Free Fatty Acid Mobilization Research Articles

HDL and the progression of atherosclerosis: new insights

Aims Lowering low-density lipoprotein (LDL) cholesterol or raising high-density lipoprotein (HDL) cholesterol can result in significant cardiovascular benefit, both in terms of reduction of events and also, to a variable extent, of atheromatous lesions. LDL and HDL have opposite roles in body cholesterol regulation and, both reduced deposition (LDL reduction) and increased removal (raised HDL) can improve vascular disease. Very recently, studies using recombinant apolipoprotein AI liposomes (in particular with the mutant apo AIMilano) have shown that direct infusion can effectively remove cellular cholesterol and dramatically reduce established atheromatous plaques in animals and in coronary patients. It has thus become of growing interest, the possibility of raising HDL by pharmacological treatments. This review will attempt to investigate existing and novel methodologies for HDL raising. Methods and results HDL raising can be achieved by using drugs active on the peroxisome proliferator activated receptor α (PPAR α) system, particularly using fibrates or n-3 fatty acids and, possibly more effectively, by using nicotinic acid. The activity of this agent has been traditionally linked to a reduced free fatty acid (FFA) mobilization from adipose tissue. More recently, it has been noted that nicotinic acid can activate the PPAR system, by stimulating all three PPAR isoforms (α, γ, δ). This mode of action seems to more effectively explain the striking HDL-raising properties of the drug. Conclusions Newly discovered mechanisms of nicotinic acid can explain, on the one hand, reduced atherosclerosis progression in secondary prevention patients treated with statins and, on the other hand, improved body cholesterol mobilization, effectively reducing cholesterol pool sizes.

Effect of niacin on lipoproteins and atherosclerosis

Niacin has been in use for the past 50 years to treat lipid disorders and atherosclerotic cardiovascular disease. We have recently demonstrated that niacin, by selective inhibition of liver diacylglycerol acyltransferae (DGAT)2, a rate-limiting enzyme in triglyceride synthesis, inhibits triglyceride synthesis thereby decreasing the secretion of apolipoprotein (Apo)B-containing very low-density lipoprotein and low-density lipoprotein particles. We have demonstrated that niacin increases ApoAI–high-density lipoprotein (HDL), mainly through the selective inhibition of hepatic uptake and removal of ApoAI–HDL (but not HDL-cholesterol ester). Emerging data from our laboratory provide evidence for the nonlipid-related effects of niacin on vascular oxidative and inflammatory processes involved in atherosclerosis. Although decreased free fatty acid mobilization from adipose tissue via a newly described niacin receptor (HM74A) is reported as a mechanism by which niacin decreases triglycerides, both physiologically ...

Nutritional Considerations in Wound Care

Statistics show that malnutrition among older adult patients is a widespread problem in US health care facilities. The 2002 Nutritional Screening Initiative, a multidisciplinary coalition led by the American Dietetic Association and the American Academy of Family Physicians, has reported rather alarming facts on the nutritional status of this patient population: 40% to 60% of hospitalized older adults are either malnourished or at risk for malnutrition; 40% to 85% of nursing home residents are malnourished; and 20% to 60% of home care patients are malnourished. 1 This is a serious problem. Lack of proper nutrition can have a significant impact on a patient’s ability to recover from illness, disease, or surgery. Malnourished patients are prone to diminished muscle strength; development of pressure ulcers, infection, or postoperative complication; and poor wound healing. 2 In addition, malnourished older adults tend to be frail or fail to thrive, 3 increasing their risk for skin breakdown. Body Response in Wound Healing Having a major wound or infection increases the body’s energy and protein needs as a result of pathologic processes and stress-induced changes. The body’s protective inflammatory response precipitates a cascade of events, including increased blood flow to the site and an increase in metabolic rate (hypermetabolism). Glycogen and protein stores are mobilized by the increased metabolism to meet the needs for glucose and stress factors (cytokines and interleukin-1 and interleukin-6). With stress, hormonal changes cause a shift in insulin and counter-regulatory hormones, such as cortisol, glucagons, and catecholamines. This results in a greater increase in counterregulatory hormones than in insulin. Because insulin assists in carbohydrate and lipid storage and protein synthesis, metabolic and energy rates increase and deplete body protein stores. Hormonal changes also lead to increased glycogen breakdown and mobilization of free fatty acids. The breakdown of glucagons increases glucose production from amino acids, ultimately resulting in a reduced storage of glucose, fatty acids, and proteins. Fat is used as an energy source, albeit

