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C A Casey

Publications and source records attributed to C A Casey.

At least 37 records · Page 2Linked to original sources
PubMed1993

Chronic ethanol administration impairs degradation of formaldehyde-treated albumin by the perfused rat liver.

Nonparenchymal cells of the liver appear to be important in the pathogenesis of various liver diseases, including that caused by ethanol. It is known that chronic ethanol administration impairs the process of receptor-mediated endocytosis in hepatocytes. Liver endothelial cells are also actively endocytic cells, playing a prominent role in the clearance from the circulation of a variety of macromolecules. In this study, we assessed the effect of ethanol administration on this "scavenger" function of liver endothelial cells by measuring the degradation of formaldehyde-treated albumin in isolated, perfused livers of ethanol-fed rats. Rats were pair-fed for 1 or 4 weeks with a liquid diet containing either ethanol as 36% of total calories or an isocaloric amount of carbohydrate. Chronic ethanol administration in this manner for 1 or 4 weeks significantly impaired the degradation of this endothelial cell ligand (by 60 +/- 9% and 37 +/- 9%, respectively). Liver perfusions were also performed on rats that had been administered ethanol acutely or in which ethanol was added to the perfusate. No acute effect of ethanol on the degradation of this ligand was seen. These results demonstrate that chronic ethanol ingestion impairs receptor-mediated endocytosis of formaldehyde-treated albumin by liver endothelial cells, indicating that the adverse effects of ethanol on protein trafficking within the liver are not limited to the hepatocytes.

Animals↗
PubMed1992

The effects of chronic ethanol administration on the rates of internalization of various ligands during hepatic endocytosis.

The purpose of the present study was to further characterize the ethanol-induced impairments in hepatic endocytosis. Specifically, we examined the effects of ethanol treatment on receptor-ligand internalization via the coated and noncoated pit pathways. Insulin, epidermal growth factor (EGF) and asialoorosomucoid (ASOR) were used as model ligands to study internalization by isolated hepatocytes. ASOR and EGF are thought to be internalized strictly in coated pit regions of the cell membrane, while insulin may be internalized in both coated and uncoated membrane regions. Ethanol administration for 5-7 weeks decreased internalization of ASOR and EGF while internalization of insulin was unchanged during a single round of endocytosis of surface-bound ligand. Similarly, a more quantitative measure of endocytosis, the endocytic rate constant, was decreased for EGF and ASOR but not for insulin in livers of experimental rats. When endocytosis of Lucifer yellow, a fluorescent dye known to be internalized in the cell by fluid-phase endocytosis was examined, the initial rates of dye uptake were not significantly altered by alcohol administration. These results indicate that ethanol may selectively impair internalization occurring by coated pits while it has a minimal effect on initial uptake of molecules which are internalized by noncoated membrane regions.

Animals↗
PubMed1992

Impaired attachment of hepatocytes to extracellular matrix components after chronic ethanol administration.

BACKGROUND: Previous studies have shown that the assembly and properties of the hepatocyte plasma membrane are altered by ethanol administration, indicating possible changes in the receptor-mediated binding of the plasma membrane to extracellular matrix substrates. In the present study, the effects of chronic ethanol consumption on the ability of hepatocytes to attach to various components of the extracellular matrix were investigated. EXPERIMENTAL DESIGN: Rats were pair-fed for 5 weeks with a liquid diet containing either ethanol (as 36% of total calories) or isocaloric carbohydrate. The effects of ethanol treatment on hepatocyte-extracellular matrix interactions was ascertained by determining the ability of isolated hepatocytes to attach to various extracellular matrix substrates. RESULTS: The attachment of hepatocytes, isolated from the ethanol-fed rats, to laminin-coated plates was significantly decreased compared with hepatocytes from chow-fed or pair-fed controls. Greater decreases in attachment were seen when higher numbers of hepatocytes were seeded in the plates. Similar inhibitions of attachment were also observed when fibronectin or type I collagen were used as matrices. Time-course cell attachment assays indicated that the maximum extent of attachment rather than the rate of attachment was primarily altered by chronic ethanol feeding. Hepatocytes from the ethanol-fed rats also detached more readily from the matrix-coated plates than those from the controls. A reduced number of functional surface receptors for matrix components is likely the most important factor that accounts for the ethanol-induced impairment of hepatocyte attachment. CONCLUSIONS: These results indicate that chronic ethanol administration impairs the interactions of hepatocytes with their extracellular matrix and that this defect could lead to alterations of hepatocyte structure and function.

