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C Grunfeld

Publications and source records attributed to C Grunfeld.

At least 145 records · Page 8Linked to original sources
PubMed1990

Diet affects the mechanisms by which TNF stimulates hepatic triglyceride production.

Tumor necrosis factor (TNF) induces hyperlipidemia in rodents by increasing hepatic triglyceride production. We now explore the mechanism of this increase. TNF does not increase phosphatidate phosphohydrolase, glycerolphosphate acyltransferase, or diacylglycerol acyltransferase, which are enzymes of triglyceride synthesis. Rather, TNF increases triglyceride production by providing increased fatty acids (FA) as substrate. In chow-fed rats, TNF increases plasma free fatty acids (FFA). The antilipolytic drug, phenylisopropyl adenosine (PIA), prevents the TNF-induced increase in plasma FFA and, most importantly, inhibits the TNF-induced increase in plasma triglycerides. Thus increased lipolysis with delivery of FA to liver contributes to TNF-induced hyperlipidemia in chow-fed animals. In contrast, in rats fed a high-sucrose diet, TNF causes hyperlipidemia without increasing plasma FFA, and PIA has no effect on TNF-induced increases in plasma triglycerides. However, in sucrose-fed rats, TNF markedly stimulates hepatic de novo FA synthesis, which provides FA. This diet determines the mechanism by which TNF stimulates hepatic triglyceride production. The use of multiple mechanisms to increase plasma triglycerides suggests that this TNF action plays an important role in the response to infection or inflammation.

Acyltransferases↗
PubMed1990

Human very low density lipoproteins and chylomicrons can protect against endotoxin-induced death in mice.

Endotoxemia stimulates many physiologic responses including disturbances in lipid metabolism. We hypothesized that this lipemia may be part of a defensive mechanism by which the body combats the toxic effects of circulating endotoxin. We tested the effects of mixtures of endotoxin, lipoproteins, and lipoprotein-free plasma and determined the ability of varying concentrations of human very low density lipoproteins (VLDL) and chylomicrons, as well as low density lipoproteins (LDL) and high density lipoproteins (HDL), and of the synthetic lipid emulsion SOYACAL to prevent endotoxin-induced death in mice. This study demonstrates that the triglyceride-rich VLDL and chylomicrons, as well as cholesterol-rich LDL and HDL, and cholesterol-free SOYACAL can protect against endotoxin-induced death. Protection required small amounts of lipoprotein-free plasma, and depended on the incubation time and the concentration of lipoprotein lipid. Despite stringent techniques to prevent exogenous endotoxin contamination eight of ten duplicate VLDL preparations contained endotoxin (5,755 +/- 3,514 ng endotoxin/mg triglyceride, mean +/- SEM) making the isolation of endotoxin-free VLDL difficult. In contrast, simultaneous preparations of LDL and HDL were relatively free of endotoxin contamination (3 +/- 3 and 320 +/- 319 ng/mg total cholesterol, respectively), suggesting that the contamination of VLDL occurs in vivo and not during the isolation procedure. These observations suggest a possible role for increased triglyceride-rich lipoproteins in the host's defense against endotoxemia and infection.

Animals↗
PubMed1990

Evidence for two classes of cytokines that stimulate hepatic lipogenesis: relationships among tumor necrosis factor, interleukin-1 and interferon-alpha.