HIV Protease Inhibitors and Hyperlipidemia

Treatment with a combination of highly active antiretroviral agents considerably reduces the morbidity and mortality of human immunodeficiency virus (HIV) infection.1 Although the clinical benefits are considerable, the protease inhibitors contained in these antiretroviral regimens produce a lipodystrophy syndrome characterized by changes in body fat distribution, hyperlipidemia, and insulin resistance.2 The hyperlipidemia is attributable to increases in very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL), and it can produce serious cardiovascular complications including endothelial dysfunction and atherosclerosis.3,4 See page 124 A number of studies indicate that the hyperlipidemia produced by HIV protease inhibitors is attributable to an increase in VLDL production. Data from HIV positive patients indicate that excessive free fatty acid (FFA) mobilization occurs because of insulin resistance in the adipose tissue,5 resulting in increased VLDL–triglyceride production and apoB synthesis. Likewise, studies in C57BL/6 mice treated with HIV protease inhibitors demonstrate increased VLDL-triglyceride production and apoB synthesis,6 and increased triglyceride synthesis also was observed in HepG2 cells and AKR/J mice incubated with protease inhibitors.7 The hyperlipidemia in the mice was attributed to elevated fatty acid and cholesterol synthesis in the liver and adipose tissue caused by activation of sterol regulatory element binding protein (SREBP) 1 and 2,8 whereas studies in cultured liver cells suggest that the mechanism involves decreased degradation of nascent apoB attributable to inhibition of the 20S proteasome.9 There is also evidence that HIV protease inhibitors do not reduce the clearance of either VLDL or triglyceride-rich lipoprotein remnants,5,6,10 providing additional support for a mechanism based on increased VLDL production. However, other studies indicate that impaired lipoprotein …

Farmacologia da niacina ou ácido nicotínico

Niacin or nicotinic acid is a soluble vitamin with hypolipidemic properties. Niacin reduces triglycerides (20 50%), LDL-c (5-25%), and raises HDL-c (15-35%). The Coronary Drug Project study showed that the use of niacin was associated with reduction on coronary events and total mortality, and more recently it has been demonstrated that niacin combined with other hypolipidemic drugs can attenuate the progression of coronary atherosclerosis. Niacin appears to reduce the mobilization of free fatty acids from the adipocytes, acting on specific receptors, diminishing the liver formation of triglyceride-rich lipoproteins. There are two forms of niacin, one of rapid absorption (crystalline), more commonly associated with flushing, and another of extended release, recently reported to be better tolerated. The use of niacin can be associated with dyspepsia, increased plasma levels of liver enzymes and also with a modest elevation in glucose and uric acid plasma levels, at least using the extended-release preparation up to 2 g/d.

Pharmacology of niacin or nicotinic acid

Niacin or nicotinic acid is a soluble vitamin with hypolipidemic properties. Niacin reduces triglycerides (20 50%), LDL-c (5-25%), and raises HDL-c (15-35%). The Coronary Drug Project study showed that the use of niacin was associated with reduction on coronary events and total mortality, and more recently it has been demonstrated that niacin combined with other hypolipidemic drugs can attenuate the progression of coronary atherosclerosis. Niacin appears to reduce the mobilization of free fatty acids from the adipocytes, acting on specific receptors, diminishing the liver formation of triglyceride-rich lipoproteins. There are two forms of niacin, one of rapid absorption (crystalline), more commonly associated with flushing, and another of extended release, recently reported to be better tolerated. The use of niacin can be associated with dyspepsia, increased plasma levels of liver enzymes and also with a modest elevation in glucose and uric acid plasma levels, at least using the extended-release preparation up to 2 g/d.

