Search PubMed⌕ Search

Biomedical subjects

K R Feingold

Publications and source records attributed to K R Feingold.

At least 217 records · Page 12Linked to original sources
PubMed1991

Tumor necrosis factor-alpha, interleukin-1, and interferon alpha stimulate triglyceride synthesis in HepG2 cells.

Tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interferon alpha (IFN-alpha) stimulate hepatic lipogenesis in vivo. We now show that TNF-alpha, IL-1, and IFN-alpha stimulate lipogenesis as measured by the incorporation of 3H-glycerol into triglyceride in cultured HepG2 cells. Incubation of HepG2 cells for approximately 24 hours with TNF or IL-1 was required to see stimulation of lipogenesis, with this effect increasing over the next four days. TNF stimulated lipogenesis by 2.4-fold after 72 hours of incubation, while a 3.5-fold stimulation was seen with IL-1. The half maximal concentration for TNF stimulation of hepatic lipogenesis was 4 ng/mL, while that for IL-1 was 0.3 ng/mL. Cells treated with TNF or IL-1 also showed increased secretion of labeled triglyceride into the media. IFN-alpha stimulated the incorporation of 3H-glycerol into triglyceride by 39% after 72 hour's incubation. In contrast, IFN-gamma had no effect on lipogenesis in HepG2 cells. These data suggest that cytokines can directly stimulate the synthesis of triglycerides in cultured Hep G2 liver cells in vitro.

Carcinoma, Hepatocellular↗
PubMed1991

The regulation and role of epidermal lipid synthesis.

One of the key functions of the epidermis is to form a barrier between the organism and the outside world. As shown in Fig. 3, disruptions of the barrier result in a cascade of events that ultimately leads to barrier repair. The initial signal that initiates this repair response is unknown. The exocytosis of preformed lipid-enriched lamellar bodies is the first step in this response, which is followed by an increase in lipid synthesis in the epidermis. Our studies demonstrate that this increase in epidermal lipid synthesis is required for the synthesis of new lamellar bodies and repair of the barrier. Inhibition of epidermal lipid synthesis by artificial membranes or drugs impairs barrier recovery by preventing the reformation of lamellar bodies and the continued secretion of lipid. Whether the stimulation of lipid synthesis is primarily regulated by disturbances in barrier function or secondarily by decreases in the lipid content of the cells due to the utilization of lipid for the formation of lamellar bodies is unknown. Additionally, the precise mechanisms by which lipid synthesis is increased (enzyme activation, transcriptional regulation, etc.) remain to be elucidated. The secretion of lipid-containing lamellar bodies results in the reaccumulation of lipid in the intercellular spaces of the stratum corneum and the recovery of normal barrier function. Epidermal lipid synthesis also is probably required to provide lipid for new cell membrane formation to allow for the increase in epidermal cell proliferation, which is stimulated following barrier disruption. Additionally, epidermal lipid synthesis may provide regulatory molecules or crucial substrates that are required for DNA synthesis. Thus, epidermal lipid synthesis plays a key role in the major biological functions of the epidermis, the cutaneous permeability barrier, and cell proliferation.

Animals↗
PubMed1991

The lovastatin-treated rodent: a new model of barrier disruption and epidermal hyperplasia.

Recent studies have linked epidermal cholesterol synthesis with maintenance of the permeability barrier. To assess directly the importance of cholesterol synthesis, we applied lovastatin, a potent inhibitor of cholesterol synthesis, to hairless mouse skin. Transepidermal water loss (TEWL) began to increase after four to six daily applications. Co-application of cholesterol blocked the expected increase in TEWL, demonstrating the importance of cholesterol for development of the lesion. The histology of lovastatin-treated skin revealed epidermal hyperplasia, accompanied by accelerated DNA synthesis. Whereas cholesterol synthesis initially was reduced in lovastatin-treated epidermis, with further treatment cholesterol synthesis normalized, while fatty acid synthesis accelerated greatly. Although the total free sterol content of lovastatin-treated epidermis remained normal, the fatty acid content increased coincident with barrier disruption. Finally, morphologic abnormalities of both lamellar body structure and their deposited, intercellular contents occurred coincident with the emerging biochemical abnormalities. Thus, the abnormal barrier function in this model can be ascribed to an initial inhibition of epidermal sterol synthesis followed by an alteration in cholesterol and fatty acid synthesis, leading to an imbalance in stratum corneum lipid composition and abnormal membrane bilayer structure.

Animals↗
PubMed1991

Barrier function regulates epidermal DNA synthesis.