Tumor necrosis factor (TNF) increases serum triglycerides in rats by increasing de novo hepatic fatty acid synthesis and very low density lipoprotein production. We have recently shown that several other cytokines increase hepatic fatty acid synthesis in the mouse. We now explore the mechanism by which these cytokines increase de novo lipogenesis and the interactions between cytokines in fed mice. TNF administration results in increased hepatic levels of citrate, the primary allosteric activator of acetyl-CoA carboxylase, which is the major rate-limiting enzyme for fatty acid synthesis. The TNF-induced increase in citrate occurs within 15 min of administration, early enough to account for the acute rise in hepatic fatty acid synthesis seen by 30 min after TNF administration. IL-1, which also increases hepatic fatty acid synthesis, produces similar increases in hepatic citrate levels. In contrast, another potent stimulator of hepatic fatty acid synthesis, interferon-alpha (IFN alpha), has no effect on hepatic citrate levels. There were no acute effects of TNF or IL-1 on the activation state of acetyl-CoA carboxylase. A trend toward an increase in the activation state of acetyl-CoA carboxylase was seen after IFN alpha administration. Low doses of TNF and IL-1 given in combination show no synergy while maximal doses are not additive. In contrast, when a low dose of either TNF or IL-1 is combined with a low dose of IFN alpha, there is synergy in stimulating hepatic fatty acid synthesis. A maximal dose of TNF or IL-1 and a high dose of IFN alpha produce a further increase in hepatic fatty acid synthesis. These data support the concept that there are two classes of cytokines that stimulate hepatic fatty acid synthesis, those that can increase hepatic citrate levels and those that cannot.

Acetyl-CoA Carboxylase↗
PubMed1990

Tumor necrosis factor acutely increases plasma levels of very low density lipoproteins of normal size and composition.

Tumor necrosis factor (TNF) has been proposed to mediate the hypertriglyceridemic response to infection by either increasing hepatic lipid synthesis or decreasing clearance of triglyceride-rich particles through inhibition of lipoprotein lipase. We demonstrate that within 90 min of administration of recombinant human TNF alpha to rats there is a rapid increase in plasma levels of very low density lipoproteins (VLDL) of normal ultracentrifugal flotation rate, apoprotein and lipid composition, and particle size, as assessed by nondenaturing gradient gel electrophoresis. Clearance of radioiodinated VLDL 90 min after TNF administration did not differ from that in control animals, consistent with other observations that increases in plasma triglyceride concentrations after TNF precede detectable reductions in tissue lipoprotein lipase activity. Between 90 min and 16 h after TNF, VLDL levels decline, and there are increases in intermediate (IDL) and low (LDL) density lipoproteins consistent with lipolytic processing of VLDL, although the findings are also compatible with direct secretion of IDL and LDL subspecies. By 16 h, there is a 50% increase in protein mass of LDL of normal composition and subspecies distribution, as assessed by nondenaturing gradient gel electrophoresis. These data suggest that the initial locus of TNF's metabolic effects is the liver, and the resulting increases in secretion and metabolic processing of VLDL may represent an early manifestation of the acute phase response.

Animals↗
PubMed1990

Small intestinal fatty acid synthesis is increased in diabetic rats.

Several studies have demonstrated that intestinal triglyceride production and secretion are increased in diabetic animals and may contribute to the hypertriglyceridemia that accompanies diabetes. There are three potential sources of fatty acids for intestinally derived triglycerides; de novo fatty acid synthesis, circulating free fatty acids, or dietarily derived fatty acids. Prior data have demonstrated that de novo cholesterol synthesis is increased in the small intestine of diabetic animals. The primary aim of the present study was to determine the effect of diabetes on small intestinal de novo fatty acid synthesis. We found that de novo fatty acid synthesis in the small intestine is increased approximately 2-fold in streptozotocin-induced diabetic rats. In contrast, hepatic fatty acid synthesis is decreased in the diabetic animals. The increase in intestinal fatty acid synthesis is observed in both the fed and fasting states. Limiting food intake by pair feeding prevents the diabetic-induced increase in small intestinal fatty acid synthesis, a finding similar to previous data on cholesterol synthesis. Thus, the increase in both small intestinal cholesterol and fatty acid synthesis is dependent on the increased food intake that accompanies poorly controlled diabetes. The present study indicates that increases in small intestinal de novo fatty acid synthesis in diabetic animals could play an important role in providing fatty acids for increased small intestinal triglyceride synthesis and secretion.

Animals↗
PubMed1990

Tumor necrosis factor-increased hepatic very-low-density lipoprotein production and increased serum triglyceride levels in diabetic rats.

