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A H Moser

Publications and source records attributed to A H Moser.

83 records · Page 5Linked to original sources
PubMed1984

Localization of cholesterol synthesis in the small intestine of diabetic rats.

Previous studies have demonstrated that cholesterol synthesis is increased twofold in the small intestine of diabetic animals. The present study demonstrates that the stimulation of small intestinal cholesterol synthesis by diabetes is a generalized phenomenon occurring in all segments of the small intestine. Quantitatively, in control animals the proximal two segments of the small intestine account for the majority of the total small intestinal cholesterol synthesis, whereas in the diabetic animals, because of the generalized stimulation in cholesterogenesis, the contribution of the terminal segments to total small intestinal cholesterol synthesis is of increased importance. The various manipulations that regulate cholesterol synthesis in the small intestine of diabetic animals also affect cholesterol synthesis in all portions of the small intestine. In diabetic animals cholesterol feeding and the limitation of food intake decrease cholesterol synthesis in the total small intestine and in all segments of the small intestine. Conversely, colestipol feeding increases cholesterol synthesis in all segments of the small intestine. These results demonstrate that, despite the obvious structural, functional, and environmental differences among the various segments of the small intestine, the stimulation of cholesterol synthesis that occurs secondary to diabetes mellitus is a generalized phenomenon. Similarly, the factors that regulate small intestinal cholesterol synthesis do so in a generalized manner.

Animals↗
PubMed1983

Altered activation state of hydroxymethylglutaryl-coenzyme A reductase in liver tumors.

Extensive studies have demonstrated that the normal inhibition of cholesterol synthesis by cholesterol feeding is decreased in all hepatomas studied in vivo. This loss of the normal feedback regulation of cholesterol synthesis has been shown to be due to the failure of cholesterol ingestion to inhibit the activity of hydroxymethylglutaryl (HMG)-CoA reductase. The basis for this absence of feedback control of cholesterogenesis is unknown. Studies to date have not demonstrated structural or kinetic differences between the HMG-CoA reductase of normal liver and hepatoma. The present study, however, demonstrates significant differences in the activation state of HMG-CoA reductase from normal liver and hepatoma. In normal liver only approximately 10-20% of the microsomal HMG-CoA reductase is in the dephosphorylated, active form while 80-90% is in the phosphorylated, inactive state. In contrast, in three different Morris hepatomas in vivo, from 53 to 73% of the HMG-CoA reductase is in the active state. That the increased activation state in hepatomas is a property of tumor tissue and is not solely due to rapid growth is demonstrated by the fact that in both fetal and regenerating liver an enhanced activation state of HMG-CoA reductase is not observed. Additionally, preincubation with magnesium and ATP results in the inhibition of HMG-CoA reductase both in tumor and in liver. Presumably, this decrease in HMG-CoA reductase activity is due to the phosphorylation of the enzyme. Similarly, the preincubation of tumor and liver microsomes with phosphatase results in an increase in HMG-CoA reductase activity presumably by the dephosphorylation of the enzyme to its active form. The relationship between the altered activation state of HMG-CoA reductase in hepatomas and the reduction in the feedback regulation of this enzyme in liver tumors remains to be explored.

Adenosine Triphosphate↗
PubMed1983

De novo sterologenesis in the intact rat.

On the basis mainly of in vitro studies, the liver and, to a lesser degree, the small intestine are widely accepted as the major sites of de novo sterologenesis. Utilizing [3H]water, we have investigated de novo sterologenesis in intact rats. Greater than 80% of labeled nonsaponifiable lipids and more than 70% of the labeled cholesterol were localized to extrahepatic, extraintestinal tissues. Feeding cholesterol markedly suppressed hepatic sterologenesis but had little influence on extrahepatic sites of sterol synthesis. Similarly, partial hepatectomy, which greatly decreased sterol synthesis in the liver, also did not significantly affect the accumulation of labeled sterols in extrahepatic tissues; therefore, the transport of sterols from the liver did not account for a significant portion of labeled sterols in extrahepatic tissues. Cannulation of the thoracic duct demonstrated that transport of newly synthesized intestinal sterols to peripheral tissues also did not account for the large accumulation of labeled sterols in extrahepatic, extraintestinal tissues. The primary extrahepatic, extraintestinal sites of sterologenesis were the skin and remaining carcass. The lung, kidney, spleen, heart, ovary, brain, muscle and adipose tissue made minor contributions to de novo sterol synthesis. Therefore, tissues other than the liver and intestine, especially the skin and remaining carcass, are important sites of de novo sterologenesis in vivo.

Animals↗
PubMed1983

Localization of de novo sterologenesis in mammalian skin.