We examined the possibility that the cutaneous permeability barrier regulates epidermal DNA synthesis in two acute and two chronic models of barrier perturbation. In animals treated topically with acetone, DNA synthesis is increased 102%, in tape-stripped animals 127%, in essential fatty acid deficient animals 50%, and in animals chronically treated with topical lovastatin 64%. This linkage between disturbances in barrier function and increased DNA synthesis is further supported by specific and correlative observations: (a) in these disparate models, artificial replacement of the barrier with a water-impermeable membrane inhibits the expected increase in DNA synthesis; (b) the extent of the burst in DNA synthesis is proportional to the degree of barrier abrogation; (c) the inhibition of DNA synthesis by membranes is directly related to the degree of permeability of these occlusive membranes, i.e., the more impermeable the greater the degree of inhibition; (d) topical treatment with lipids that restore barrier function corrects the increase in DNA synthesis; and (e) barrier abrogation with acetone produces an increase in epidermal DNA synthesis without altering bulk protein synthetic rates in contrast to events known to follow injury or cell replacement. Autoradiographic studies show that the increase in DNA synthesis after acetone treatment is limited to the epidermal basal layer. This constellation of findings strongly suggests that cutaneous barrier function is one factor that regulates epidermal DNA synthesis.

Animals↗
PubMed1991

Sphingolipids are required for mammalian epidermal barrier function. Inhibition of sphingolipid synthesis delays barrier recovery after acute perturbation.

Stratum corneum lipids comprise an approximately equimolar mixture of sphingolipids, cholesterol, and free fatty acids, arranged as intercellular membrane bilayers that are presumed to mediate the epidermal permeability barrier. Prior studies have shown that alterations in epidermal barrier function lead to a rapid increase in cholesterol and fatty acid synthesis which parallels the early stages of the repair process. Despite an abundance of indirect evidence for their role in the barrier, the importance of sphingolipids has yet to be demonstrated directly. Whereas sphingolipid synthesis also increases during barrier repair, this response is delayed in comparison to cholesterol and fatty acid synthesis (Holleran, W.M., et al. 1991. J. Lipid Res. 32:1151-1158). To further delineate the role of sphingolipids in barrier homeostasis, we assessed the impact of inhibition of sphingolipid synthesis on epidermal barrier recovery. A single topical application of beta-chloro-L-alanine (beta-CA), an irreversible inhibitor of serine-palmitoyl transferase (SPT), applied to acetone-treated skin of hairless mice resulted in: (a) greater than 75% inhibition of SPT activity at 30 min (P less than 0.001); (b) a global decrease in sphingolipid synthesis between 1 and 3 h (P less than 0.02); (c) reduction of epidermal sphingolipid content at 18 h (P less than 0.01); (d) delayed reaccumulation of histochemical staining for sphingolipids in the stratum corneum; and (e) reduced numbers and contents of lamellar bodies in the stratum granulosum. Finally, despite its immediate, marked diminution of sphingolipid synthesis, beta-CA slowed barrier recovery only at late time points (greater than 6 h) after acetone treatment. This inhibition was overridden by coapplications of ceramides (the distal SPT product), indicating that the delay in repair was not due to non-specific toxicity. These studies demonstrate a distinctive role for epidermal sphingolipids in permeability barrier homeostasis.

Acyltransferases↗
PubMed1991

Intestinal and hepatic cholesterogenesis in hypercholesterolemic dyslipidemia of experimental diabetes in dogs.

We previously reported that dog diabetes results in hypercholesterolemia and the accumulation of a high-density lipoprotein (HDL) subclass, HDL1. Hypercholesterolemic diabetic rodents exhibit hyperphagia, intestinal hypertrophy, and increased intestinal cholesterol synthesis and absorption; intestinal 3-hydroxy-3-methylglutaryl (HMG) CoA reductase activity is increased, whereas hepatic activity is unchanged or reduced. To determine whether similar mechanisms operate in the hypercholesterolemic diabetic dog, we measured hepatic and intestinal cholesterologenesis. Streptozocin-alloxan-induced diabetic dogs allowed access to food ad libitum were hyperphagic and hypercholesterolemic (10.1 vs. 4.47 mM) but normotriglyceridemic. Plasma HDL1 concentrations were markedly increased. Differences in renal and hepatic function were not statistically significant, except serum alkaline phosphatase, which was elevated 4-fold (P = 0.0003). Urinary mevalonate, an index of whole-body cholesterol synthesis, was increased 6-fold. Intestinal and hepatic weights were both increased, and direct measurements showed crypt and villus thickening. The activity of HMG CoA reductase per gram organ weight was increased 1.7-fold in liver and 2.1-fold in intestine. Calculated whole-organ activity in intestine was nearly twice that in liver. These observations provide strong evidence that intestinal cholesterogenesis is involved in the pathogenesis of hypercholesterolemia in dog diabetes and support the conclusion that increased cholesterol synthesis plays a role in the hypercholesterolemia of diabetes.