Endocrinal responses in exercising horses

The intensity and duration of exercise exert a major influence on energy expenditure and physiological changes in the horse. Stressful environmental conditions, acclimation, and training status may further modify these responses. To maintain functional homeostasis during exercise, changes in autonomic nervous activity and hormone secretion are coupled to both the feedforward and the feedback mechanisms that control substrate mobilisation and utilisation. During exercise, both the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis are activated, which increases the circulating levels of adrenocorticotropin (ACTH), cortisol, adrenaline and noradrenaline. Furthermore, adrenaline inhibits the release of insulin from the pancreas. Catecholamines, adrenaline, and noradrenaline increase glycogen breakdown in the muscles. In the liver, catecholamines, together with cortisol, increase blood glucose by activating glycogen breakdown and gluconeogenesis. Cortisol and catecholamines also enhance the mobilisation of free fatty acids from fat stores. In addition to efficient energy metabolism, the ability to exercise is highly dependent on the well-coordinated neuroendocrine control of cardiovascular function. Catecholamines increase oxygen delivery during exercise by enhancing cardiac output, splenic erythrocyte release, and skeletal muscle flow. Furthermore, cardiovascular homeostasis is maintained by changes in plasma renin activity and in plasma concentrations of atrial natriuretic peptide (ANP), arginine vasopressin, and aldosterone.

Lipolysis in the absence of hormone-sensitive lipase: evidence for a common mechanism regulating distinct lipases.

Hormone-sensitive lipase (HSL) is presumed to be essential for lipolysis, which is defined as the mobilization of free fatty acids from adipocytes. In the present study, we investigated the effects of various lipolytic hormones on the lipolysis in adipocytes derived from mouse embryonic fibroblasts (MEF adipocytes) prepared from HSL-deficient mice (HSL-/-). HSL-/- MEF differentiated into mature adipocytes in a manner indistinguishable from that of wild-type mice. Both isoproterenol (ISO) and tumor necrosis factor (TNF)-alpha stimulated the rate of lipolysis in HSL-/- MEF adipocytes, although to a lesser extent than in wild-type cells, and these lipolytic activities were inhibited by H-89, a cAMP-dependent protein kinase inhibitor, and troglitazone, respectively. Thus, the responses of the residual lipolytic activity to lipolytic hormones and TNF-alpha were well conserved in the absence of HSL. Extracts from HSL-/- MEF adipocytes hydrolyzed triacylglycerol (TG) but not cholesterol ester, indicating that the residual lipolytic activity was mediated by another TG-specific lipase. The TG lipase activity, which was decreased in cytosolic fraction in response to ISO, was increased in fat cake fraction. Therefore, translocation of the TG lipase may explain, at least partially, the ISO-stimulated lipolysis in HSL-/- adipocytes. In conclusion, lipolysis is mediated not only by HSL but also by the non-HSL TG lipase, whose responses to lipolytic hormones are similar to those of HSL. We propose that both lipases are regulated by common mechanism of lipolysis.

Systemic fatty acid responses to transient focal cerebral ischemia: influence of neuroprotectant therapy with human albumin.

Human albumin therapy is highly neuroprotective in focal cerebral ischemia. Because albumin is the main carrier of free fatty acids (FFA) in plasma, we investigated the content and composition of plasma FFA in jugular vein (JV), femoral artery (FA) and femoral vein (FV) of rats given intravenous human albumin (1.25 g/kg) or saline vehicle (5 mL/kg) 1 h after a 2 h middle cerebral artery occlusion (MCAo) or sham surgery. Arachidonic acid was the only FFA significantly increased by MCAo in all plasma samples prior to albumin administration, remaining at the same level regardless of subsequent treatments. Albumin treatment induced in both MCAo- and sham-groups a 1.7-fold increase in total plasma FFA (mainly 16:0, 18:1, 18:2n-6) during 90-min reperfusion. MCAo selectively stimulated the albumin-mediated mobilization of n-3 polyunsaturated fatty acids (PUFA), with an early increase in 22:5n-3 and 22:6n-3 in the FA prior to detectable changes in the JV. In the MCAo-albumin group, the lower level of FFA in JV as compared with FA and FV suggests an albumin-mediated systemic mobilization and supply of FFA to the brain, which may favor the replenishment of PUFA lost from cellular membranes during ischemia and/or to serve as an alternative source of energy, thus contributing to albumin neuroprotection.

Endocrine regulation of subcutaneous fat metabolism during cold exposure in humans.

