normal in elderly, how lipolysis is impaired in aging remains unknown 2,4. Here we uncover that the adipose tissue macrophages (ATMs) regulate age-related reduction in adipocyte lipolysis by lowering the bioavailability of norepinephrine (NE). Unexpectedly, unbiased whole transcriptome analyses of adipose macrophages revealed that aging upregulates genes controlling catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in aging restored catecholamine-induced lipolysis through downregulation of growth differentiation factor-3 (GDF3) and monoamine oxidase-a (MAOA) that is known to degrade NE. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing MAOA and caspase-1. Furthermore, inhibition of MAOA reversed age-related reduction in adipose tissue NE concentration and restored lipolysis with increased levels of key lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-innate signaling between sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.

Combined androgen excess and Western-style diet accelerates adipose tissue dysfunction in young adult, female nonhuman primates.

What are the separate and combined effects of mild hyperandrogenemia and consumption of a high-fat Western-style diet (WSD) on white adipose tissue (WAT) morphology and function in young adult female nonhuman primates? Combined exposure to mild hyperandrogenemia and WSD induces visceral omental (OM-WAT) but not subcutaneous (SC-WAT) adipocyte hypertrophy that is associated with increased uptake and reduced mobilization of free fatty acids. Mild hyperandrogenemia in females, principally in the context of polycystic ovary syndrome, is often associated with adipocyte hypertrophy, but the mechanisms of associated WAT dysfunction and depot specificity remain poorly understood. Female rhesus macaques were randomly assigned at 2.5 years of age (near menarche) to receive either cholesterol (C; n = 20) or testosterone (T; n = 20)-containing silastic implants to elevate T levels 5-fold above baseline. Half of each of these groups was then fed either a low-fat monkey chow diet or WSD, resulting in four treatment groups (C, control diet; T alone; WSD alone; T + WSD; n = 10/group) that were maintained until the current analyses were performed at 5.5 years of age (3 years of treatment, young adults). OM and SC-WAT biopsies were collected and analyzed longitudinally for in vivo changes in adipocyte area and blood vessel density, and ex vivo basal and insulin-stimulated fatty acid uptake and basal and isoproterenol-stimulated lipolysis. In years 2 and 3 of treatment, the T + WSD group exhibited a significantly greater increase in OM adipocyte size compared to all other groups (P < 0.05), while the size of SC adipocytes measured at the end of the study was not significantly different between groups. In year 3, both WAT depots from the WSD and T + WSD groups displayed a significant reduction in local capillary length and vessel junction density (P < 0.05). In year 3, insulin-stimulated fatty acid uptake in OM-WAT was increased in the T + WSD group compared to year 2 (P < 0.05). In year 3, basal lipolysis was blunted in the T and T + WSD groups in both WAT depots (P < 0.01), while isoproterenol-stimulated lipolysis was significantly blunted in the T and T + WSD groups only in SC-WAT (P < 0.01). At this stage of the study, subjects were still relatively young adults, so that the effects of mild hyperandrogenemia and WSD may become more apparent with increasing age. The combination of mild hyperandrogenemia and WSD accelerates the development of WAT dysfunction through T-specific (suppression of lipolytic response by T), WSD-dependent (reduced capillary density) and combined T + WSD (increased fatty acid uptake) mechanisms. These data support the idea that combined hyperandrogenemia and WSD increases the risk of developing obesity in females. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award number P50 HD071836 to C.T.R. and award number OD 011092 from the Office of the Director, National Institutes of Health, for operation of the Oregon National Primate Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

In vivo tissue sampling using solid-phase microextraction for non-lethal exposome-wide association study of CYP1A1 induction in Catostomus commersonii

Fish are widely used for monitoring aquatic ecosystem health and water contamination by organic toxicants from natural and anthropogenic sources. However, most of these studies only focused on the measurement of specific toxicants and did not examine the impact of chemical mixtures. In this study, we examined whether the tissue exposome captured in vivo with solid-phase microextraction (SPME) without lethal sampling and analyzed by liquid chromatography-high resolution mass spectrometry can detect differences between Catostomus commersonii exhibiting a significant induction of CYP1A1, through case/control comparisons, controlling for false discovery rates. We observed the presence of environmental toxicants in induced case fish known as potential inducers of CYP1A1. We also found significant changes in the levels of anti-oxidants, short-lived oxysterols and other lipids associated with CYP1A1 induction, possibly due to oxidative stress, lipid peroxidation and free fatty acids mobilization to maintain homeostatic state. In vivo SPME opens the way to perform repeated sampling on the same animal over the time and explore the individual internal exposome trajectory for better characterization of the links between toxicant load and health effects, at the individual scale.