Animals↗
PubMed1991

Regulation of epidermal sphingolipid synthesis by permeability barrier function.

A mixture of sphingolipids, cholesterol, and free fatty acids forms the intercellular membrane bilayers of the stratum corneum which are presumed to regulate epidermal barrier function. Prior studies have shown that both cholesterol and fatty acid synthesis are rapidly regulated by epidermal barrier requirements. In contrast, the importance of sphingolipids in barrier function has not been directly demonstrated. Here, we have assessed both sphingolipid synthesis by [3H]H2O incorporation and serine palmitoyl transferase (SPT) activity in relation to modulations in barrier function. Incorporation of [3H]H2O into sphingolipids increased after barrier disruption with acetone, with maximal increase (170%) occurring 5-7 h after treatment (P less than 0.005). As barrier function returned to normal over 24 h, incorporation of tritium into sphingolipids normalized. SPT activity also increased after barrier disruption, peaking at 6 h (150%) (P less than 0.05), and returning towards normal by 24 h. Artificial restoration of the barrier with a water vapor-impermeable membrane prevented the increases in both [3H]H2O incorporation into sphingolipids and enzyme activity. Finally, SPT activity was increased in two other models of barrier dysfunction, cellophane tape-stripping and essential fatty acid deficiency. Occlusion normalized SPT activity in both of these models as well. These studies: a) demonstrate a distinctive, delayed increase in epidermal sphingolipid synthesis in response to barrier requirements that contrasts with the immediate responses of cholesterol and fatty acid synthesis; and b) suggest that sphingolipids are important for the maintenance of the epidermal permeability barrier.

Acetone↗
PubMed1991

The regulation of epidermal lipid synthesis by permeability barrier requirements.

A major function of the skin is to prevent the loss of fluids. The barrier to fluid loss resides in the intercellular lipids (primarily sterols, fatty acids, and sphingolipids) of the stratum corneum. The epidermis is a very active site of lipid synthesis and when the permeability barrier is disrupted by topical solvents or detergents a marked stimulation of sterol, fatty acid, and sphingolipid synthesis occurs. Essential fatty acid deficient mice, with a chronic disturbance in barrier function, also have an increase in epidermal lipid synthesis. When the defect in barrier function is artificially corrected by occlusion with a water vapor impermeable membrane the increase in epidermal lipid synthesis is prevented, suggesting that water flux may be a regulatory factor. The activity of the key rate limiting enzyme in cholesterol synthesis, HMG CoA reductase is increased following barrier disruption due to both an increased quantity of enzyme and an increase in activation state. Similarly, the activity of serine palmitoyl transferase, the rate limiting enzyme in sphingolipid synthesis is also increased following barrier disruption. Occlusion prevents the increase in HMG CoA reductase and serine palmitoyl transferase activity. When the increase in epidermal lipid synthesis is inhibited by occlusion the characteristic rapid return of stratum corneum lipids and recovery of barrier function is prevented. Moreover, when epidermal cholesterol synthesis is inhibited by lovastatin, an inhibitor of HMG CoA reductase, the rate of recovery of barrier structure and function is delayed. Similarly, B chloroalanine, an inhibitor of serine palmitoyl transferase and sphingolipid synthesis, also impairs barrier recovery. Thus, disruption of the barrier stimulates epidermal lipid synthesis which provides the lipids necessary for the repair of the barrier. The signals that initiate and coordinate this response are yet to be defined, but the understanding of this process may allow for pharmacological interventions that will specifically disrupt the barrier and allow for the transcutaneous delivery of drugs.

Animals↗
PubMed1991

Circulating interferon-alpha levels and hypertriglyceridemia in the acquired immunodeficiency syndrome.