Previous studies demonstrated that administration of tumor necrosis factor (TNF) to diabetic rats rapidly increases serum triglyceride levels and stimulates hepatic lipogenesis without affecting the activity of adipose tissue lipoprotein lipase or serum insulin levels. The purpose of this study was to determine the mechanism by which TNF increases serum triglyceride levels and stimulates hepatic fatty acid synthesis in diabetic animals. The maximal increase (approximately 2-fold) in serum triglyceride levels in diabetic rats is seen with a dose of 10 micrograms TNF/200 g body wt, and the half-maximal effect is observed with 5 micrograms TNF/200 g body wt. The clearance of labeled triglyceride-rich lipoproteins from the circulation is not affected by TNF administration (triglyceride t 1/2; diabetic vs. TNF-administered diabetic, 3.5 +/- 0.7 vs. 4.0 +/- 0.6 min, respectively; NS). The production of triglyceride, measured by the Triton WR-1339 technique, is increased twofold in diabetic animals after TNF administration. These results indicate that the rapid increase in serum triglyceride levels after TNF treatment is accounted for by increased hepatic lipoprotein secretion. TNF administration did not alter either the amount or activation state of hepatic acetyl-CoA carboxylase, a key regulatory enzyme in fatty acid synthesis. There was also no change in the hepatic levels of fatty acyl-CoA, an allosteric inhibitor of acetyl-CoA carboxylase. However, there was a 71% increase in hepatic citrate concentrations. Citrate is an allosteric activator of acetyl-CoA carboxylase, and changes in hepatic citrate concentrations have been shown to mediate changes in the rates of fatty acid synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1989

Persistence of the hypertriglyceridemic effect of tumor necrosis factor despite development of tachyphylaxis to its anorectic/cachectic effects in rats.

The administration of a single injection of tumor necrosis factor (TNF) produces a variety of acute and sustained biological effects, including hyperlipidemia, stimulation of hepatic lipogenesis, decreases in adipose tissue lipoprotein lipase activity, and anorexia with weight loss. Chronic administration of a fixed dose of TNF produces tachyphylaxis to the anorectic/cachectic effects of TNF. We now report that the hyperlipidemic effect of TNF persists during chronic TNF administration in the absence of any cachectic effect of TNF. Sprague-Dawley rats injected with TNF (250 micrograms/kg) show a significant decrease in weight over the next 24 h which can be accounted for by decreases in food and water intake accompanied by an increase in urine output. With subsequent daily injections of TNF, treated rats begin eating and rapidly regain weight. Hypertriglyceridemia persists for up to 10 days of daily injections of TNF. After three daily injections of TNF, no decreases were seen in lipoprotein lipase activity in a wide variety of tissues. De novo hepatic lipogenesis remained increased in TNF-treated animals after four daily injections, but by the fifth day hepatic lipogenesis returned to normal. After 5 days of TNF treatment the acute incorporation of labeled glycerol into serum triglycerides remained elevated. These data indicate that hyperlipidemia persists during multiple daily injections of TNF and that TNF induced hypertriglyceridemia is not inevitably linked to the syndrome of cachexia.

Animals↗
PubMed1989

Hypertriglyceridemia in the acquired immunodeficiency syndrome.

PURPOSE: A relationship between the induction of hypertriglyceridemia by cytokines and the cachexia seen in chronic infection has been proposed by other investigators. Since patients with the acquired immunodeficiency syndrome (AIDS) often experience progressive tissue wasting, we decided to examine serum lipid levels and body cell mass in patients with AIDS. PATIENTS AND METHODS: Serum lipid levels and body cell mass were measured in 32 patients with the acquired immunodeficiency syndrome (AIDS), eight asymptomatic subjects who were anti-human immunodeficiency virus (HIV) antibody positive, and 17 heterosexual and homosexual control subjects who did not have antibodies to HIV. RESULTS: Mean triglyceride concentrations and the prevalence of hypertriglyceridemia (50 percent) were significantly increased in patients with AIDS compared with control subjects (p less than 0.002 and p less than 0.005, respectively), whereas the mean triglyceride levels of HIV-positive subjects were intermediate. There were no differences in cholesterol levels among the three groups. Using total body potassium adjusted for height and age (KHT) as a measure of body cell mass, 16 of 32 patients with AIDS but none of the HIV-positive or control subjects had significant depletion of body cell mass. There was no direct relationship between triglyceride levels and KHT among AIDS or HIV-positive subjects. In patients with AIDS, mean triglyceride levels and the prevalence of hypertriglyceridemia were similar in the presence and absence of wasting. CONCLUSION: Hypertriglyceridemia is a common finding in AIDS and is independent of the degree of wasting.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Effect of tumor necrosis factor (TNF) on lipid metabolism in the diabetic rat. Evidence that inhibition of adipose tissue lipoprotein lipase activity is not required for TNF-induced hyperlipidemia.