Increased oxidation of carbohydrates and free fatty acids is a well-known phenomenon during cold stress. Nevertheless, sources of the fuels used have not been fully clarified as yet. Thus, the aim of our study was to evaluate the effect of acute cold exposure on lipid and carbohydrate metabolism in human subcutaneous adipose tissue and to identify the possible regulatory mechanisms involved. Ten volunteers were exposed for 30 min to an ambient temperature of 4 degrees C. Interstitial metabolism was assessed with the aid of the microdialysis technique. Lipolysis intensity was evaluated from changes of glycerol concentration in plasma and in dialysate. Cold exposure induced a significant increase of glycerol concentration both in plasma (by 199 +/- 16%, p < 0.01) and in dialysate (by 308 +/- 58%, p < 0.001). No changes in glucose concentration were found whether in plasma or in the dialysate. Ethanol concentration in dialysate increased (148 +/- 15%, p < 0.01), indicating a slower blood flow in the subcutaneous region. Plasma concentrations of various gluco- and/or lipid-regulatory hormones remained unaffected by the cold exposure, except for norepinephrine, which rose about threefold (309 +/- 41%, p < 0.001). The data indicate an important role for subcutaneous adipose tissue in mobilization of free fatty acids during cold exposure. This process seems to be regulated by the sympathetic nervous system, whereas hormones involved in the regulation of lipid metabolism, such as epinephrine, insulin, cortisol, and growth hormone, may play a less significant role-at least under the conditions studied.

Muscarinic cholinergic receptor blockade impairs free fatty acid mobilization during fasting in pigeons (Columba livia).

The effects of intracerebroventricular pretreatment with muscarinic (scopolamine or methylscopolamine; 2.7 nmol or 5.4 nmol) or nicotinic (mecamylamine, 2.7 nmol or 5.4 nmol) cholinergic receptor antagonists on plasma free fatty acid increases induced by intracerebroventricular injections of carbachol in conscious resting pigeons (Columba livia) were examined. Plasma glucose levels were also measured throughout the experiments. Pretreatment with methylscopolamine suppressed the lipolytic effect of carbachol injections, while mecamylamine left this response unchanged. Neither carbachol treatment alone, nor the pretreatments with cholinergic agents affected glucose levels. Subsequently, the effects of intracerebroventricular injections of methylscopolamine were investigated in 24-h food-deprived pigeons. The increase in free fatty acid levels after fasting was of a magnitude similar to that observed after carbachol treatment; intracerebroventricular injections of methylscopolamine (5.4 nmol) transiently but powerfully decreased plasma free fatty acids in 24-h food-deprived pigeons to levels comparable to those of free-feeding animals. The fasting-induced decrease in glucose levels was not affected by this treatment. These data indicate that the lipolytic response induced by carbachol may be mediated by central muscarinic cholinergic receptors and that this central cholinergic mechanism partially contributes to plasma free fatty acid increases observed during fasting. Furthermore, the absence of effects on glucose levels suggests that these cholinergic mechanisms participate selectively in the lipolytic component of the metabolic response to fasting.

Atherogenesis: Historical Perspective, Biochemical Mechanism, and Current Status

Collation and integration of diverse multidisciplinary research reports into a compatible sequence of biochemical reactions in atherosclerosis defines a primary dysfunctional site residing in the metabolic processing of acetyl Co-A in oxidative phosphorylation. This site, subject to dysfunctional gene expression in the later phase of the mammalian life process, is also subject to evolutionary genetic speciation events defined by orthologous genes. Depressed processing of acetyl Co-A in the citric acid-oxidative phosphorylation cycle can account for increased plasma free fatty acid (FFA), depressed clearing of alimentary lipemia, chylomicrons, increased uploading of plasma protein with lipid (LDL), increased plasma triglycerides and cholesterol, all of which serve as historical biochemical indices of atherosclerosis. Depressed function of this citric acid-oxidative phosphorylation sequence of biochemical reactions embraces multiple sequentially related reaction sites including deficient biosynthesis and transfer of methyl groups, deficient heparin induced lipoprotein lipase, declining rate of albumin biosynthesis, declining generation of high energy phosphate (ATP), increased generation or mobilization of FFA, increased thrombin, depressed activation of plasminogen and increased biosynthesis and turnover of fibrinogen into polymerized fibrin atheroma.

Roles of insulin-like growth factor-I and growth hormone in mediating insulin resistance in acromegaly.

