Biomedical subjects

K R Feingold

Publications and source records attributed to K R Feingold.

At least 235 records · Page 13Linked to original sources

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

Cholesterol synthesis in bypassed segments of the small intestine in hyperphagic rats.

Previous studies have demonstrated that a variety of conditions that result in an increase in food intake lead to an increase in small-intestinal cholesterol synthesis. In the present study, it was determined whether hyperphagia induces an increase in cholesterol synthesis in segments of the small intestine excluded from contact with the food stream and whether this increase would occur in bypassed segments of the proximal or mid-small intestine. In hyperphagic diabetic rats, cholesterol synthesis is increased 91% in the proximal portion of the small intestine excluded from contact with nutrients. In lactating rats, another model of hyperphagia, cholesterol synthesis is increased 2.4-fold in midintestinal segments excluded from contact with the food stream and 2.9-fold in segments of the proximal intestine that have been bypassed. These observations demonstrate that the hyperphagia-induced increase in small-intestinal cholesterol synthesis will occur in portions of the small intestine, even if contact with the food stream is prevented. In addition, this data demonstrated that the mass of the bypassed portion of the small intestine is increased in hyperphagic animals. In diabetic animals, the weight of the bypassed proximal intestine is increased 2.1-fold, whereas in lactating animals the mass is increased 50% in the bypassed midintestine and 74% in the bypassed proximal small intestine. In conclusion, the present study suggests that circulating or neurologic factors, or both, play a role in stimulating intestinal cholesterol synthesis in hyperphagic animals. These findings also suggest that indirect factors play a role in the increase in intestinal mass associated with hyperphagia.

Animals↗

PubMed1989

Inhibition of endogenous lactate turnover with lactate infusion in humans.

The extent to which lactate infusion may inhibit endogenous lactate production, though previously considered, has never been critically assessed. To examine this proposition, single injection tracer methodology (U-14C Lactate) has been used for the estimation of lactate kinetics in 12 human subjects under basal conditions and with the infusion of sodium lactate. The basal rate of lactate turnover was measured on a day before the study with lactate infusion, and averaged 63.7 + 5.5 mg/kg/h. Six of these individuals received a stable lactate infusion at an approximate rate of 160 mg/kg/h, while the remaining six individuals were infused at the approximate rate of 100 mg/kg/h. It has been found that stable lactate infused at rates approximating 160 mg/kg/h consistently produced a complete inhibition of endogenous lactate production. Infusion of lactate at 100 mg/kg/h caused a lesser and more variable inhibition of endogenous lactate production (12% to 64%). In conclusion, lactate infusion significantly inhibits endogenous lactate production.

Carbon Radioisotopes↗

PubMed1989

Cutaneous xanthoma in association with paraproteinemia in the absence of hyperlipidemia.

In the present report we describe a patient with multiple myeloma and long-standing paraproteinemia who developed xanthoma in the absence of an elevation in plasma cholesterol or triglyceride concentrations. Studies demonstrated that our patient's monoclonal IgG antibody interacted with apoprotein B-100. The LDL-antibody complex isolated from our patient did not affect the degradation of LDL by human fibroblasts, indicating that while IgG derived from our patient interacted with LDL it did not alter the metabolism of this lipoprotein by the LDL receptor pathway. Since the LDL receptor pathway is the major route of LDL metabolism, this probably explains why our patient was not hyperlipidemic. In contrast to an absence of effect on the LDL receptor, our patient's LDL-antibody complex stimulated cholesterol esterification within macrophages indicating the uptake and degradation of the LDL-antibody complex. The LDL-antibody complex inhibited the degradation of acetyl LDL by macrophages (scavenger pathway), demonstrating that our patient's LDL-antibody complex was recognized as a modified LDL. Moreover, mixing Ig from our patient with normal LDL also resulted in the normal LDL increasing the esterification of cholesterol by macrophages. One can hypothesize that our patient's monoclonal IgG-LDL complex interacted with the macrophage scavenger receptor, thereby resulting in the occurrence of xanthoma in the absence of hyperlipidemia.

Acetylation↗

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

Prospective studies of muscle capillary basement membrane width in prediabetics.