Tumor necrosis factor (TNF) administration produces an increase in plasma triglycerides that may be due to inhibition of adipose lipoprotein lipase activity and/or a stimulation of hepatic lipogenesis. We now report that TNF administration to insulinopenic diabetic rats increases serum triglycerides (2 h, 2.4-fold; 17 h, 4.3-fold). Adipose tissue lipoprotein lipase activity was markedly decreased in diabetic animals compared with controls and was not further inhibited by TNF. Incorporation of tritiated water into fatty acids in the liver was increased 45% 1-2 h after TNF and 87% at 16-17 h. These results indicate that the TNF-induced increase in circulating lipid levels can occur in the absence of a TNF-induced inhibition of adipose tissue lipoprotein lipase activity. Moreover, the clearance from the circulation of triglycerides in chylomicrons was similar in control and TNF-treated animals; these results provide further evidence that the removal of triglyceride-rich lipoproteins is not altered in the TNF-treated animals. Our data suggest that the TNF-induced stimulation of hepatic lipid synthesis may play an important role in the increase in serum triglycerides. In addition, TNF administration to diabetic animals leads to an elevation in serum glucose levels (73% at 17 h) without a change in serum insulin levels. Thus, TNF stimulation of hepatic lipogenesis is independent of changes in insulin.

Adipose Tissue↗
PubMed1989

Tumor necrosis factor stimulates hepatic lipid synthesis and secretion.

Previous studies have shown that tumor necrosis factor (TNF) administration acutely increases serum triglyceride levels and stimulates hepatic de novo fatty acid synthesis. We now demonstrate that 60-90 min after TNF administration the incorporation of glycerol into triglycerides in the liver is increased 57% in chow-fed rats. Additionally, the quantity of labeled lipid in serum is increased 96% in the TNF-treated animals. TNF also acutely increases hepatic lipid synthesis and the quantity of labeled lipids in serum in rats fed a high sucrose diet. Moreover, using the Triton WR-1339 method, from 1-2 h after TNF administration there is a 52% increase in total hepatic triglyceride secretion. In contrast, in animals fasted before TNF administration, the characteristic increase in serum triglyceride levels is not observed, and neither the incorporation of glycerol into hepatic lipids nor the quantity of labeled lipids in the circulation are increased. By 17 h after TNF administration the incorporation of glycerol into hepatic lipid and the quantity of labeled lipid in the serum are no longer increased. These results indicate that in addition to TNF acutely stimulating de novo fatty acid synthesis, TNF also acutely stimulates hepatic triglyceride synthesis. The increase in hepatic triglyceride synthesis leads to increased secretion of lipids into the circulation. These observations provide strong support for our hypothesis that a TNF-induced stimulation of hepatic lipid synthesis and secretion contributes to the TNF-induced hyperlipidemia.

Animals↗
PubMed1989

Multiple cytokines stimulate hepatic lipid synthesis in vivo.