GH signaling in human adipose and muscle tissue during 'feast and famine': amplification of exercise stimulation following fasting compared to glucose administration.

Fasting and exercise stimulates, whereas glucose suppresses GH secretion, but it is uncertain how these conditions impact GH signaling in peripheral tissues. To test the original 'feast and famine hypothesis' by Rabinowitz and Zierler, according to which the metabolic effects of GH are predominant during fasting, we specifically hypothesized that fasting and exercise act in synergy to increase STAT-5b target gene expression. Eight healthy men were studied on two occasions in relation to a 1 h exercise bout: i) with a concomitant i.v. glucose infusion ('feast') and ii) after a 36 h fast ('famine'). Muscle and fat biopsy specimens were obtained before, immediately after, and 30 min after exercise. GH increased during exercise on both examination days and this effect was amplified by fasting, and free fatty acid (FFA) levels increased after fasting. STAT-5b phosphorylation increased similarly following exercise on both occasions. In adipose tissue, suppressors of cytokine signaling 1 (SOCS1) and SOCS2 were increased after exercise on the fasting day and both fasting and exercise increased cytokine inducible SH2-containing protein (CISH). In muscle, SOCS2 and CISH mRNA were persistently increased after fasting. Muscle SOCS1, SOCS3, and CISH mRNA expression increased, whereas SOCS2 decreased after exercise on both examination days. This study demonstrates that fasting and exercise act in tandem to amplify STAT-5b target gene expression (SOCS and CISH) in adipose and muscle tissue in accordance with the 'feast and famine hypothesis'; the adipose tissue signaling responses, which hitherto have not been scrutinized, may play a particular role in promoting FFA mobilization.

FGF21 Mediates Alcohol‐Induced Adipose Tissue Lipolysis by Activation of Systemic Release of Catecholamine in Mice

Alcohol consumption leads to adipose tissue lipoatrophy and mobilization of free fatty acids (FFA), which contributes to hepatic fat accumulation in alcoholic liver disease (ALD). Fibroblast growth factor 21 (FGF21) is a metabolic regulator and plays an important role in glucose and lipid homeostasis in various diseases. Here, we demonstrate that FGF21 knockout (KO) mice are resistant to chronic‐binge alcohol exposure‐induced epididymal white adipose tissue lipolysis. Alcohol consumption increases FGF21 expression both in the liver and adipose tissue. Alcohol exposure causes adipose intracellular cAMP elevation, and lipolytic enzymes and coating protein activation, leading to FFA mobilization in both wild type and FGF21 KO mice. However, alcohol‐induced systemic elevation of catecholamine release, which is known to be a major player in adipose lipolysis by binding to the β‐adrenergic receptor and subsequently PKA activation, was markedly inhibited in KO mice. Supplementation with recombinant human FGF21 to alcohol‐exposed KO mice caused increased fat loss in parallel with an increase of circulating norepinephrine concentration. Furthermore, alcohol consumption‐induced fatty liver is blunted in the KO mice, indicating an inhibition of fatty acid reverse transport from adipose to the liver in the KO mice. In conclusion: FGF21 deficient mice are protected from alcohol‐induced adipose tissue excess‐lipolysis through a mechanism involving sympathetic nervous system (SNS) activation and catecholamine release. Strategies targeting the SNS activation to block FGF21‐mediated excess‐adipose lipolysis might be developed to prevent/treat alcohol‐induced fatty liver disease.

The Molecular Mechanism Underlying Continuous Exercise Training-Induced Adaptive Changes of Lipolysis in White Adipose Cells.