In 1968, this laboratory reported that muscle capillary basement membrane thickening was present in approximately 50% of nondiabetic individuals who had a strong genetic predisposition for developing diabetes mellitus. In the present manuscript we report the 20-yr follow-up observations in this group of prediabetics. We were able to obtain information regarding the presence or absence of diabetes in 17 of 33 subjects (51.5%). In these 17 individuals, 8 (47%) developed diabetes over the ensuing 20+ yr of observation. Initial (1964) glucose tolerance tests in the subjects that developed diabetes were not significantly different from those that did not develop diabetes. One- and 2-h glucose values on follow-up (4-8 yr later) glucose tolerance tests were significantly higher in the group that developed diabetes. On initial biopsy, muscle capillary basement membrane width was similar in the 2 groups; in the follow-up specimens the mean muscle capillary basement membrane width tended to be greater in the group that ultimately developed diabetes, but this difference was not statistically significant. However, in the group that developed diabetes the follow-up muscle capillary basement membrane width increased significantly compared to the initial measurement, whereas in the nondiabetic group the muscle capillary basement membrane width decreased with time (diabetics, +75.50 +/- 23.66; nondiabetic, -14.44 +/- 28.71 A/yr; P less than 0.05). Seven of 8 (87%) of the individuals who developed diabetes showed progressive thickening of their muscle capillary basement membrane thickness, whereas in the nondiabetic group 5 of 8 had a decrease in width. These results suggest that an increase in muscle capillary basement membrane width over time might serve as a marker to detect individuals who are at increased risk to develop diabetes. The detection of an increased susceptibility for diabetes could potentially allow for interventions that could delay or prevent the development of diabetes.

Adult↗

PubMed1989

Importance of small intestine in diabetic hypercholesterolemia.

Numerous studies have demonstrated that poor glycemic control is associated with elevated plasma cholesterol levels in diabetic patients. Experiments have shown that cholesterol synthesis is increased in the small intestine of various diabetic animals. This increase is a generalized phenomenon occurring in all segments of the small intestine. Insulin therapy that normalizes blood glucose levels markedly decreases intestinal cholesterol synthesis in diabetic animals to a level similar to that observed in control animals. Studies have suggested that the hyperphagia that accompanies poorly controlled diabetes is the chief stimulus for the increase in intestinal cholesterol synthesis. However, the direct contact of the intestinal mucosa with nutrients is not the sole trigger for increasing cholesterol synthesis in the small intestine, suggesting that circulating and/or neurological factors play a role. The transport of newly synthesized cholesterol, most of which is in the chylomicron lipoprotein fraction, from the intestines to the circulation is increased in diabetic rats. The sterols associated with these chylomicrons are rapidly cleared from the circulation and delivered to the liver. The increased transport of chylomicrons from the intestine to the circulation in diabetic patients could potentially result in several alterations in lipid metabolism that may increase the risk of atherosclerotic vascular disease.

Cholesterol↗

PubMed1989

Total gastrectomy and small intestinal cholesterol synthesis in diabetic rats.

Cholesterol synthesis is increased two- to threefold in the small intestine of diabetic rats. We have observed, in three separate experiments, that the characteristic increase in small intestinal cholesterol synthesis (SICS) in diabetic rats was prevented by total gastrectomy. Food intake was increased twofold, and the small intestine hypertrophied in the gastrectomized diabetic animals. In normal animals, total gastrectomy resulted in only a very small increase in intestinal cholesterol synthesis. In hyperphagic lactating animals, total gastrectomy did not prevent the characteristic increase in SICS that is usually observed in this hyperphagic model. These results indicate that the effects of total gastrectomy on preventing an increase in SICS are relatively specific for the diabetic state. The mechanism by which total gastrectomy prevents the increase in intestinal cholesterol synthesis in diabetic animals is unknown. Vagotomy did not prevent the typical increase in intestinal synthesis in diabetic animals. Additionally, selectively removing either the antrum or fundus of the stomach did not prevent the increase in SICS in diabetic animals, indicating that the inhibition requires the removal of the entire stomach. It can be speculated that the stomach produces a substance that induces the increase in SICS observed in diabetic animals and that total gastrectomy removes this stimulatory substance.

Animals↗

PubMed1989

Transepidermal water loss: the signal for recovery of barrier structure and function.