We have previously shown that administration of tumor necrosis factor-alpha (TNF alpha) to intact rats results in an acute (within 60-120 min) stimulation of hepatic fatty acid synthesis, which persists for an extended period. Hepatic cholesterol synthesis is also stimulated by 16-17 h after TNF alpha treatment. We now demonstrate, using intact mice, that stimulation of hepatic lipid synthesis is not solely the property of the cytokine TNF alpha. Incorporation of 3H2O into fatty acids in the liver was increased 60-120 min and 16-17 h after the administration of TNF beta, interleukin-1 (IL-1), and interferon-alpha (IFN alpha). TNF alpha, IL-1, and IFN alpha all rapidly stimulate hepatic fatty acid synthesis (within 0-30 min), with the peak occurring at 60-120 min. The half-maximal doses of TNF alpha (200 ng) and IL-1 (20 ng) that stimulate hepatic fatty acid synthesis are similar to those that induce fever, a well recognized biological effect of these cytokines. Additionally, hepatic cholesterol synthesis was increased 16-17 h after TNF beta, IL-1, and IFN gamma treatment. The present study demonstrates that multiple cytokines from different cell types which act through different receptors can stimulate hepatic fatty acid and cholesterol synthesis. Previous studies have shown that multiple cytokines can inhibit the synthesis and storage of fat in cultured adipose cells. Taken together, these data indicate that multiple signals to perturb lipid metabolism may be produced as a consequence of an immunological or inflammatory response.

Animals↗
PubMed1989

Peptide-based radioimmunoassay for insulin receptor. Detection of insulin-stimulated downregulation in IM-9 lymphocytes.

To overcome the difficulties encountered in quantifying the insulin receptor number by Scatchard analysis, a radioimmunoassay (RIA) for the human insulin receptor (hIR) has been developed that uses an antibody raised against a synthetic peptide (Gly-Lys-Lys-Asn-Gly-Arg-Ile-Leu-Thr-Leu-Pro-Arg-Ser-Asn-Pro-Ser) corresponding to the carboxyl terminal of the hIR. A second peptide (Tyr-Gly-Arg-Ile-Leu-Thr-Leu-Pro-Arg-Ser-Asn-Pro-Ser) was used as a standard and allowed preparation of monoiodinated derivative of theoretical specific activity for use as the radioactive ligand. The assay is specific, highly reproducible, and sensitive, with a detection limit of 10 fmol of receptor. One mole of purified receptor, measured by Scatchard analysis or amino acid analysis, is read as one mole of receptor in the RIA with peptide being the standard. The assay is effective with receptor from multiple sources and could determine the decrease in number of insulin receptors seen in IM-9 lymphocytes after treatment with insulin (downregulation).

Female↗
PubMed1989

Prevalence of foot pathology and lower extremity complications in a diabetic outpatient clinic.

Multiple risk factors interplay in the formation of foot ulceration and/or limb amputation in the diabetic patient. This study defines the prevalence of foot pathology, lower extremity complications, and known risk factors for ulceration in a cross-sectional analysis of 92 diabetic patients in a Veterans Affairs Metabolic Clinic. Sixteen percent of patients had a history of lower extremity complications including pedal ulceration and/or amputation, previously requiring 1480 hospital days of care. Sixty-eight percent of patients had structural pathology in the foot, including: 51 percent callus, 32 percent hammertoes, 8 percent bunions, and 1 percent Charcot foot. Thirty-four percent of patients were insensate, while 25 percent had autonomic neuropathy. Twenty-two percent of patients had atherosclerosis obliterans as defined by an ankle brachial index less than 0.9; 13 percent suffered from intermittent claudication. The following pathologies were significantly more prevalent in diabetic patients with a history of ulceration and/or amputation compared to those patients without ulceration or amputation: hammertoe deformity (p less than .0001), abnormal cutaneous pressure sensation (p less than .05), abnormal R-R interval (p less than .05), intermittent claudication (p less than .05), and abnormal ankle brachial index (p less than .05). An important finding was that 41 percent of insensate patients were not aware of their sensory deficit. In addition, two-thirds of the patients with vascular disease had palpable pulses. All patients with diabetes should be entered into a basic foot education program. The high prevalence of lower extremity pathology coupled with the inadequacy of history and physical examination in detecting neuropathy and vascular disease emphasize the need for vigorous screening to determine whether patients are at high risk of ulceration/amputation. These patients should be entered into aggressive prophylactic treatment programs.

Adult↗
PubMed1989

Effect of tumor necrosis factor administration in vivo on lipoprotein lipase activity in various tissues of the rat.