Physical exercise accelerates the mobilization of free fatty acids from white adipocytes to provide fuel for energy. This happens in several tissues and helps to regulate a whole-body state of metabolism. Under these conditions, the hydrolysis of triacylglycerol (TG) that is found in white adipocytes is known to be augmented via the activation of these lipolytic events, which is referred to as the “lipolytic cascade.” Indeed, evidence has shown that the lipolytic responses in white adipocytes are upregulated by continuous exercise training (ET) through the adaptive changes in molecules that constitute the lipolytic cascade. During the past few decades, many lipolysis-related molecules have been identified. Of note, the discovery of a new lipase, known as adipose triglyceride lipase, has redefined the existing concepts of the hormone-sensitive lipase-dependent hydrolysis of TG in white adipocytes. This review outlines the alterations in the lipolytic molecules of white adipocytes that result from ET, which includes the molecular regulation of TG lipases through the lipolytic cascade.

Interleukin-6 contributes to early fasting-induced free fatty acid mobilization in mice

Contracting muscle releases interleukin-6 (IL-6) enabling the metabolic switch from carbohydrate to fat utilization. Similarly, metabolism is switched during transition from fed to fasting state. Herein, we examined a putative role for IL-6 in the metabolic adaptation to normal fasting. In lean C57BL/6J mice, 6 h of food withdrawal increased gene transcription levels of IL-6 in skeletal muscle but not in white adipose tissue. Concomitantly, circulating IL-6 and free fatty acid (FFA) levels were significantly increased, whereas respiratory quotient (RQ) was reduced in 6-h fasted mice. In white adipose tissue, phosphorylation of hormone-sensitive lipase (HSL) was increased on fasting, indicating increased lipolysis. Intriguingly, fasting-induced increase in circulating IL-6 levels and parallel rise in FFA concentration were absent in obese and glucose-intolerant mice. A causative role for IL-6 in the physiological adaptation to fasting was further supported by the fact that fasting-induced increase in circulating FFA levels was significantly blunted in lean IL-6 knockout (KO) and lean C57BL/6J mice treated with neutralizing IL-6 antibody. Consistently, phosphorylation of HSL was significantly reduced in adipose tissue of IL-6-depleted mice. Hence, our findings suggest a novel role for IL-6 in energy supply during early fasting.

Brown adipose tissue dynamics in wild-type and UCP1-knockout mice: in vivo insights with magnetic resonance

We used noninvasive magnetic resonance imaging (MRI) and magnetic resonance spectroscopy to compare interscapular brown adipose tissue (iBAT) of wild-type (WT) and uncoupling protein 1 (UCP1)-knockout mice lacking UCP1-mediated nonshivering thermogenesis (NST). Mice were sequentially acclimated to an ambient temperature of 30°C, 18°C, and 5°C. We detected a remodeling of iBAT and a decrease in its lipid content in all mice during cold exposure. Ratios of energy-rich phosphates (ATP/ADP, phosphocreatine/ATP) in iBAT were maintained stable during noradrenergic stimulation of thermogenesis in cold- and warm-adapted mice and no difference between the genotypes was observed. As free fatty acids (FFAs) serve as fuel for thermogenesis and activate UCP1 for uncoupling of oxidative phosphorylation, brown adipose tissue is considered to be a main acceptor and consumer of FFAs. We measured a major loss of FFAs from iBAT during noradrenergic stimulation of thermogenesis. This mobilization of FFAs was observed in iBAT of WT mice as well as in mice lacking UCP1. The high turnover and the release of FFAs from iBAT suggests an enhancement of lipid metabolism, which in itself contributes to the sympathetically activated NST and which is independent from uncoupled respiration mediated by UCP1. Our study demonstrates that MRI, besides its potential for visualizing and quantification of fat tissue, is a valuable tool for monitoring functional in vivo processes like lipid and phosphate metabolism during NST.

