Increased Serum Free Fatty Acids Research Articles

Role of serum free fatty acids in L-tryptophan transport into the liver.

A large part of L-tryptophan (Trp) present in the plasma or serum is bound to albumin (McMenamy et al., 1957). It is known (Curzon et al., 1974; Kragh-Hansen, 1983) that this binding of Trp to albumin is affected by various substances such as free fatty acids (FFA). It has been shown (Madras et al., 1974; Curzon et al., 1972) that in the plasma of rats under feeding of a high fat diet, starvation, and immobilization, free Trp levels are enhnaced by an increase in FFA levels. Madras et al. (1974) have demonstrated that in rats fed a protein-car-bonhydrate diet with various amounts of fat, liver Trp content dose not correlate with an increase in free serum Trp levels consequent to increased serum FFA levels. Recently, we have reported (Sasaki et al, 1993) that in rats fed a 40% lard-containing diet, there are little changes in the disappearance of blood Trp and the content of liver Trp under a marked increase in free serum Trp levels, and have suggested that under physiological levels of serum Trp and albumin, increased serum FFA levels do not have a large influence on Trp transport into the liver. However, it is still unclear whether or not serum FFA plays a facilitating role in Trp transport into the liver of rats, although increased serum FFA levels seem to have little effect on Trp transport into the liver under physiological levels of serum Trp and albumin. We, therefore, attempted to further clarify the role of serum FFA in Trp transport into the liver using analbuminemic rats, which are the mutant strain established from Sprague-Dawley rats and are genetically lacking in plasma albumin (Nagase et al., 1979).

Lipolysis-induced partitioning of free fatty acids to lipoproteins: effect on the biological properties of free fatty acids.

Free fatty acids (FFA) released during the lipolysis of triglyceride (TG)-rich lipoproteins in vivo are generally believed to be bound to serum albumin. When hypertriglyceridemic (HTG) sera were lipolyzed in vitro by purified bovine milk lipoprotein lipase (LpL), there was an 11- to 18-fold increase in serum FFA levels, and a major portion (> 80%) of the FFA in serum was partitioned to lipoprotein fractions. The greatest portion (33%) of FFA in lipolyzed HTG serum was associated with newly formed flocculent remnants that banded just below low density lipoproteins (LDL) in the density gradient tube. Very low density lipoprotein (VLDL), LDL, and high density lipoprotein (HDL) fractions in lipolyzed HTG serum contained 18- to 29-times more FFA molecules than those in prelipolysis serum. Analysis of the fatty acyl chain composition of FFA in lipolyzed HTG serum showed that the extent of partitioning of saturated FFA into the lipoprotein fractions relative to that of polyunsaturated FFA was about 4.5- to 11-times greater than that partitioned into the free protein fraction; most (84%) of FFA partitioned into flocculent remnants were saturated fatty acids. In vivo lipolysis of TG-rich lipoproteins in HTG subjects, induced by heparinization, resulted in only a small (2.8-fold) increase in serum FFA and little or no increase in the partitioning of FFA to lipoproteins. However, in vitro incubation of the postheparin serum at 37 degrees C for 90 min resulted in a 2.9- to 6.8-fold increase in the serum FFA level and the partitioning of > 66% of total serum FFA into lipoprotein fractions. Studies of the interaction of various plasma fractions from control and in vitro lipolyzed HTG serum with cultured mouse peritoneal macrophages (MPM) showed that FFA partitioned to lipoprotein fractions were highly cytotoxic to cultured MPM, whereas FFA partitioned to albumin at a 10 x greater concentration were not cytotoxic. The cytotoxic potencies of FFA bound to lipoproteins and albumin were further compared after in vitro incorporation of FFA (oleic acids) into LDL and to albumin. FFA bound to LDL but not to albumin were cytotoxic to cultured MPM; the cytotoxicity of FFA bound to LDL was more closely related to the FFA to LDL-cholesterol molar ratio than to the total FFA concentration in the culture dish. The ability of FFA bound to LDL and albumin to induce foam cell formation was studied in THP-1 monocyte-derived macrophages, which were less susceptible to cytotoxicity produced by FFA bound to LDL than MPM.(ABSTRACT TRUNCATED AT 400 WORDS)

Low Serum Ionized to Total Calcium Ratio: Association with Geriatric Diabetes mellitus and with Other Cardiovascular Risk Factors?