PURPOSE: The metabolic disturbances seen during infection are thought to be due to cytokines, modulators of the immune response. The acquired immunodeficiency syndrome (AIDS) is characterized by a high prevalence of hypertriglyceridemia and at times depletion of body cell mass (wasting). Elevated circulating levels of cytokines have also been reported in AIDS. Therefore, we determined the relationship between circulating cytokine levels and lipid levels and between circulating cytokine levels and wasting in AIDS and human immunodeficiency virus (HIV) infection. PATIENTS AND METHODS: Serum samples from 45 patients with AIDS, 13 subjects with evidence of HIV infection by presence of antibody but without AIDS (HIV positive), and 17 seronegative control subjects who had previously undergone body composition analysis were analyzed for triglyceride, cholesterol, interferon, tumor necrosis factor (TNF), and interleukin-1 levels. Eleven subjects with AIDS or HIV infection had sequential measurements. Interferon was analyzed by bioassay with identification using specific antibodies. TNF and interleukin-1 were assayed by enzyme-linked immunosorbent assay. Lean body mass was assessed by total body potassium. RESULTS: Serum interferon-alpha levels were significantly elevated in patients with AIDS (p less than 0.001 compared to controls), with detectable levels in 84% of AIDS patients. Interferon-alpha was not detectable in serum from controls, while three of 13 HIV-positive subjects had detectable interferon-alpha levels. There was a significant correlation between interferon-alpha levels and serum triglyceride levels in AIDS and HIV-positive patients (R = 0.446, p less than 0.002). There was no relationship between interferon-alpha and serum cholesterol levels (R = -0.039, NS). In contrast only 11% of AIDS patients had detectable circulating TNF levels; the mean value for and the prevalence of detectable serum TNF levels were not significantly different from those of control subjects. Interleukin-1 was not detected in the circulation. There was no correlation between the presence of circulating TNF and serum triglycerides. There was no relationship between circulating interferon-alpha or TNF levels and the presence of wasting as measured by total body potassium. CONCLUSION: These studies suggest that interferon-alpha, which has previously been shown to modulate lipid metabolism in vivo and in vitro, may be responsible for the hypertriglyceridemia found in AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Localization of tumor necrosis factor-stimulated DNA synthesis in the liver.

Tumor necrosis factor and other cytokines mediate the body's response to infection and inflammation. Long-term administration of tumor necrosis factor causes liver hypertrophy, and our laboratory has shown that tumor necrosis factor acutely increases hepatic DNA synthesis. The purpose of this study was to determine which specific cell types in the liver undergo DNA synthesis in response to tumor necrosis factor. Light microscopic autoradiographs of 3H-thymidine incorporation demonstrate that tumor necrosis factor stimulates DNA synthesis in nonparenchymal cells, whereas the low level of DNA synthesis normally found in hepatocytes remains unaffected. Tumor necrosis factor increased labeling in sinusoidal cells that appeared to be Kupffer cells and in cells localized to the portal tracts. With electron microscopy and histochemical staining for endogenous peroxidase, the sinusoidal cells were clearly identified as Kupffer cells. The exact identity of the cells in the portal tract is less certain, but some of the cells shared the characteristics of bile duct precursors. With long-term administration of tumor necrosis factor, a striking proliferation of bile ducts was seen. The functional role of the proliferation of bile ducts in response to tumor necrosis factor is unclear, and it is not known whether the increase is a beneficial or deleterious response. The increased DNA synthesis in Kupffer cells could result in a potentially beneficial response to infection by increasing an animal's ability to phagocytize and clear microorganisms. However, under some circumstances, an expansion of the number of Kupffer cells could be deleterious by increasing an animal's ability to produce tumor necrosis factor and other cytokines that in large quantities can have toxic effects.

Animals↗
PubMed1990

Search for mediators of the lipogenic effects of tumor necrosis factor: potential role for interleukin 6.

The significance of potential second messengers as mediators of the metabolic effects of tumor necrosis factor (TNF) was explored by studying their role in stimulating hepatic lipogenesis. Platelet-activating factor and prostaglandins have previously been suggested to mediate some of the toxic effects of TNF. An inhibitor of platelet-activating factor (WEB 2086) and two inhibitors of the synthesis of prostaglandins (ibuprofen and aspirin) had no effect on the ability of TNF to increase hepatic lipogenesis or serum triglyceride levels in the rat. Another inhibitor of the toxic effects of TNF, pentoxifylline, also had no effect on lipid metabolism in the rat. Catecholamines are increased after TNF administration, but alpha- and beta-adrenergic blockade did not prevent the lipogenic effects of TNF. However, interleukin 6, a cytokine whose synthesis and secretion are induced by TNF, is able to acutely stimulate hepatic lipogenesis in mice. Interleukin 6 stimulates hepatic lipogenesis by increasing hepatic citrate concentrations, the same mechanism by which TNF stimulates hepatic lipogenesis. These data suggest that interleukin 6, but not platelet-activating factor, prostaglandins, or catecholamines, could potentially mediate the lipogenic effects of TNF.