Metabolic effects of a caffeinated sports drink consumed during a soccer match

The purpose of this study was to verify the effect of the intake of a caffeinated sport drink (CAFD) compared to a commercial carbohydrate drink (CHOD) on biochemical parameters and rate of perception exertion in youth soccer players. The experiment was setup in a double-blind crossover design where athletes consumed 5mL.Kg-1 body weight (BW) before the game and 3mL.Kg-1 BW every 15 minutes during the game. Intake of the CAFD resulted in increased blood glucose (BG) and blood lactate (BL) levels and average of maximum heart rate compared to consumption of the CHOD (p = 0.01). No difference was observed in the other variables. CAFD promoted greater plasmatic concentration of BG and BL compared with the CHOD. The CAFD did not increase the mobilization of free fatty acids, did not alter the plasma potassium concentration and was not able to reduce subjective perceived exertion.

Angptl3 Deficiency Is Associated With Increased Insulin Sensitivity, Lipoprotein Lipase Activity, and Decreased Serum Free Fatty Acids

Angiopoietin-like 3 (Angptl3) is a regulator of lipoprotein metabolism at least by inhibiting lipoprotein lipase activity. Loss-of-function mutations in ANGPTL3 cause familial combined hypolipidemia through an unknown mechanism. We compared lipolytic activities, lipoprotein composition, and other lipid-related enzyme/lipid transfer proteins in carriers of the S17X loss-of-function mutation in ANGPTL3 and in age- and sex-matched noncarrier controls. Gel filtration analysis revealed a severely disturbed lipoprotein profile and a reduction in size and triglyceride content of very low density lipoprotein in homozygotes as compared with heterozygotes and noncarriers. S17X homozygotes had significantly higher lipoprotein lipase activity and mass in postheparin plasma, whereas heterozygotes showed no difference in these parameters when compared with noncarriers. No changes in hepatic lipase, endothelial lipase, paraoxonase 1, phospholipid transfer protein, and cholesterol ester transfer protein activities were associated with the S17X mutation. Plasma free fatty acid, insulin, glucose, and homeostatic model assessment of insulin resistance were significantly lower in homozygous subjects compared with heterozygotes and noncarriers subjects. These results indicate that, although partial Angptl3 deficiency did not affect the activities of lipolytic enzymes, the complete absence of Angptl3 results in an increased lipoprotein lipase activity and mass and low circulating free fatty acid levels. This latter effect is probably because of decreased mobilization of free fatty acid from fat stores in human adipose tissue and may result in reduced hepatic very low density lipoprotein synthesis and secretion via attenuated hepatic free fatty acid supply. Altogether, Angptl3 may affect insulin sensitivity and play a role in modulating both lipid and glucose metabolism.

Hepatitis C as a metabolic disease

Before liver cirrhosis and hepatocellula carcinoma can develop, the early and long lasting features of hepatitis C are host metabolism modifications with a specific and so far unique metabolic syndrome that may associate insulin resistance, liver steatosis and hypo-betalipoproteinemia. These metabolic perturbations are directly induced by heptatitis C virus (HCV) replication and regress after viral suppression. Symmetrically HCV depends on glucose and lipid metabolism for its replication. HCV induced insulin resistance is both hepatic and peripheral. The insulin receptor pathway is impacted at several steps by viral proteins with probable functional consequences. Mechanism of peripheral insulin resistance remains obscure and the viral signals send to adipose tissue or muscles have to be identified. One major IR metabolic consequence might contribute to the mobilization of free fatty acids from periphery to the liver and to the constitution of liver steatosis. Importantly, HCV modifies with genotype-specific differences, the synthesis, degradation and secretion of lipid in a coordinated fashion to promote the accumulation of neutral lipids. The lipid droplets (LD) that are the lipid storage organelles are mandatory platforms for the assembly of infectious viral particles. In particular localization of core protein and NS5A on LD and mobilization of the LD are essential steps that control viral infectivity. Interestingly, the efficiency of HCV to the LD disposal and use correlates to viral production and may influences the extent of hepatic accumulation of lipids. The most striking association of HCV with lipid metabolism resides in the coincidence of the betalipoproteins and viral particles pathways with the formation of unique hybrid viral particles. Indeed HCV depends on a functional very low density lipoproteins (VLDL) assembly and secretion process to be secreted. HCV also modifies at different degree the VLDL composition forming sub viral particles, which are minimally modified VLDL that bear the viral envelop glycoproteins, or hybrid viral particles known as lipo-viral-particles (LVP), which contain all the viral and VLDL components that are highly infectious. Functions of these hybrid particles on the disease features and progression as well as therapeutic targets remain to be fully characterized. Thus, HCV appears to have developed an original and so far unique way with major clinical consequences to modify and use the lipid metabolism to persist in the host.