Previous studies have demonstrated that the skin is an important site of de novo sterol synthesis and that there is a sex difference in cutaneous sterologenesis with male animals synthesizing more sterols than females. The aim of the present study was to localize the major sites of sterol synthesis within the skin and to determine which of these sites accounted for the sex differences in sterologenesis. In male and female rats whose dermal and epidermal layers are separated by dithiothreitol treatment, the dermis is the major site of skin sterologenesis (males 86% of total, females 82% of total). Moreover, the sex difference in skin sterol synthesis is quantitatively localized primarily within the dermal layer (approximately 2.5-fold greater in the dermis of males). Sterol synthesis is also increased in the epidermis of males. To rule out the possibility that sebaceous gland production accounted for our observations, we treated animals with isotretinoin (13-cis-retinoic acid), a drug that suppresses sebaceous gland sebum production. Sterol synthesis in the skin of both male and female rats is not significantly altered by isotretinoin administration and the sex difference in skin sterologenesis is unaffected. To further localize the sites of sterol synthesis within the skin, studies of hairless mice whose skin was split by DTT were initiated. In hairless mice, DTT separates the epidermis into upper (stratum corneum and granulosum) and lower (basal and spinous cells) strata. The basal layer was separated from the dermis by gentle scraping. As in rats, the dermis is the chief site of sterol synthesis in the skin. In addition, the lower layer of the epidermis (basal and spinous cells) is also a very active site of sterologenesis, accounting for 20% of total skin nonsaponifiable lipid synthesis. The upper epidermis accounted for only a small portion of total skin synthesis. It is highly likely that the bulk of cutaneous sterol synthesis occurs in the pilosebaceous epithelium.

Animals↗
PubMed1983

Differences in de novo cholesterol synthesis between the intact male and female rat.

Three different isotopes were used to quantify de novo sterologenesis in intact male and female rats. All three substrates (i.e. [14C]acetate, [14C]octanoate, and [3H]water) were incorporated into nonsaponifiable lipids and cholesterol at significantly greater rates in males than in females. Even with cholesterol feeding, male animals synthesized significantly more cholesterol and nonsaponifiable lipids than females. The primary site of this sex difference in sterologenesis is extrahepatic, extraintestinal tissues (e.g. carcass). In the carcass this sex difference is chiefly due to an enhancement of sterol synthesis in the skin of male rats. Cholesterol synthesis is 73% greater and nonsaponifiable lipid synthesis is 85% greater in the skin of males than in females. Moreover, de novo sterologenesis in skin is hormonally dependent. In castrated females, testosterone treatment results in a 2-fold stimulation of skin sterol synthesis compared to that in animals administered estradiol or oil vehicle alone. In castrated males, estradiol treatment caused a 30% reduction in skin cholesterol and nonsaponifiable lipid synthesis compared to that in animals administered testosterone. The effects of sex steroid hormones on skin are, therefore, probably responsible for mediating the observed sex difference in de novo sterol synthesis. Additionally, this study demonstrates that the administration of estradiol and testosterone in physiological doses to castrated animals has no effect on cholesterol or nonsaponifiable lipid synthesis in liver, intestine, or other nondermal tissues.

Animals↗
PubMed1983

The effect of cholesterol feeding and alterations in bile acid homeostasis on de novo sterologenesis in diabetic rats.

Previous studies have demonstrated that de novo cholesterol synthesis is increased two- to threefold in the intestines of diabetic animals. This increase is due to a stimulation of cholesterogenesis in both the small and large intestine but, quantitatively, the small intestine is primarily responsible for the observed increase. The present study examined the effect of cholesterol feeding and alterations of bile acid homeostasis on de novo sterol synthesis in intact normal and diabetic animals. Cholesterol feeding in the control animals did not affect sterol synthesis in the small intestine, but in diabetic animals cholesterol feeding markedly inhibited small intestinal sterologenesis. The threefold stimulation of small intestinal sterol synthesis observed in diabetic animals is completely obliterated by cholesterol ingestion. Moreover, this inhibition of sterol synthesis by cholesterol feeding in the small intestine of diabetic animals occurred very rapidly (within 36 h). In the large intestine, cholesterol feeding did not influence sterol synthesis in either the diabetic or control animals. In the liver, cholesterol feeding markedly inhibited sterol synthesis to similar degrees in the diabetics and controls. Colestipol feeding and biliary drainage, procedures that reduce bile acid pool size, stimulated sterol synthesis in the liver and small intestine of both diabetic and control animals. However, reductions in bile acid pool size increased sterologenesis in the large intestine in control animals but had no effect in the diabetics. Bile acid ingestion did not alter either small or large intestinal sterologenesis in the diabetic or control animals. In conclusion, the present study demonstrates the sterol synthesis is enhanced in the small and large intestine of diabetic animals and, moreover, both the cholesterol- and bile acid-mediated regulation of cholesterol synthesis in the intestines of the diabetic animals is altered from normal.

