Biomedical subjects

A H Moser

Publications and source records attributed to A H Moser.

At least 73 records · Page 4Linked to original sources

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

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

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

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

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↗

PubMed1988

Mechanisms by which tumor necrosis factor stimulates hepatic fatty acid synthesis in vivo.

We have previously shown that bolus intravenous administration of tumor necrosis factor (TNF) to normal rats results in a rapid (within 90 min) stimulation of hepatic fatty acid synthesis, which is sustained for 17 hr. We now demonstrate that TNF stimulates fatty acid synthesis by several mechanisms. Fatty acid synthetase and acetyl-CoA carboxylase (measured after maximal stimulation by citrate) were not higher in livers from animals that had been treated with TNF 90 min before study compared to controls. In contrast, 16 hr after treatment with TNF, fatty acid synthetase was slightly elevated (35%) while acetyl-CoA carboxylase was increased by 58%. To explain the early rise in the hepatic synthesis of fatty acids, we examined the regulation of acetyl-CoA carboxylase. The acute increase in fatty acid synthesis was not due to activation of acetyl-CoA carboxylase by change in its phosphorylation state (as calculated by the ratio of activity in the absence and presence of 2 mM citrate). However, hepatic levels of citrate, an allosteric activator of acetyl-CoA carboxylase, were significantly elevated (51%) within 90 min of TNF treatment. TNF also induces an acute increase (within 90 min) in the plasma levels of free fatty acids. However, hepatic levels of fatty acyl-CoA, which can inhibit acetyl-CoA carboxylase, did not rise 90 min following TNF treatment and were 35% lower than in control livers by 16 hr after TNF. These data suggest that TNF acutely regulates hepatic fatty acid synthesis in vivo by raising hepatic levels of citrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyl-CoA Carboxylase↗

PubMed1987

Localization of cholesterol synthesis along villus-crypt axis in diabetic rats.

In diabetic animals cholesterol synthesis is increased in the small intestine, and this increase occurs in all segments along the duodenal-ileal axis. In the present study we have determined the sites along the villus-crypt axis in which cholesterol synthesis is increased. In diabetic animals cholesterol synthesis is increased in the proximal small intestine, and this is chiefly due to an increased synthesis in the crypt cells. In the midintestine cholesterol synthesis is increased in all cell fractions, but again the crypt cells are the major site accounting for the increase. In the distal small intestine synthesis is increased in all cell fractions, but the increase is greatest in the upper villus cells. Thus the basis for the increase in intestinal cholesterol synthesis in diabetic animals is dependent on location. Additionally, in the proximal small intestine the increase in synthesis is due to an increased mass of cells, whereas in the distal small intestine the increase is due to an increased synthesis per unit of tissue. In cholesterol-fed diabetic animals we observed a decrease in cholesterol synthesis in the proximal and midintestine that was due to a decrease in synthesis in all cell fractions. This decrease in synthesis is accounted for by a decrease in synthesis per unit of tissue. Restricting food intake in the diabetic animals decreased cholesterol synthesis in all cell layers, and this decrease is due to a decrease in cell mass.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗

PubMed1987

Effect of hypocholesterolemia on cholesterol synthesis in small intestine of diabetic rats.

Studies by our and other laboratories have demonstrated that cholesterol synthesis is increased in the small intestine of insulinopenic diabetic animals. In normal animals, many factors have been shown to regulate cholesterol synthesis in the small intestine, including changes in plasma cholesterol levels. The purpose of this study was to determine the effect of lowering plasma cholesterol levels on small intestine cholesterol synthesis in streptozocin-induced diabetic rats. In diabetic rats, 4-aminopyrazolo[3,4-d]pyrimidine (4-APP)-induced hypocholesterolemia (plasma cholesterol levels less than 20 mg/dl) resulted in a 2.5-fold increase in small intestine cholesterol synthesis, which was most marked in the distal small intestine, decreasing proximally. In the distal small intestine the incorporation of 3H2O into cholesterol was 0.28 +/- 0.04 mumol.h-1.g-1 in diabetic rats versus 1.60 +/- 0.38 in diabetic rats administered 4-APP (P less than .01). This stimulation of cholesterol synthesis occurred in the upper villus, middle villus, and crypt cells isolated from the middle intestine of the 4-APP-treated diabetic animals. In agreement with these observations, "functional hypocholesterolemia" due to Triton WR-1339 administration also stimulated cholesterol synthesis 2.5-fold in the small intestine of normal and diabetic animals. In the distal small intestine, cholesterol synthesis was 0.43 +/- 0.10 mumol.h-1.g-1 in the diabetic rats versus 1.08 +/- 0.21 in diabetic rats treated with Triton WR-1339 (P less than .05). In both the 4-APP and Triton WR-1339 experiments, the response of the diabetic rats was similar to that observed in normal rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine↗