Serum total calcium concentrations (CaT) were increased, ionized calcium concentrations (CaI) normal, and the CaI/CaT ratios decreased in 125 geriatric diabetics as compared with 379 non-diabetic controls. In the whole population of 558 consecutive geriatric inpatients, the CaI/CaT ratios were inversely correlated with body weight, diastolic blood pressure and plasma glucose. The findings and calculations help to explain some inconsistencies and discrepancies in previous studies concerning calcaemia in diabetes, hypertension and the 'metabolic syndrome' of clustered risk factors for cardiovascular diseases. They also demonstrate that CaT and the 'correction' of CaT for serum albumin concentration can be biased in diabetes and other conditions closely associated with cardiovascular risks. Increased serum free fatty acids could at least in part explain low ratios.

S-Mg Does Not Change Inversely to S-FFA During Acute Stress Situations

The apparently divergent changes in serum magnesium (S-Mg) and serum free fatty acids (S-FFA) in stress situations associated with elevated levels of circulating adrenaline were studied experimentally in 12 healthy volunteers, who were each given three adrenaline infusions (0.05 micrograms/kg bw/min over one hundred twenty minutes). Before the adrenaline infusions the volunteers were treated for three days with either a non-selective beta-blocking agent (propranolol) or a beta-1-selective agent (atenolol) or with placebo. Six of the volunteers underwent a fourth adrenaline infusion after pretreatment with a beta-2-selective beta-blocking agent (ICI 118551). S-Mg and S-FFA were determined every fifteen minutes. After pretreatment with placebo, adrenaline infusion caused an increase in S-FFA from 0.22 +/- 0.20 mmol/L (mean +/- SD) to max 0.59 +/- 0.39 mmol/L after thirty minutes of adrenaline infusion (p less than 0.001). At one hundred twenty minutes S-FFA had decreased to 0.35 +/- 0.26 mmol/L. Thirty minutes after cessation of the adrenaline infusion, S-FFA had returned to the same level as before the infusion. S-Mg before the adrenaline infusion was 0.83 +/- 0.05 mmol/L, rose to 0.85 +/- 0.05 at fifteen minutes, and then decreased to 0.78 +/- 0.05 at one hundred thirty-five minutes (p less than 0.05). Pretreatment with atenolol did not change this pattern, although the changes in S-FFA and S-Mg were of a smaller magnitude but still statistically significant.

Intrahypothalamic microinfusion of corticotropin-releasing factor elevates blood glucose and free fatty acids in rats

Three experiments examined whether intrahypothalamic microinfusions of corticotropin releasing factor (CRF) can affect circulating levels of the metabolic fuels, glucose and free fatty acids. Infusions of CRF into the paraventricular nucleus dose-dependently increased serum glucose levels; greater increases were seen in acute than in chronic preparations. The greater effectiveness could not be accounted for by anesthetization per se. CRF infusion into the ventromedial nucleus did not affect serum glucose. Infusions into both sites, however, significantly increased serum free fatty acids. Neither glucose nor free fatty acids were altered by infusions into the lateral hypothalamus or the caudate-putamen. These data suggest that the previously identified CRF binding sites and CRF neuronal terminals in the paraventricular and ventromedial nuclei may be involved in the central regulation of metabolic fuel release. Additionally, it appears that the importance of CRF in the paraventricular nucleus in regulating serum glucose may be greater under some conditions than others.

Fat bodies and reproduction in female Anolis carolinensis

AbstractThe role of the fat body in supporting ovarian growth was studied in the lizard Anolis carolinensis. Environmental and social stimulation of ovarian growth in well‐fed animals was not accompanied by reductions in fat body weight or by increases in serum nonesterified fatty acid (NEFA) levels. Adiposectomy had no effect on serum NEFA, but did reduce hepatic glycogen compared to sham‐operated controls. Adiposectomized lizards receiving injections (either hormone or carrier) also had lower hepatic glycogen levels when compared to uninjected controls. Administration of estradiol to ovariectomized lizards was effective in increasing serum levels of NEFAs, but had little effect on fat body weights. Follicle‐stimulating hormone (FSH) administration increased serum free fatty acid levels in sham‐operated lizards but was without effect in adiposectomized animals. It is concluded that the lipids contained in the lizard fat body are not preferentially utilized for reproduction and may not be used for that purpose if adequate energy is supplied from other sources.