Animals↗
PubMed1990

The effect of diet on tumor necrosis factor stimulation of hepatic lipogenesis.

Previous studies have demonstrated that tumor necrosis factor (TNF) acutely increases serum triglyceride levels and stimulates hepatic lipid synthesis. In this study, we determined the effects of TNF on serum lipid levels and hepatic lipid synthesis in animals whose diets and feeding conditions were varied to induce changes in baseline serum lipid levels and/or rates of hepatic lipid synthesis. In animals studied at both the nadir and peak of the diurnal cycle of hepatic lipid synthesis, TNF acutely increases serum triglyceride levels, stimulates hepatic fatty acid synthesis, and increases the quantity of newly synthesized fatty acids found in the serum. Similarly, in animals ingesting either high-sucrose or cholesterol-enriched diets, TNF induces the characteristic rapid increase in serum triglyceride levels, hepatic fatty acid synthesis, and quantity of labeled fatty acids in the serum. In animals fed a diet high in triglycerides, using either corn oil or lard, TNF stimulates hepatic fatty acid synthesis and increases the quantity of newly synthesized fatty acids in the serum, but serum triglyceride levels do not change. However, TNF inhibits gastric emptying, which results in a marked decrease in fat absorption in TNF-treated animals. It is likely that a decrease in the dietary contribution to serum triglyceride levels during high-triglyceride feeding counterbalances the increased hepatic contribution induced by TNF treatment. In animals fasted before TNF administration there was no acute change in either serum lipid levels, hepatic fatty acid synthesis, or the quantity of labeled fatty acids in the serum. Thus, TNF stimulates hepatic fatty acid synthesis and increases serum triglyceride levels under many diverse dietary conditions, suggesting that there is a strong linkage between the immune system and lipid metabolism that is independent of most dietary manipulations and may be of fundamental importance in the body's response to infection.

Animals↗
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

Regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity in murine epidermis. Modulation of enzyme content and activation state by barrier requirements.

Epidermal cholesterol biosynthesis is regulated by barrier function. We quantitated the amount and activation state (phosphorylation-dephosphorylation) of the rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, in epidermis before and after barrier disruption. In murine epidermis we found high enzyme activity (1.75 +/- 0.02 nmol/min per mg protein). After acute barrier disruption, enzyme activity began to increase after 1.5 h, reaching a maximum increase by 2.5 h, and returned to normal by 15 h. Chronic barrier disruption increased total enzyme activity by 83%. In normal epidermis, measurement of HMG CoA reductase activity in microsomes isolated in NaF- vs. NaCl-containing buffers demonstrated that 46 +/- 2% of the enzyme was in the active form. After acute or chronic barrier disruption, a marked increase in the percentage of HMG CoA reductase in the active form was observed. Acute disruption increased enzyme activation state as early as 15 min, reaching a maximum after 2.5 h, with an increase still present at 15 h, indicating that changes in activation state had a close temporal relationship with barrier function. Increases in total HMG CoA reductase activity occurred only after profound barrier disruption, whereas changes in activation state occur with lesser degrees of barrier disruption. Artificial correction of barrier function prevented the increase in total HMG CoA reductase activity, and partially prevented the increase in enzyme activation. These results show that barrier requirements regulate epidermal cholesterol synthesis by modulating both the HMG CoA reductase amount and activation state.

Acetone↗
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

Cholesterol synthesis is required for cutaneous barrier function in mice.

Previous studies have shown that topical acetone treatment results in the removal of stratum corneum lipids and disruption of the permeability barrier. This disruption stimulates epidermal lipid synthesis which is associated with the rapid restoration of stratum corneum lipids and barrier function. The aim of this study was to determine the role of cutaneous cholesterol synthesis in the barrier recovery. Here we show that topical lovastatin, a competitive inhibitor of HMG CoA reductase, inhibits cholesterol synthesis. After acetone disruption of the barrier, the normal rapid return of cholesterol to the stratum corneum and recovery of barrier function is impaired in animals treated topically with lovastatin. When lovastatin animals are simultaneously treated topically with either mevalonate, the immediate product of HMG CoA reductase, or cholesterol, the final end product of the pathway, the recovery of the barrier is normalized. Lovastatin resulted in the delayed secretion and abnormal appearance of lamellar bodies. These results provide the first evidence demonstrating that cholesterol synthesis is required for the maintenance of barrier structure and function and suggests a crucial role for cholesterol synthesis in allowing for terrestrial existence.

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↗