PubMed1986

The effect of substrates and competitive inhibitors on the phosphatase-dependent activation of hepatic hydroxymethylglutaryl CoA reductase.

Previous studies have demonstrated that the in vitro activation of microsomal hepatic hydroxymethylglutaryl (HMG) CoA reductase by dephosphorylation is inhibited by HMG CoA or NADPH, the substrates of HMG CoA reductase (13). In the present study the effect of three competitive inhibitors of HMG CoA reductase on the activation of HMG CoA reductase was investigated. Adenosine-2'-monophospho-5'-diphosphoribose, a competitive inhibitor for the NADPH binding site, blocked the phosphatase-mediated activation of HMG CoA reductase. By contrast, neither compactin nor mevinolin, competitive inhibitors for the HMG CoA binding site, altered the activation of HMG CoA reductase. Moreover, the HMG CoA-mediated inhibition of the activation of HMG CoA reductase was not blocked even by very high concentrations of either compactin or mevinolin. These observations suggest that HMG CoA can bind to two sites on HMG CoA reductase. One site of HMG CoA binding serves as a catalytic site and is competitively blocked by compactin or mevinolin, and the second binding site is an allosteric site to which only HMG CoA is capable of binding. The binding of HMG CoA to this second site inhibits the activation of HMG CoA reductase by phosphatases.

Adenosine Diphosphate Ribose↗

PubMed1986

Effect of essential fatty acid deficiency on cutaneous sterol synthesis.

The fact that the skin is a major site of total body sterologenesis, coupled both with the apparent absence of low density lipoprotein receptors on keratinocytes and with the lack of influence of serum cholesterol on epidermal sterologenesis, has created the impression that epidermal lipid synthesis might be autonomous, i.e., nonregulatable. Recent studies have shown, however, that disruption of cutaneous barrier function with acetone or detergents stimulates epidermal sterologenesis (J Lipid Res 26:418-427, 1985). To correlate further sterologenesis with barrier function, we measured de novo synthesis of cholesterol and total nonsaponifiable lipids in essential fatty acid-deficient (EFAD) hairless mice. Animals with defective barrier function, manifested by abnormal transepidermal water loss, demonstrated a 2-fold increase in epidermal cholesterol and total nonsaponifiable lipid synthesis over controls while synthesis in the dermis was unchanged. Epidermal sterologenesis in EFAD animals, repleted with linoleic acid either systematically or topically, returned toward normal as barrier function improved. Moreover, plastic occlusion of EFAD mouse skin normalized epidermal sterologenesis at 1 and 3 days. These results provide further evidence that epidermal sterologenesis is not entirely autonomous, and can be regulated by water barrier requirements.

Animals↗

PubMed1986

Effect of food intake on intestinal cholesterol synthesis in rats.