Previous studies have demonstrated that perturbations in barrier function stimulate epidermal lipid synthesis and that this increase can be prevented by occlusive membranes. These observations suggest that epidermal lipid synthesis might be related to barrier function and raised the question whether transcutaneous water flux might regulate epidermal lipogenesis. In the present study we first abrogated the barrier with acetone, and then compared the rate of repletion of stainable lipids, barrier recovery, and epidermal lipogenesis in animals covered with occlusive membranes or vapor-permeable membranes versus uncovered animals. Acetone treatment of hairless mice removed stainable neutral lipids from the stratum corneum, with repletion evident both biochemically and histochemically within 48 hr in uncovered animals. In contrast, when the animals were covered with an occlusive membrane, the usual return of stratum corneum lipids was aborted. Since application of vapor-permeable membranes allowed normal lipid repletion, occlusion alone is not responsible for the inhibition of lipid repletion. Acetone treatment also perturbed epidermal barrier function, which returned to normal in uncovered animals in parallel with the reappearance of stratum corneum lipid. However, when animals were covered with an occlusive membrane, barrier function did not recover normally. In contrast, occlusion with vapor-permeable membranes allowed barrier function to recover normally. Finally, whereas occlusive membranes prevented the characteristic increase in epidermal lipid synthesis that follows barrier perturbation, epidermal lipid synthesis was increased in animals covered with a vapor-permeable membrane. These results point to transepidermal water flux itself as the signal that regulates epidermal lipid synthesis, which is associated first with the redeposition of stratum corneum lipids and then the normalization of stratum corneum barrier function.

Acetone↗

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↗

PubMed1989

Lipid content and lipid type as determinants of the epidermal permeability barrier.

During terminal differentiation, mammalian epidermal lipids undergo striking changes in both composition and distribution. Phospholipids and neutral lipids are replaced by a mixture of ceramides and neutral lipids organized in intercellular lamellar bilayers. Whether all of these lipids and/or whether specific lipid classes regulate permeability barrier function is not known. When hairless mice were treated with acetone, the degree of barrier perturbation (measured as transepidermal water loss, TEWL) increased linearly with the amount of lipid removed. Moreover, virtually all lipid species appeared to be removed by acetone treatment. In contrast, the nonpolar organic solvent, petroleum ether, while removing greater amounts of lipids, provoked lesser barrier abnormalities. As determined by both quantitative thin-layer chromatography and histochemistry, petroleum ether selectively extracted nonpolar lipids leaving sphingolipids and free sterols in place. In petroleum ether-treated animals, subsequent acetone treatment removed additional sphingolipids and produced a dramatic increase in TEWL. A linear relationship existed for the quantities of sphingolipid removed and degree of barrier disruption in acetone-treated, but not petroleum ether-treated animals. These results support a relationship between the total lipid content of the stratum corneum and barrier function. Secondly, although the results demonstrate the participation of the total lipid mixture in the barrier, removal of nonpolar species alone appears to cause only a modest level of barrier disruption, while removal of sphingolipids and free sterols leads to a more profound level of barrier perturbation.

Acetone↗

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

Regulation of cholesterol metabolism in a slow-growing hepatoma in vivo.

Cholesterol metabolism and its regulation are altered in hepatomas as compared to normal liver. We investigated parameters of cholesterol metabolism and their regulation in rats bearing the well-differentiated Morris hepatoma 9108. The numbers of membrane associated receptors recognizing chylomicron remnants, the lipoproteins that deliver dietary lipid to the liver, were substantially decreased in the 9108 tumor relative to the host liver. Cholesterol synthetic rates were 2-3-fold higher in the tumor, while the activity of 3-hydroxy-3-methylglutarylcoenzyme A reductase (EC 1.1.1.88), a rate-limiting enzyme for sterol synthesis, was elevated 6-14-fold. Although tumor free and esterified cholesterol contents were elevated, the activity of acylcoenzyme A:cholesterol acyltransferase (EC 2.3.1.26), the enzyme responsible for intracellular sterol esterification, was unchanged. Similar to the host liver, cholesterol synthesis and 3-hydroxy-3-methylglutarylcoenzyme A reductase were inhibited in the tumor when rats were fed a diet containing cholesterol, cholate and lard, and there was no effect on the numbers of chylomicron remnant receptors. Administering an intravenous bolus of very low density lipoproteins obtained from hypercholesterolemic rats caused an inhibition of tumor reductase activity, but had little effect on cholesterol content or cholesterol esterification. Thus, hepatoma 9108 expressed quantitative differences in cellular parameters involved in the uptake, metabolism, and synthesis of cholesterol and their susceptibility to regulation when compared with the host liver. These differences are best explained by changes in the hepatoma of multiple factors involved in the regulation of normal hepatic cholesterol metabolism.

Animals↗