The Acute Phase Protein Serum Amyloid A Induces Lipolysis and Inflammation in Human Adipocytes through Distinct Pathways

BackgroundThe acute phase response (APR) is characterized by alterations in lipid and glucose metabolism leading to an increased delivery of energy substrates. In adipocytes, there is a coordinated decrease in Free Fatty acids (FFAs) and glucose storage, in addition to an increase in FFAs mobilization. Serum Amyloid A (SAA) is an acute phase protein mainly associated with High Density Lipoproteins (HDL). We hypothesized that enrichment of HDL with SAA, during the APR, could be implicated in the metabolic changes occurring in adipocytes.Methodology/Principal Findings In vitro differentiated human adipocytes (hMADS) were treated with SAA enriched HDL or recombinant SAA and the metabolic phenotype of the cells analyzed. In hMADS, SAA induces an increased lipolysis through an ERK dependent pathway. At the molecular level, SAA represses PPARγ2, C/EBPα and SREBP-1c gene expression, three transcription factors involved in adipocyte differentiation or lipid synthesis. In addition, the activation of the NF-κB pathway by SAA leads to the induction of pro-inflammatory cytokines and chemokines, as in the case of immune cells. These latter findings were replicated in freshly isolated mature human adipocytes.Conclusions/SignificanceBesides its well-characterized role in cholesterol metabolism, SAA has direct metabolic effects on human adipocytes. These metabolic changes could be at least partly responsible for alterations of adipocyte metabolism observed during the APR as well as during pathophysiological conditions such as obesity and conditions leading to insulin resistant states.

Healthy Lifestyle Behaviors and Triglycerides

Healthy Lifestyle Behaviors and Triglycerides

The molecular mechanism of human hormone-sensitive lipase inhibition by substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones

Hormone-sensitive lipase (HSL) plays an important role in the mobilization of free fatty acids (FFA) from adipocytes. The inhibition of HSL may offer a pharmacological approach to reduce FFA levels in plasma and diminish peripheral insulin resistance in type 2 diabetes. In this work, the inhibition of HSL by substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones has been studied in vitro. 5-methoxy-3-(3-phenoxyphenyl)-1,3,4-oxadiazol-2(3H)-one (compound 7600) and 5-methoxy-3-(3-methyl-4-phenylacetamidophenyl)-1,3,4-oxadiazol-2(3H)-one (compound 9368) were selected as the most potent HSL inhibitors. HSL is inhibited after few minutes of incubation with compound 7600, at a molar excess of 20. This inhibition is reversed in the presence of an emulsion of lipid substrate. The reactivation phenomenon is hardly observed when incubating HSL with compound 9368. The molecular mechanism underlying the reversible inhibition of HSL by compound 7600 was investigated using high performance liquid chromatography and tandem mass spectrometry. The stoichiometry of the inhibition reaction revealed that specifically one molecule of inhibitor was bound per enzyme molecule. The inhibition by compound 7600 involves a nucleophilic attack by the hydroxy group of the catalytic Ser of the enzyme on the carbon atom of the carbonyl moiety of the oxadiazolone ring of the inhibitor, leading to the formation of covalent enzyme–inhibitor intermediate. This covalent intermediate is subsequently hydrolyzed, releasing an oxadiazolone decomposition product, carbon dioxide and the active HSL form. On the basis of this study, a kinetic model is proposed to describe the inhibition of HSL by compound 7600 in the aqueous phase as well as its partial reactivation at the lipid–water interface.

Lowering of plasma triglycerides as a result of decreased free fatty acid mobilization.

Abstract 3, 5-Dimethylpyrazole and its metabolite 3-carboxy-5-methylpyrazole lower plasma FFA and decrease the level of plasma triglycerides. The metabolite given intravenously is more rapidly effective than 3, 5-dimethylpyrazole. Plasma cholesterol and phospholipids as well as blood glucose were not affected by these acute treatments.