Most patients with acromegaly have some degree of insulin resistance. The principal mediator of insulin resistance in acromegaly is hypersecretion of growth hormone. Growth hormone acts at several levels to block insulin actions including inhibiting phosphorylation of the insulin receptor and one of its principal signaling molecules IRS-1 in response to insulin administration. This leads to reduced sensitivity to insulin in the periphery in stimulating peripheral glucose uptake and to increased resistance to insulin's ability to suppress gluconeogenesis. Furthermore growth hormone excess leads to mobilization of free fatty acids which inhibit insulin stimulated glucose oxidation by acting as a competitive energy source thus leading to further worsening of insulin resistance. These abnormalities can be overcome by administering agents which either lower growth hormone secretion or block growth hormone action. The role of elevated IGF-I in acromegaly in mediating insulin resistance is more difficult to analyze. Indirect inferences from the data that are available suggest that IGF-I is acting to enhance insulin sensitivity and partially counteracting the insulin antagonistic effects of growth hormone. In a recent study administration of IGF-I to acromegalics was shown to improve insulin sensitivity over and above the level that could be achieved by simply blocking growth hormone action. Therefore it appears that the net effect of IGF-I is to counterbalance some of the effects of growth hormone hypersecretion on insulin resistance.

Fatty acid kinetics and carbohydrate metabolism during electrical exercise in spinal cord-injured humans.

Motor center activity and reflexes from contracting muscle have been shown to be important for mobilization of free fatty acids (FFA) during exercise. We studied FFA metabolism in the absence of these mechanisms: during involuntary, electrically induced leg cycling in individuals with complete spinal cord injury (SCI). Healthy subjects performing voluntary cycling served as controls (C). Ten SCI (level of injury: C5-T7) and six C exercised for 30 min at comparable oxygen uptake rates (approximately 1 l/min), and [1-14C]palmitate was infused continuously to estimate FFA turnover. From femoral arteriovenous differences, blood flow, muscle biopsies, and indirect calorimetry, leg substrate balances as well as concentrations of intramuscular substrates were determined. Leg oxygen uptake was similar in the two groups during exercise. In SCI, but not in C, plasma FFA and FFA appearance rate fell during exercise, and plasma glycerol increased less than in C (P < 0.05). Fractional uptake of FFA across the working legs decreased from rest to exercise in all individuals (P < 0.05) but was always lower in SCI than in C (P < 0.05). From rest to exercise, leg FFA uptake increased less in SCI than in C subjects (14 +/- 3 to 57 +/- 20 vs. 41 +/- 13 to 170 +/- 57 micromol x min(-1) x leg(-1); P < 0.05). Muscle glycogen breakdown, leg glucose uptake, carbohydrate oxidation, and lactate release were higher (P < 0.05) in SCI than in C during exercise. Counterregulatory hormonal changes were more pronounced in SCI vs. C, whereas insulin decreased only in C. In conclusion, FFA mobilization, delivery, and fractional uptake are lower and muscle glycogen breakdown and glucose uptake are higher in SCI patients during electrically induced leg exercise compared with healthy subjects performing voluntary exercise. Apparently, blood-borne mechanisms are not sufficient to elicit a normal increase in fatty acid mobilization during exercise. Furthermore, in exercising muscle, FFA delivery enhances FFA uptake and inhibits carbohydrate metabolism, while carbohydrate metabolism inhibits FFA uptake.

Thiazolidinediones increase plasma-adipose tissue FFA exchange capacity and enhance insulin-mediated control of systemic FFA availability.