When added to murine adipocytes in culture, tumor necrosis factor (TNF) decreases the levels of lipoprotein lipase (LPL). Semb et al (1987. J. Biol Chem. 262: 8390-8394) have shown that administration of murine TNF to rats decreases lipoprotein lipase (LPL) in the epididymal fat pad with maximal inhibition requiring several hours. We have now tested the effects of treatment of rats with TNF on LPL activity in a variety of tissues and find that few show decreases in LPL under conditions that acutely increase serum triglycerides. Ninety minutes after treatment of male rats with human TNF (25 micrograms/200 g, i.v.), serum triglycerides rose 2.2-fold but there was no decrease in LPL activity in epididymal fat. Sixteen hours after TNF treatment LPL activity had decreased by 44% in epididymal fat, consistent with the previously reported data. In contrast, in female rats, no significant decrease was seen in LPL activity in parametrial adipose tissue at either 90 min or 16 hr after TNF administration despite increases in serum triglycerides (1.8-fold and 1.5-fold, respectively). There was little change in LPL activity in most other adipose tissue sites of male or female rats at either time after TNF treatment. No effect of TNF was seen on heart or diaphragm muscle LPL at any time. TNF treatment of both male and female rats produces consistent increases in de novo hepatic lipogenesis in vivo under conditions that increase serum triglycerides. It is unlikely that the limited effects of TNF on LPL in vivo can account for the rapid and sustained increase in serum triglycerides.

Adipose Tissue↗
PubMed1988

Tumor necrosis factor stimulates DNA synthesis in the liver of intact rats.

TNF is cytotoxic to tumor cell lines but enhances growth of some nontransformed cells. Because animals administered TNF have an increase in liver size, we studied the [3H]thymidine incorporation into DNA in the liver of intact rats. A significant increase in [3H]thymidine incorporation is seen 20 hours following TNF administration and peaks at 24 hours. The lowest dose of TNF that increases DNA synthesis is 10 micrograms/200 g rat with a maximal increase occurring with 25 micrograms/200 g, considerably less than the dose required for maximally increasing plasma triglycerides. The increase in [3H]thymidine incorporation was shown to be due to an increase in DNA polymerase alpha activity (associated with the replication of DNA) rather than DNA polymerases beta (associated with DNA repair) plus gamma activity. These results indicate that TNF administration stimulates DNA replication in the liver of intact animals.

Animals↗
PubMed1988

Neutral lipid storage disease with ichthyosis: lipid content and metabolism of fibroblasts.

Neutral lipid storage disease with ichthyosis is a newly recognized heritable disorder characterized by widespread cellular triglyceride storage. Lipid metabolism in fibroblasts cultured from three affected family members was studied. The stored lipid is triglyceride composed of an unremarkable fatty acid profile and derived from both exogenously-supplied and endogenously-synthesized fatty acids. Lipid storage could not be corrected by prolonged culture in lipid-depleted media. Acetyl CoA carboxylase activity and beta-oxidation of palmitate were both normal. Taken together, these studies exclude a primary defect of fatty acid uptake, over-synthesis or impaired beta-oxidation. Moreover, triacylglycerol lipase activity of homogenates of fibroblasts from patients with NLSDI examined over the range of pH 3.5-8.5 was normal.

Fatty Acids↗
PubMed1988

The acute effects of human growth hormone administration on thyroid function in normal men.

GH replacement therapy may lead to alterations in serum TSH and/or thyroid hormone values in GH-deficient patients, but there is no consensus on the explanation for these changes. We examined the effect of GH administration (0.125 mg, sc, daily for 4 days) on thyroid function in 20 normal men. Serum T4 levels decreased by 8%, and serum free T4 index values decreased by 5%. In contrast, serum T3 levels increased by 21%; serum rT3 did not change. These changes were accompanied by a 54% decrease in the mean serum TSH level. While it is not possible to draw conclusions about hormone production and disposal rates from changes in serum levels, these data are most consistent with enhanced extrathyroidal (including intrapituitary) conversion of T4 to T3 and a compensatory decrease in TSH secretion.

Adult↗