The mechanism by which diabetes results in an increase in small intestinal cholesterol synthesis is unknown. Previous studies have demonstrated that limiting food intake prevents the increase in intestinal cholesterol synthesis, and it has therefore been proposed that the stimulation of cholesterol synthesis in the small intestine is secondary to the hyperphagia that is associated with poorly controlled diabetes. To shed further light on the role of hyperphagia we have studied the effect on cholesterol synthesis of a variety of conditions that increase food intake. In third-trimester pregnant animals, lactating animals, obese animals, and in animals infused intragastrically with 16 g glucose/day vs. 8 g glucose/day, we have observed that an increase in food intake is associated with an increase in small intestinal cholesterol synthesis. Furthermore, these findings support the hypothesis that hyperphagia is the chief stimulus for the increase in cholesterol synthesis in the small intestine of diabetic animals. Additional studies have demonstrated that simply increasing the bulk of food ingested by adding Alphacel to the diet does not alter cholesterol synthesis in the small intestine. Lastly, in animals in whom Thiry fistulas were surgically constructed we observed that cholesterol synthesis is increased in the diabetic animals in both the segment of the small intestine in contact with the food stream and the segment of the small intestine that is excluded from contact. This observation suggests that the direct contact of the intestinal mucosa with caloric sources is not the sole trigger for increasing small intestinal cholesterol synthesis in hyperphagic diabetic animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

The effect of diabetes mellitus on the lymphatic transport of intestinal sterols.

Previous studies have demonstrated that in intact animals, de novo cholesterol synthesis is increased in the small and large intestines of streptozotocin-induced diabetic rats. The aim of this study was to determine if this enhanced intestinal cholesterol synthesis in diabetic animals results in the increased transport of newly synthesized sterols from the intestines to the peripheral circulation. Thoracic ducts were cannulated in control and diabetic animals and the quantity of newly labeled sterols in the lymph determined after the administration of tritiated water. Labeled sterols in the 24-hour lymph drainage were increased fourfold in the diabetic animals as compared to control animals. Additionally, the percentage of newly synthesized sterols synthesized in the small intestine and transported by the lymph is almost twofold greater in the diabetics. Thus, the increased quantity of labeled sterols present in the thoracic duct lymph of diabetic animals is accounted for by two factors, an enhancement of small intestinal sterol synthesis in diabetic animals and the increased percentage transport of newly synthesized sterols from the small intestine to the bloodstream. In both control and diabetic animals, chylomicrons were the major lipoprotein fraction in which the newly synthesized sterols were transported in the lymph. These findings demonstrate that the increased sterologenesis observed in the intestine of diabetic animals results in the increased transport of newly synthesized cholesterol from the intestines to the circulation.

Animals↗

PubMed1985

Effect of lactation on cholesterol synthesis in rats.

Lactation induces a variety of morphological and functional changes in the gastrointestinal tract. In the present study we employed tritiated water as the substrate to demonstrate that in the intact rat lactation results in a twofold increase in cholesterol synthesis in the small intestine. Feeding a high-cholesterol diet did not markedly inhibit small intestinal cholesterol synthesis in either control or lactating animals, and the difference in cholesterol synthesis between the two groups persisted. In the large intestine, cholesterol synthesis is increased threefold in the lactating animals, and feeding a high-cholesterol diet did not affect synthesis in either the control or lactating animals. In the liver, lactation stimulated cholesterol synthesis, and quantitatively this increase in hepatic cholesterol synthesis is much greater than the increase observed in the intestines. Feeding the rats a high-cholesterol diet markedly inhibited hepatic cholesterol synthesis in both control and lactating animals, a finding that demonstrates that the feedback inhibition of cholesterol synthesis in the liver is not impaired by lactation. In the lactating animals, the quantity of labeled cholesterol in 1 ml of serum is 2.4 times greater than observed in controls. Feeding the rats a high-cholesterol diet markedly decreased the quantity of labeled cholesterol in the serum in both groups and obliterated the difference between control and lactating animals. This suggests that the increased hepatic cholesterol synthesis in the lactating animals is responsible for the differences in labeled cholesterol in the serum. Cholesterol feeding also reduced the quantity of labeled cholesterol localized to the mammary glands in lactating animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Effect of glucose or fructose feeding on cholesterol synthesis in diabetic animals.