We studied the effects of thiazolidinedione treatment (rosiglitazone 1 or 10 micromol.kg(-1).day(-1) or darglitazone 1.3 micromol.kg(-1).day(-1) for 3 weeks) on lipid metabolism in obese Zucker rats. In the basal 7-h fasted state, rosiglitazone (10 micromol.kg(-1).day(-1)) and darglitazone corrected the hypertriglyceridemia by increasing plasma triglyceride (TG) clearance and decreasing hepatic TG production, as assessed using Triton WR 1339. Free fatty acid (FFA) metabolism was assessed using 3H-palmitate tracer by estimating rates of plasma FFA appearance (Ra), whole-body FFA oxidation (Rox), and tissue-specific nonoxidative FFA disposal (Rfs). Basal Ra, plasma FFA levels, and clearance were increased by both thiazolidinediones. Detailed studies were conducted with darglitazone, which under basal conditions increased Ra (+114%), Rox (+51%), and Rfs in adipose tissues. During euglycemic clamps performed at insulin levels corresponding to those observed postprandially, darglitazone increased the glucose infusion rate from 4.7 to 13.3 mg.min(-1) and, in contrast to the basal state, it decreased Ra (-67%), Rox (-84%), and Rfs in adipose tissue, muscle, and liver. We concluded that thiazolidinediones 1) ameliorate hypertriglyceridemia by lowered hepatic TG production and augmented TG clearance (two separate kinetic effects), 2) enhance insulin-mediated suppression of systemic FFA mobilization while increasing the capacity to mobilize FFA during fasting, 3) increase FFA trafficking into adipose tissue by increasing the ability of adipose tissue to take up and store FFA, and 4) enhance metabolic flexibility by improving glucoregulation under hyperinsulinemic conditions (possibly involving reduced skeletal muscle and liver exposure to fatty acids) and augmenting the capacity to utilize FFAs during fasting.

Inhibition of thyroid hormone binding to the nuclear receptor by mobilization of free fatty acids.

Through binding to its nuclear receptor (TR), thyroid hormone (T3) activates the expression of the thyroid hormone-responsive genes that are essential for the regulation of energy consumption. Previously, we found that free fatty acids (FFAs) and their CoA esters strongly inhibited the binding of T3 to its nuclear receptor in vitro. In the present study, we have examined the physiological relevance of this inhibitory mechanism. TRs in isolated nuclei and in a solubilized free form were half-maximally inhibited with oleic acid at 120 and 2.8 microM, respectively. The lower sensitivity of the nuclear TR as compared with free TR was attributed to the nuclear envelope and the association of TR with chromatin. Among TRs in chromatin, those in the transcriptionally active chromatin exhibited the highest sensitivities to FFAs and were inhibited half-maximally by oleic acid at 10 microM. While the plasma concentration of FFAs in total was 0.4 to 1 mM, their nuclear concentration was about 5 microM. Thus, the sensitivities of TRs in active chromatin and in solubilized form were at physiological levels with respect to the nuclear FFA concentration. We further examined the effect of FFA mobilization on the T3-binding to TR in animals. Nuclear T3-binding was significantly inhibited when plasma and cellular FFAs were increased by norepinephrine in vivo. The increase in cellular FFAs and the TR-inhibition were well correlated, and much larger in the heart than in the liver and kidney. These results suggest that TR is negatively controlled by increased FFAs in a tissue-dependent manner.

Physical activity as a metabolic stressor

Both physical activity and diet stimulate processes that, over time, alter the morphologic composition and biochemical function of the body. Physical activity provides stimuli that promote very specific and varied adaptations according to the type, intensity, and duration of exercise performed. There is further interest in the extent to which diet or supplementation can enhance the positive stimuli. Prolonged walking at low intensity presents little metabolic, hormonal, or cardiovascular stress, and the greatest perturbation from rest appears to be from increased fat oxidation and plasma free fatty acid mobilization resulting from a combination of increased lipolysis and decreased reesterification. More intense jogging or running largely stimulates increased oxidation of glycogen and triacylglycerol, both of which are stored directly within the muscle fibers. Furthermore, these intramuscular stores of carbohydrate and fat appear to be the primary substrates for the enhanced oxidative and performance ability derived from endurance training-induced increases in muscle mitochondrial density. Weightlifting that produces fatigue in brief periods (ie, in 15-90 s and after 15 repetitive contractions) elicits a high degree of motor unit recruitment and muscle fiber stimulation. This is a remarkably potent stimulus for altering protein synthesis in muscle and increasing neuromuscular function. The metabolic stress of physical activity can be measured by substrate turnover and depletion, cardiovascular response, hormonal perturbation, accumulation of metabolites, or even the extent to which the synthesis and degradation of specific proteins are altered, either acutely or by chronic exercise training.

Changes in intermediary metabolism in severe surgical illness.