Bacteria-derived human growth hormone lacks lipolytic activity in rat adipose tissue

Bacteria-derived human growth hormone (hGH) shows little in vitro lipolytic activity in adipose tissue from fed rats. In adipose tissue from fasted rats no lipolytic activity is observed. However, bacteria-derived hGH increased serum free fatty acids after intraperitoneal administration to hypophysectomized rats to the same extent as purified pituitary hGH. The dose response of the bacteria-derived hGH tested for in vitro insulin-like activity was very similar to the pituitary extracted material. Thus bacteria-derived hGH behaves in a manner indistinguishable from highly purified preparations of pituitary hGH.

The influence of free fatty acids on valproic acid plasma protein binding during fasting in normal humans.

The effect of physiologic variations of free fatty acid levels on in vivo valproic acid plasma protein binding was studied in 6 healthy adult subjects. 14 blood samples were taken during a 12-h dosing interval at steady state while in a fed condition and also during a 27 h fast. Free fraction and total valproate concentration were determined by equilibrium dialysis and GLC, respectively. Free fatty acid levels were determined from both fresh samples and samples incubated at 37 degrees C for 12 h, the latter in order to simulate equilibrium dialysis conditions. Fasting resulted in increased serum free fatty acid levels in all subjects, ranging from 34-182% (p less than 0.01). Incubation also caused free fatty acid levels to rise, more so in fed samples (50-87%, p less than 0.01) than in fasting samples (10-50%, p less than 0.01). Fasting resulted in a 9% increase in the mean free fraction for all subjects combined (P less than 0.01). Regression analysis of 180 sets of values for free fraction, total valproate concentration and free fatty acid level suggested that valproate concentration accounts for 17% and free fatty acid level for 37% of the variation in free fraction. Mean clearance was unchanged by fasting despite an increased free fraction suggesting decreased intrinsic clearance (i.e. decreased metabolism) of valproate under these conditions.

Lipolytic responses induced by intracerebroventricular administration of histamine in the rat.

Histamine (10-50 microgram) administered intraventricularly in conscious rats induced an increase in serum-free fatty acids. The maximum, significant increase appeared 30-60 min after administration. Histamine H1-receptor antagonists, mepyramine and chloropyramine, when injected 2 h prior to histamine, abolished considerably hyperlipaemic responses to histamine. H2-Receptor antagonists, metiamide and cimetidine, given i.c.v. only moderately diminished histamine-induced hyperlipaemia. Histamine injected i.c.v. also increased serum corticosterone levels considerably. This elevation was prevented significantly by the H1-receptor antagonist, mepyramine, but not by the H2-receptor blocker, cimetidine. It seems likely that histamine given i.c.v. induces lipolysis through the release of ACTH, one of the known lipid-mobilizing hormones. The central lipid-mobilizing mechanism after histamine depends more on activation of H1- than H2-receptors.

Abnormal thyroid function tests in devere non-thyroidal illness: diagnostic and pathophysiologic aspects.

In vitro thyroid function tests were studied in twenty-three patients with serious non-thyroidal illness. All had reduced protein binding of serum thyroxine (T4) and serum triiodothyronine (T3) as reflected in increased T4 and T3 uptake tests. The mean T4-binding prealbumin (TBPA) capacity and concentration were about one third the normal levels, whereas the decrease in R4-binding globulin (TBG) was much smaller. Increased serum free fatty acids and reverse T3 were frequently observed, but in vitro displacement of thyroid hormones from their binding sites was achieved only with much high concentrations of these compounds. Other still unrecognized substances significantly inhibiting binding of thyroid hormones might, however, occur in sera of severely ill patients. Evidence in favour of this possibility was the disproportionately high serum T4 by TBG-binding assay relative to T4 by radioimmunoassay. In most of the patients the dual-stage free T4 was elevated, whereas the single-stage free T4 index (CT4I) was within the reference interval. However, neither of these indices reflected the moderately increased dialysable free T4 concentration very accurately. The free T3 index was depressed in most of the patients, whereas the dialysable free T3 concentration was not affected. For practical purposes the combination of normal serum T4 and CT4I in a severely ill patient indicates absence of an associated thyrometabolic disorders.

