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Biomedical subjects

E Shafrir

Publications and source records attributed to E Shafrir.

At least 91 records · Page 5Linked to original sources
PubMed1983

Enzymatic and metabolic responses to affluent diet of two diabetes-prone species of spiny mice: Acomys cahirinus and Acomys russatus.

The adaptive responses to sucrose and fat diets were investigated in two species of spiny mice, Acomys russatus and Acomys cahirinus, in relation to their propensity to develop diabetic-like symptoms. A russatus gained weight pronouncedly, both on regular and fat-rich seed diet, did not exhibit hyperglycemia or hyperlipidemia but had highly increased hepatic triglyceride content in association with high levels of circulating free fatty acids and incidence of ketonuria in 10 of 41 animals. On the other hand, A. cahirinus exhibited a moderate weight gain on the fat diet which was accompanied by hyperglycemia but no hyperlipidemia or ketonuria. Neither weight gain nor ketonuria were evident in A. russatus and A. cahirinus on the sucrose-rich diet, but there was hyperlipidemia in the latter species. A. cahirinus, in particular, showed many-fold induction of liver enzymes, of regulatory importance in the pathways of glycolysis and lipogenesis, which could be linked to the hyperlipidemia in this species. On the fat diet there was a smaller increase in activity in enzymes related to gluconeogenesis in A. russatus compared with A. cahirinus, as well as a smaller suppression of glycolytic and lipogenic enzymes. Adipose tissue lipoprotein lipase activity rose in response to the fat-rich diet, more markedly in A. russatus than A. cahirinus in correlation to the more marked weight gain and hyperinsulinemia in this species. The affluent diets, especially sucrose, elicited an increase in circulating triiodothyronine levels which was more pronounced in A. cahirinus than in A. russatus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Effect of pregnancy and diabetes on myofibrillar protease activity in maternal and fetal muscles.

The activity of protease was investigated by cleavage of 14C-labelled globin by the isolated myofibrillar fraction of maternal and fetal muscles of nonpregnant, pregnant, and pregnant diabetic rats, on days 15 and 20 of pregnancy. Diabetes was produced by i.p. streptozotocin injection on day 5 or 12 of pregnancy. There was no change in muscle protease activity on day 15 of pregnancy in nondiabetic rats, compared to nonpregnant control rats, whereas on day 20 protease activity rose in the gastrocnemius by 25%, in the diaphragm by 30%, and only slightly in the heart. Diabetes, imposed during days 12-20 of pregnancy, induced a further increase in protease activity in the gastrocnemius (42%), diaphragm (47%), and heart (25%). In rats with diabetes lasting from day 5 to 20 of gestation there were only slight further increases in protease activity. In contrast, maternal diabetes did not induce changes in myofibrillar protease activity of fetal leg or heart muscles compared with the corresponding muscles of fetuses of nondiabetic rats. The increased protease activity on the maternal side occurred at low insulin levels and/or reduced insulin sensitivity, whereas the absence of changes in protease activity on the fetal side was associated with sustained or even increased presence of insulin. This suggests that the adaptive changes in protease activity, in both pregnancy and superimposed diabetes, are related to insulin availability and its effectiveness.

Adaptation, Physiological↗
PubMed1982

Placental lipid and glycogen content in human and experimental diabetes mellitus.

To assess whether placental DNA, glycogen, and fat are affected by diabetes mellitus and whether the changes correlate with the disturbance in maternal fuels, placentas were examined at delivery in women with normal carbohydrate metabolism, gestational diabetes mellitus, and Classes B to F diabetes and in rats rendered diabetic by the administration of streptozotocin 2 weeks before mating. Plasma glucose values during late pregnancy were higher in patients with Classes B to F diabetes than in the patients with gestational diabetes mellitus so that they were judged to have more severe metabolic disturbances; rats were also divided into groups with "mild" or "severe" diabetes on the basis of blood sugar. In rats, as in humans, diabetes tended to increase placental mass, DNA, glycogen, and lipids. However, the relative changes in glycogen and fat exceeded the alterations in mass and DNA, especially in those with more severe diabetes, so that a true increase in glycogen and fat per placental cell may have occurred. Thus, placental glycogen/DNA and placental triglycerides/DNA significantly exceeded control values in patients with Classes B to F diabetes and in rats with severe diabetes but not in women with gestational diabetes mellitus or rats with mild diabetes. Total placental triglycerides and total placental glycogen were significantly correlated (r = 0.952; p less than 0.001) in rats with experimental diabetes, which suggests that these alterations in placental composition during late pregnancy may share communal dependencies.