Under normal circumstances there is a reciprocal relation between the availability of free fatty acids (FFAs) and glucose in plasma. In the fasted state, FFAs predominate in both availability and the relative contribution to energy production, whereas the same is true for glucose in the fed state. The extent of glucose oxidation is directly determined by its availability, whereas FFAs are normally available well in excess of their rate of oxidation. The rate of FFA oxidation is determined by the rate of transfer into the mitochondria via the carnitine palmitoyltransferase (CPT) enzyme system, which in turn is regulated by the metabolism of glucose. With critical illness the stress response involves mobilization of both plasma glucose and FFAs simultaneously in both the fed and fasted states. In the situation of excess availability of substrates, the metabolism of glucose limits the oxidation of FFAs, thereby channeling those fatty acids into triglyceride (TG) stores in the muscle and the liver. The high FFA concentrations and increased tissue TG stores can limit glucose clearance from the blood, thereby contributing to the development of hyperglycemia. Also, the excessive metabolism of glucose can result in lacticacidemia and can contribute to the depletion of muscle glutamine. The nutritional treatment of such patients must account for these underlying metabolic responses to avoid amplifying potentially detrimental responses to the excess availability of substrates already present in the fasting state.

Free and esterified fatty acid and cholesterol synthesis in adult males and its effect on the doubly-labelled water method.

The purpose of the present study was to estimate whole-body fatty acid and cholesterol synthesis in weight-stable adults and to determine the likely effect on the doubly-labelled water (DLW) method for measuring energy expenditure. Synthesis was measured by 2H incorporation over 14 d in six adult males in approximate energy balance following noradrenaline infusion to maximize mobilization of free fatty acid from adipose tissue. The inter-individual variation in synthesis rates was large and in one subject the proportion of free fatty acid synthesized was ten times that of the mean of the rest of the group; the fasting concentration of esterified fatty acid in this subject was five times that of the rest of the group indicating likely violation of the assumptions underlying the calculation of whole-body synthesis. After 14 d of labelling in the other five subjects, 0.9 (SEM 0.3)% of the circulating free fatty acid, 9.3 (SEM 3.0)% of the esterified fatty acid, 14.6 (SEM 2.4)% of the free cholesterol and 28.3 (SEM 3.7)% of esterified cholesterol had been synthesized de novo. A high rate of synthesis correlated with a low pre-dose 2H abundance both within and between lipid classes suggesting that natural 2H abundance variations in some lipid classes may be used to determine their metabolic origin. Whole-body synthetic rates were 8 g/d for fatty acid and 0.3-0.5 g/d for cholesterol. These values correspond to very small errors on DLW-derived estimates of CO2 production; -2.5 litres/d for fatty acid and -0.1 to -0.2 litres/d for cholesterol. These results, obtained in subjects typically consuming a diet with a lower fat and cholesterol content that the typical Western diet, suggest that the DLW method is unlikely to be affected by fatty acid and cholesterol synthesis in subjects in energy balance consuming a typical Western diet.

Albumin inhibits apolipoprotein AI and AII production in human hepatoblastoma cell line (Hep G2): additive effects of oleate–albumin complex

Although the role of multiple humoral agents (such as plasma albumin, glucose, hormones etc.) are implicated in lipoprotein metabolism, the mechanism of action of these agents on various steps of the synthesis and secretion of lipoproteins and apolipoproteins (protein moieties of lipoproteins) are not completely understood. Specifically, the hepatocellular mechanisms of the effect of albumin and fatty acids on apolipoprotein (apo) AI and AII [major proteins of high density lipoproteins (HDL)] synthesis and secretion are not known. Using human hepatoblastoma cells (Hep G2) as an in vitro model system, this study examined the effect of albumin and fatty acids on the synthesis, secretion, and the steady-state mRNA expression of apo AI and AII. The data indicated that the incubation of Hep G2 cells with albumin, dose-dependently, inhibited apo AI and AII accumulation (secretion) in the media, de novo synthesis, and the steady-state mRNA expression. Albumin did not alter total protein synthesis; thus the effect of albumin appeared to be specific for the synthesis and secretion of apo AI and apo AII. Free fatty acids (FFA) are transported by albumin and diseases characterized by enhanced FFA mobilization (e.g. diabetes mellitus) are associated with low HDL levels. Studies were therefore performed to examine the effect of albumin-bound-oleic acid on apo AI and apo AII production. The results showed that the albumin–oleate complex further increased the inhibitory effects of albumin on apo AI and apo AII production. These data suggest how HDL metabolism may be affected at the hepatocellular level by alterations in plasma albumin concentrations and/or fatty acid mobilization in clinical situations characterized by altered HDL levels.