Animals↗
PubMed1983

Activation of HMG-CoA reductase by microsomal phosphatase.

HMG-CoA reductase activity can be modulated by a reversible phosphorylation-dephosphorylation with the phosphorylated form of the enzyme being inactive and the dephosphorylated form, active. Phosphatases from diverse sources, including cytosol, have been shown to dephosphorylate and activate HMG-CoA reductase. The present study demonstrates phosphatase activity capable of activating HMG-CoA reductase that is associated with purified microsomes. The incubation of microsomes at 37 degrees C for 40 min results in a twofold stimulation of HMG-CoA reductase activity, and this stimulation is blocked by sodium fluoride or phosphate. The ability of microsomes to increase HMG-CoA reductase activity occurs regardless of whether microsomes are prepared by ultracentrifugation or calcium precipitation. Additionally, phosphatases capable of activating HMG-CoA reductase are present in both the smooth and rough endoplasmic reticulum. Freeze-thawing does not prevent microsomes from activating HMG-CoA reductase but preincubation results in a significant decrease in the ability of microsomes to increase HMG-CoA reductase activity. Thus, the present study demonstrates that purified liver microsomes contain phosphatase activity capable of activating HMG-CoA reductase.

Animals↗
PubMed1983

De novo cholesterogenesis in pregnancy.

Hypercholesterolemia occurs during pregnancy in rats and human beings, beginning in the second trimester and increasing progressively throughout the remainder of pregnancy. The present study quantified de novo cholesterol synthesis in vivo and in vitro in pregnant animals using 3H2O as the substrate for measuring cholesterogenesis. In the third trimester, cholesterol synthesis by pregnant rat gut and carcass (all tissues not specifically studied) was not significantly different from that observed in controls. However, hepatic cholesterol synthesis was markedly stimulated in third trimester pregnant rats. Additionally, cholesterol synthesis in the placenta and fetus occurred at a very substantial rate. The magnitude of placental cholesterol synthesis was similar to that observed in the liver of control animals whereas fetal cholesterogenesis was considerably greater. Cholesterol feeding greatly suppressed hepatic cholesterol synthesis in both control and pregnant animals, so that the difference between control and pregnant animals was obliterated. Cholesterol feeding did not significantly affect the accumulation of newly synthesized cholesterol in either the placenta or fetus. In the Saguines fusciollis monkey, pregnancy similarly stimulated hepatic cholesterol synthesis, and the fetus and placenta were important sites of in vivo de novo cholesterogenesis.

Animals↗
PubMed1982

The effect of diabetes mellitus on sterol synthesis in the intact rat.

Diabetes mellitus in both humans and animals is characterized by elevations in plasma cholesterol concentrations. The cause of this hypercholesterolemia is unknown. The present study employed tritiated water to quantity sterol synthesis in intact diabetic and control animals. Sterologenesis was 60-246% greater in the gut of diabetic animals than in controls. This enhancement of sterol synthesis occurred soon after the onset of diabetes and persisted for at least 3 wk. Moreover, insulin therapy markedly decreased gut sterol synthesis in diabetic animals to levels only slightly greater than in controls. Diabetes increased sterol synthesis primarily in the small intestine, but a small increase was also observed in the large intestine. Subfractionation of the small intestine into epithelial cell and muscularis cell layers revealed an increased sterologenesis in both layers. Quantitatively, though, the epithelial layer accounted for the majority of the enhancement of small intestine sterol synthesis observed in diabetic animals. De novo sterologenesis in tissues other than the intestines (liver, skin, stomach, or remaining carcass) was not significantly altered by diabetes. This study demonstrates that diabetes markedly stimulates sterol synthesis, an effect that is specifically localized to the intestines.

Animals↗
PubMed1982

De novo sterologenesis in intact primates.

Recent studies have demonstrated that in intact rodents, extrahepatic tissues are much more important sites of de novo sterologenesis than previously appreciated. The present investigation was undertaken to localize the sites of cholesterol and nonsaponifiable lipid synthesis in intact primates. Tritiated water was employed as the radiolabeled tracer for quantifying sterol synthesis. Our results indicate that in the intact primate, tissues other than the liver account for the majority of the newly synthesized cholesterol (74.5% to 84.4%) and nonsaponifiable lipids (77.3% of 86.5%). This extrahepatic sterologenesis is primarily localized to the intestine, skin, and carcass (all tissues not specifically analyzed). Sterologenesis in the other tissues made only a minor contribution to total animal cholesterol and nonsaponifiable lipid synthesis. Moreover, cholesterol feeding that inhibited hepatic and small intestinal sterol synthesis did not greatly affect skin or carcass sterologenesis. This indicates that transport of sterols from either the live or intestine to peripheral tissues does not contribute greatly to the newly synthesized sterols localized in extrahepatic, extraintestinal sites.

Animals↗