Animals↗
PubMed1982

Maternal-fetal fat transport versus new fat synthesis in the pregnant diabetic rat.

Rats were made diabetic by the injection of streptozotocin on day 12 of pregnancy and were investigated on days 17 and 20 of pregnancy. A significant correlation between both maternal plasma triglyceride and nonesterified fatty acid levels with placental or fetal triglyceride content was found, although fetal weight did not change significantly. In order to investigate the source of the placental and fetal fat the rats received, intragastrically 24 h earlier, 1-14C-triolein (as a preformed fatty acid tracer) and tritiated water (as a marker of de novo fatty acid synthesis). Several maternal tissues, placenta, and fetuses were extracted and analysed for fatty acid radioactivity. Compared with non-diabetic pregnant rats, maternal 14C-label storage was reduced. In contrast, the placental and fetal tissues demonstrated a significant rise in 14C-label, similar in magnitude to the rise in their triglyceride content. The pattern of 3H incorporation also indicated a pronounced decrease in maternal fatty acid synthesis, but no increase in de novo fatty acid synthesis in the fetus or placenta. The findings show that fetal lipids in the pregnant rat originate both from maternal fatty acids and those synthesized in situ. The diabetes-induced increment in fetal triglyceride content is derived, however, from preformed maternal triglycerides or non-esterified fatty acids secondary to the increase in their concentration in the maternal circulation.

Animals↗
PubMed1982

Gastric lipase in the newborn rat.

A substantial portion of rat milk triglycerides was hydrolyzed in the ligated stomach of suckling rats with excised lingual gland and pancreas, due to the action of gastric lipase. Free fatty acids were the main lipolytic products. There were some diglycerides and traces of monoglycerides. Medium chain length (C8-C12) fatty acids were predominantly recovered in the free fatty acid fraction, whereas the remaining tri- and diglycerides became richer in long chain (greater than or equal to C14) fatty acids suggesting a preferential lipolysis of medium chain fatty acid ester bonds. The lipase activity in extracts of stomach wall and sublingual gland tissue was more stable at acid pH and more resistant to the action of pepsin than the activity of pancreatic lipase. Trypsin strongly affected lingual lipase activity but only moderately reduced gastric and pancreatic lipase activity. Presence of sodium taurocholate made the lingual and gastric lipases less sensitive to proteolytic attack. It was also found that the activity of gastric lipase, related to the tissue protein content, decreased with the age of rats, whereas that of lingual lipase increased. The joint capacity of the stomach and lingual gland lipases amounted to about 50% of the total digestive lipolytic capacity 6 days after rat birth but decreased to about 20% at 60 days of life. This was due mainly to the considerable increase in the pancreatic gland size.

Age Factors↗
PubMed1982

Increased protease activity in muscles of obese- (ob/ob) mice.

Muscles of genetically-obese animals exhibit decreased binding of and metabolic responses to insulin. Muscle protein catabolism was investigated by measuring the activity of alkaline, myofibril-bound protease in male (ob/ob) mice, fed ad libitum, or fasted for 5 d. Enzyme activity in the isolated myobrillar fraction was determined by the degradation of 14C-globin. Compared to the lean siblings, protease activity in the obese mice was 2.0, 1.5 and 1.3-fold higher in gastrocnemius, diaphragm and soleus muscle respectively, but without change in heart. The higher protease activity in gastrocnemius, diaphragm and soleus was associated with a parallel decrease in the weight and protein mass of the muscles. The muscles of obese mice also showed a 3 to 4-fold increase in triglyceride and a 2-fold increase in glycogen content. After 5-d starvation, the activity of protease rose in the gastrocnemius of obese mice only 1.5 fold, while it increased as much as 4 and 2 fold in gastrocnemius and diaphragm, respectively, in the lean mice. There was no significant change in heart enzyme activity. After 5-d starvation, serum insulin in obese mice fell markedly but remained still higher than that in ad libitum fed lean mice. Insulin-dependent serum metabolites, as well as adipose tissue lipoprotein lipase and hepatic enzymes related to lipogenesis and gluconeogenesis were consequently much less affected in obese mice and the prevalence of adequate insulin supply appeared to be the cause for lack of significant effect on muscle protease activity in fasting obese mice. It is suggested, therefore, that the induction of myofibrillar protease in obesity is linked to the decrease in cellular responsiveness to insulin and may also be interrelated with the intracellular metabolic adjustments to the enhanced muscle lipid availability.