Comparative effects of amphetamine and fenfluramine on lipid biosynthesis and absorption in the rat

The effects of amphetamine and fenfluramine on lipid biosynthesis and intestinal absorption of triglycerides in the rat were observed independently of the anorectic activity of these drugs. Amphetamine and fenfluramine significantly reduced de novo lipogenesis and cholesterogenesis from 3H 2O and [ 14C] alanine in isolated hepatocytes. Fenfluramine was four times more potent an inhibitor than amphetamine. At high concentrations (above 2 mM), fenfluramine inhibited 14CO 2production from [ 14C] alanine in isolated hepatocytes while amphetamine stimulated 14CO 2 production at all concentrations tested (0.25 to 8 mM). Lipogenesis in liver and adipose tissue was not reduced in vivo by the acute administration of amphetamine. It, however, reduced lipogenesis in the small intestine. Fenfluramine significantly depressed in vivo lipogenesis in liver, small intestine and adipose tissue at 10 and 20 mg/kg, i.p. Hepatic cholesterogenesis was depressed significantly in vivo by both drugs. Fenfluramine increased serum free fatty acids while amphetamine produced no change. Triglycerides were increased significantly by fenfluramine only. Serum cholesterol and phospholipids were unchanged. Fenfluramine at 40 and 60 mg/kg, p.o., diminished significantly the intestinal absorption of triglycerides and depressed the accumulation of lipid in the liver. Analogous effects were not observed with amphetamine. Amphetamine was a weak inhibitor of rat pancreatic lipase (EC 3.1.1.3) ( K i = 21 mM) and fenfluramine was a stronger inhibitor ( K i = 3.3 mM).

Metabolism of adipose tissue in the fat tail of the sheep in vivo

The metabolism of the large mass of adipose tissue constituting the fat tail of the Syrian sheep has been investigated by measuring arteriovenous concentration (A-V) differences. The tail in situ in the intact anesthetized animal, as well as the isolated tail perfused with blood through a constant flow pump oxygenator, was used. In fed animals, the adipose tissue took up glucose and ketone bodies and released lactate and free fatty acids (FFA), although in some animals uptake of FFA also occurred. After 48-144 hr of fasting, uptake of glucose and ketone bodies continued and the FFA release increased. Total lipid esters and phospholipids were not released even after food had been withheld for 6 days. Insulin increased the A-V difference and the uptake of glucose, and reduced the FFA release. Adrenaline increased the A-V difference and uptake of glucose; the simultaneous increase in serum FFA was not accompanied by an increase in A-V difference for FFA in most experiments, which suggests that this adipose tissue is relatively insensitive to the lipolytic effect of the hormone. The effect of noradrenaline was similar to that of adrenaline. Glucagon hyperglycemia was not accompanied by increase in glucose uptake in most experiments.

Adipokinetic Activity of Porcine Fraction H in the Rabbit—Guinea Pig—Rat and Mouse

Previous reports described the preparation from hog pituitary glands of a fraction (labeled “Fraction H”) which is highly active in mobilizing free fatty acids (FFA) into the serum of the rabbit. In this report, certain metabolic changes produced in the rabbit by porcine Fraction H are examined in more detail. The adipokinetic activity of porcine Fraction H in the rabbit, guinea pig, rat and mouse are compared. The injection of 3 mg of porcine Fraction H in the rabbit caused a 10-fold increase in serum FFA within 2 hours, which persisted for more than 8 hours. The adipose tissue of the rabbit treated with Fraction H exhibited hyperemia and contained an 11-fold greater average concentration of FFA than that of the normal rabbit. Lowering of serum CO2 content occurred during the mobilization of FFA. A slight reduction in R.Q. was found but there was no change in blood sugar concentration. Acetonemia did not appear. Four hours after the injection, there were 5- to 8-fold increases in the concentrations of li...