Previous studies have demonstrated that cholesterol synthesis is increased twofold in the small intestines of rats with streptozotocin-induced diabetes. The purpose of the present study was to determine the effect of adding glucose or fructose to standard rat chow on cholesterol synthesis in control and diabetic rats. In control rats a 25% glucose or fructose diet fed for 21 days markedly inhibited hepatic cholesterol synthesis in the liver. In contrast, in diabetic animals only fructose inhibited hepatic cholesterol synthesis. In both control and diabetic animals the addition of these simple sugars to the diet did not markedly alter extrahepatic cholesterol synthesis. The enhancement of small intestinal cholesterol synthesis observed in diabetic animals was present regardless of the dietary manipulations. Further studies demonstrated that the addition of smaller concentrations of fructose (10%) to standard rat chow decreased hepatic cholesterol synthesis in both control and diabetic rats. Similarly the addition of fructose to the diet of control and diabetics for a period as short as 2 days was also sufficient to inhibit hepatic cholesterol synthesis. In both control and diabetic animals, fructose feeding decreased hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity but did not alter the percentage of HMG-CoA reductase in the active form. Finally, the intestinal hypertrophy and stimulation of intestinal cholesterogenesis that are characteristic of streptozotocin-induced diabetes occurred when either glucose or fructose was the sole caloric source.

Animal Feed↗

PubMed1985

De novo sterologenesis in the skin. II. Regulation by cutaneous barrier requirements.

Recent studies suggest: that the epidermis and pilosebaceous epithelium are important sites of de novo sterol synthesis, and that the rate of cutaneous cholesterol synthesis does not change with alterations in circulating sterol levels. Since cutaneous sterols may be important for permeability barrier function, we studied the effect of experimentally altered barrier function on de novo sterologenesis in the epidermal and dermal layers of the skin. Epidermal sterologenesis appeared to be modulated by the skin's barrier requirements because topical detergent and acetone treatment stimulated de novo synthesis of nonsaponifiable lipids in the epidermis, but not in the dermis. Synthetic activity paralleled both the return of barrier function toward normal and the extent of prior damage to the barrier. Moreover, plastic-wrap occlusion of solvent-treated sites simultaneously corrected both the barrier abnormality and normalized sterol synthesis, further linking increased epidermal sterologenesis to barrier requirements. Whereas topical applications of a variety of other topical lipids did not down-regulate synthesis, epicutaneously applied 25-hydroxycholesterol appeared to diminish synthesis. These results suggest that maintenance of barrier function is one purpose of epidermal de novo nonsaponifiable lipid synthesis, and demonstrate further that, despite a lack of low density lipoprotein receptors, epidermis can regulate its lipid-synthetic apparatus in response to certain specific requirements.

Acetone↗

PubMed1984

De novo cholesterol synthesis in three different animal models of diabetes.

Recent studies have demonstrated that cholesterol synthesis is increased two- to threefold in the intestines of streptozotocin-induced diabetic rats. Cholesterol synthesis in tissues other than the intestines, including the liver, was not significantly altered by diabetes. In diabetic Chinese hamsters, cholesterol synthesis was increased 2.5-fold in both the small and large intestine. These observations are similar to our findings in diabetic rats and suggest that a stimulation of intestinal cholesterogenesis may be a uniform phenomenon in insulinopenic diabetes. In db/db mice, cholesterol synthesis was increased in both the liver and intestines but quantitatively the increase in hepatic cholesterogenesis was of much greater magnitude. Cholesterol feeding, which markedly inhibited hepatic cholesterol synthesis in both control and db/db mice, did not obliterate this difference in hepatic cholesterol synthesis. In ob/ob mice, the severity of the metabolic disturbances was less than that observed in db/db mice and no abnormalities in cholesterol synthesis were observed in animals ingesting a low cholesterol diet. However, in ob/ob mice fed a high cholesterol diet, hepatic cholesterol synthesis was increased. These observations suggest that in obese insulin resistant diabetic animals of milder severity, the abnormality in hepatic cholesterol synthesis manifests itself only when the animals are ingesting a high cholesterol diet. The results of this and previous studies suggest that in insulinopenic diabetes there is a stimulation of cholesterol synthesis that is localized to the intestines, whereas in obese, insulin-resistant diabetic animals, cholesterol synthesis is altered in the liver.

Animals↗