Animals↗
PubMed1982

Intermediary metabolism during the development of obesity and diabetes in the desert rodent Acomys cahirinus.

The spiny mouse Acomys cahirinus, which exhibits beta-cell hyperplasia but low insulin secretion in captivity responded with hyperlipidemia without obesity or diabetes on a sucrose diet and became obese, and glucose-intolerant on a diet of fat-rich seeds. A three-month sucrose diet induced a marked rise in the activity of regulatory enzymes of glycolysis and lipogenesis in the liver but not in adipose tissue. There was also increased energy waste on this diet evident from a three-fold rise in the activity of hepatic mitochondrial FAD-glycerophosphate oxidase associated with an elevation in circulating triodothyronine. The obesity in mice maintained for three months on fat rich seeds was associated with moderate hyperglycemia, mild hyperinsulinemia and little change in circulating lipids. There was a decrease in the activity of glycolytic and lipogenic enzymes both in the liver and adipose tissue. Adipose tissue lipoprotein lipase activity rose, suggesting that the chylomicrons carrying the exogenous fat were better assimilated than the very-low-density lipoproteins synthesized from the dietary carbohydrate. Along with adipose tissue gain, triglyceride deposition was apparent in several muscles, accompanied by increased tissue free fatty acid, citrate and glycogen content. This suggested relation of increased muscle fat utilization with decreased glucose metabolism and insulin sensitiveness. Diverse responses to diets were thus elicited, which were particularly discernible in desert animals surviving on a limited caloric intake. Detailed follow up of these enzymatic and endocrine adaptation patterns to selective nutritional affluence may promote the understanding of the mechanisms leading to hyperlipidemia with leanness and normal glucose homeostasis versus obesity with diabetes but without hyperlipidemia.

Adipose Tissue↗
PubMed1981

Origin and pattern of glucocorticoid-induced hyperlipidemia in rats. Dose-dependent bimodal changes in serum lipids and lipoproteins in relation to hepatic lipogenesis and tissue lipoprotein lipase activity.

Rats maintained for five days on a low dose of triamcinolone (0.5 mg/kg) showed a 2-fold increase in serum triacylglycerol concentration, paralleled by a rise in all very low density lipoprotein (VLDL) components but no significant change in serum cholesterol or high density lipoproteins (HDL). In contrast, a high dose of triamcinolone (12.5 mg/kg) produced a fall in triacylglycerol and VLDL to the range of control levels coincident with doubling in serum cholesterol and HDL. The rise in VLDL was attributed in a large part to enhanced hepatic fatty acid synthesis as evident from the marked rises in activity of rate-limiting enzymes of lipogenesis and in 3H incorporation into liver and serum fatty acids from in vivo administered 3H2O. The induction of fatty acid synthesis was linked to pronounced hyperinsulinemia, elicited by the triamcinolone treatment, to which the liver remained selectively responsive, contrary to the general insulin antagonism in peripheral tissues. Triamcinolone treatment also resulted in small rises in serum glucagon but these changes did not appear to be of importance for the observed bimodal serum lipoprotein perturbations. Dexamethasone, prednisolone and cortisol, administered in doses equipotent to 0.5 mg/kg triamcinolone, produced similar changes in the levels of serum triacylglycerol and insulin and activities of hepatic enzymes of lipogenesis.

Acetyl-CoA Carboxylase↗
PubMed1981

Effect of age on myofibrillar protease activity and muscle binding of glucocorticoid hormones in the rat.

Age-related and muscle tissue-specific alterations in myofibrillar protease activity were observed in different muscles of the rat. Utilizing exogenous, denatured and 3 H-labelled hemoglobin as substrate, proteolytic activity of the myofibrillar enzyme was found to decrease with age in the gastrocnemius muscle while the same activity in the diaphragm and heart muscles increased with age. The extent of response of the enzymes to administration of the potent glucocorticoid triamcinolone was, however, found to be similar in young and old animals, and each muscle retained its specific mode of response to the exogenous glucocorticoid, for example enhancement of the activity in skeletal and diaphragm muscles and diminution of the activity in the heart. Development was associated with a marked reduction in the number of glucocorticoid-specific binding sites in the cytosol of both gastrocnemius and heart muscles, with only negligible changes in the affinity of hormone binding. It is concluded that while the ability of the enzyme to response to exogenous, pharmacological doses of glucocorticoids is not affected by development, development does modify the myofibrillar protease activity in a tissue-specific manner.

Aging↗
PubMed1981

Urine protease and antiprotease activity in experimental aminonucleoside nephrotoxicity.

Induction of nephrosis in rats with aminonucleoside of puromycin (ANP) was followed by an increase in urinary protease activity, measured by the cleavage of 14C-globin, as well as in antiprotease activity measured by trypsin inhibition. The excretion of protease and protease inhibitor coincided with but did precede the onset of proteinuria when the ANP was injected subcutaneously for 5 days and lagged after proteinuria when the ANP was given as a single intravenous dose. Serum protease activity did not change throughout ANP treatment or later, whereas serum antiprotease capacity declined coincidently with proteinuria, most probably due to the loss in urine. Kidney proteolytic activity was markedly reduced in ANP nephrosis. Treatment of rats with proteolysis inhibitors, trasylol, episilon-aminocaproic acid, soybean trypsin inhibitor, or hexapron, together with ANP failed to prevent, delay or reduce the proteinuria. We believe that the urinary protease in ANP nephrosis does not originate from the circulation but from the release of kidney protease as a consequence of the glomerular lesion, and does not appear to be involved in its causation.

Animals↗
PubMed1981

Patterns of glucose intolerance and free fatty acid behavior in viral hepatitis.

Twenty-one viral hepatitis patients underwent i.v. glucose tolerance tests during the acute phase of the illness. The results, expressed as the constant of glucose disappearance (Kg), were compared with those of 10 healthy control subjects. When the patients were grouped according to Kg-less than 0.9 or greater than 1.2 min-1-it was found that eight showed a delayed glucose disappearance together with a moderate hypoinsulinemic response (pattern 1). Another eight showed a normal glucose disappearance together with a hyperinsulinemic response (pattern 2). Five patients had intermediate Kg values. High levels of plasma free fatty acids (FFA) were a consistent finding in all patients, indicating that unrestrained lipolysis is an important feature of hepatitis. The extent of decrease in plasma FFA in response to the glucose load was markedly lower in all hepatitis patients than in the control subjects; the rate of decrease was most delayed in the pattern 1 patients. This suggested that the increased FFA availability is an expression of adipose tissue insulin resistance, which, in contrast to glucose disappearance, remains uncompensated by the relative hyperinsulinemia. It may contribute to the diminished peripheral glucose utilization, particularly in pattern 1 patients. We conclude that the different patterns of response in hepatitis may be discerned in one patient group by extending the diagnostic criteria of the glucose tolerance test. In addition to the differences in the magnitude of the peripheral insulin resistance, the main distinction between the two patterns lies in the capacity of the pancreas to adjust insulin secretion in order to maintain normal glucose homeostasis.

Adolescent↗
PubMed1981

Lipoprotein profiles in a heterogeneous group of patients with nephrotic syndrome.

Lipoprotein composition was determined by ultracentrifugation in 13 unselected hospitalized patients with nephrotic syndrome (proteinuria 6.2 +/- 0.5 g/24 h) and compared with that of 13 healthy subjects. Plasma levels of cholesterol and triglycerides (TG) were 407 +/- 45 (mean +/- SE) and 285 +/- 35 mg/dl in the patients vs. 195 +/- 11 and 108 +/- 12 mg/dl in the control group. Type IIb was the only hyperlipoproteinemia pattern in 10 patients (77%). The protein component of very low density lipoproteins (VLDL) was the only slightly elevated, but cholesterol and TG were markedly increased in relation to protein. Low density lipoproteins (LDL) were considerably elevated, and their cholesterol and TG components rose in relation to protein. Of interest was a small but distinct rise in high density lipoproteins (HDL), which was not observed by other investigators studying patients mostly with higher proteinuria and VLDL elevations. The mean HDL/LDL cholesterol ratio, and apparent atherogenic index, was not significantly reduced. Both plasma cholesterol and TG were inversely related to plasma albumin. Plasma cholesterol and even HDL cholesterol were positively related to proteinuria. The finding that in nephrosis with moderate proteinuria all lipoproteins are elevated and enriched in their lipid content, and that HDL rise along with VLDL--contrary to their reciprocal behavior in other lipoproteinemias--indicates that the elevation was due to a universal increase in lipoprotein synthesis. With regard to atherogenicity of nephrosis, no salient, general lipoprotein-related change was discerned. An individual appraisal of lipoprotein composition, including the extent of urinary HDL loss, is suggested.

Adolescent↗
PubMed1980

Triacylglycerol metabolism and triacylglycerol lipase activities of cultured human skin fibroblasts.

The relative contribution of lipoproteins and free fatty acid to the cellular triacylglycerol content of cultured human fibroblasts was tested. Fibroblasts accumulated triacylglycerol in proportion to the molar ratio of free fatty acid (oleic acid) to albumin in the medium. Fibroblasts also accumulated triacylglycerol when exposed to medium containing human very low density liproprotein. This accumulation of triacylglycerol was apparently due to direct uptake of intact very low density lipoprotein particles initiated by binding of very low density lipoprotein to cell surface receptors. The amount of 125I-labeled very low density lipoprotein protein internalized and degraded by the cell saturated at the same very low density lipoprotein concentration that produced the maximum increase in cell triacylglycerol. Preincubations with lipoprotein-deficient serum, which enhanced the cell's ability to bind 125I-labeled very low density lipoprotein, increased the amount of 125I-labeled very low density lipoprotein internalized and degraded by the cell in parallel with increased levels of cellular triacylglycerol. Results suggest that the triacylglycerol that accumulates in the presence of very low density lipoprotein represents a lysosomal pool of partially degraded very low density lipoprotein. Measurements of lipase activity of fibroblast homogenates revealed three pH optima at (in descending order of magnitude of activity) pH 4, pH 6, and pH 8. The pH 8 lipase does not appear to represent lipoprotein lipase, since it is not activated by either serum or heparin. Exposure of the cells to medium with varying lipid composition had no effect on the lipase activities. The lipase activities of fibroblasts from donors with familial hypertriglyceridemia appear to be normal.

Adult↗
PubMed1980

Lipoprotein lipid and protein synthesis in experimental nephrosis and plasmapheresis: II. Perfused rat liver.

Livers from rats with experimental hypoproteinemia induced by aminonucleoside-nephrosis or plasmapheresis were perfused with a [14C]-labeled amino acid mixture at physiological concentration. Compared to control rats, a significantly increased incorporation of the amino acid label was found in the apolipoproteins of the ultracentrifugally separated very low and high density lipoproteins (VLDL, HDL), and into albumin secreted into the perfusate. However, no increase in the amino acid-derived lable was detected in VLDL-or HDL-borne lipids in nephrosis or plasmapheresis. Perfusion with U-[14C]leucine as a lipogenesis precursor at < 10 times higher than physiological concentration resulted in 5-fold increase in the label incorporation into perfusate proteins in nephrosis but only in a slightly significant increase in perfusate lipids. In contrast, the incorporation of a preformed fatty acid, 9,10-[3H] oleate into VLDL and HDL lipids increased 3- to 4-fold in nephrosis. Both with leucine and oleate as precursors, the increments in the label appearing in perfusate proteins or lipids, respectively, were markedly greater than the increases in hepatic tissue proteins or lipids. The results indicate that amino acids are preferentially directed by the liver into the synthesis of circulating apolipoproteins and albumin in hypoproteinemia and do not seem to constitute an important precursor of the liporpotein lipids. The increased production of apolipoproteins is associated with an increased incorporation of preformed fatty acids into lipoprotein lipids in addition to the previously reported stimulation of hepatic de novo lipid synthesis from recursors other than amino acids.

Animals↗