Animals↗
PubMed1991

Chronic ethanol-induced impairments in receptor-mediated endocytosis of insulin in rat hepatocytes.

The effects of chronic ethanol administration on the receptor-mediated endocytosis of insulin were investigated in isolated hepatocytes. When hepatocytes were isolated from rats that were fed an ethanol liquid diet for 5-6 weeks, these cells bound 25% less insulin to their surface membrane than did cells from the chow-fed or pair-fed controls. This decreased binding was likely a result of reduced surface receptor number rather than changes in receptor affinity. Rates of insulin degradation were also reduced by 25-30% in hepatocytes from the ethanol-fed animals. In addition, chronic ethanol feeding induced a defect in the internalization of the receptor-insulin complex and altered the hepatocellular processing of the internalized insulin. These results indicate that chronic ethanol administration impairs both the surface binding and the endocytosis of insulin by the liver.

Alcoholism↗
PubMed1991

Effects of alcohol on hepatic protein metabolism and trafficking.

Ethanol administration disorders protein trafficking in the liver. The protein secretory and plasma membrane assembly pathways have been shown to be impaired in the liver of ethanol-treated animals; however, traffic along the receptor-mediated endocytosis (RME) pathway appears to be especially susceptible to alterations by ethanol. Using asialoglycoproteins as model ligands for studying RME, we have identified at least three steps of this multi-step pathway that are affected by ethanol treatment. These altered steps are recycling of the receptor, internalization of the receptor-ligand complex and dissociation of the ligand from its receptor in endosomes. Ethanol-induced derangements of RME are more severe in the perivenule region, where alcoholic liver injury starts and predominates, than in the periportal region of the liver. Recent studies have shown that the endocytosis of other ligands, including epidermal growth factor and insulin, is also altered by ethanol treatment. Mechanisms which have been proposed to explain faulty RME include: acetaldehyde adducts to tubulin resulting in impaired microtubule function, improper acidification of endosomes and defective receptor clustering in coated pits. Since RME represents an important process by which levels of various hormones, growth factors and other ligands are regulated, and since RME may also be an integral process by which the biological effects of various ligands are elicited, changes in this important process could disrupt numerous metabolic and homeostatic events in the liver.

Alcoholism↗
PubMed1991

Zonal differences in ethanol-induced impairments in receptor-mediated endocytosis of asialoglycoproteins in isolated rat hepatocytes.

We have shown previously that ethanol-induced defects in receptor-mediated endocytosis of asialoorosomucoid occurred as early as 1 wk after ethanol feeding. This study was undertaken as an initial attempt to establish a possible role of defective receptor-mediated endocytosis in liver injury by investigating whether differences exist in the effects of ethanol on receptor-mediated endocytosis in hepatocytes isolated from different regions of the liver. Perivenule cells, present in the distal half of the liver, are thought to be more susceptible to ethanol-induced liver injury than are the periportal cells located in the proximal half of the liver acini. For these studies, we fed male Sprague-Dawley rats for 7 days with liquid diets containing either ethanol (36% of calories) or isocaloric carbohydrate. Perivenule and periportal hepatocytes were then isolated using a digitonin-collagenase perfusion method. In control animals, cells isolated from the perivenule region bound significantly more ligand than did cells from the periportal region. Amounts of ligand internalized and degraded were also greater in perivenule than in periportal cells in these animals. After ethanol feeding, cells isolated from both the perivenule and periportal regions bound significantly less ligand than their respective controls. This impairment in surface and total binding was more pronounced in perivenule than in periportal cells. Internalization and degradation of the ligand were also more adversely affected in the centrilobular region as shown by decreases of greater than 60% in perivenule cells and by only 20% to 30% in periportal cells of ethanol-fed animals compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Effect of chronic ethanol administration on the uptake and degradation of asialoglycoproteins by the perfused rat liver.

We have shown previously reduced binding, internalization, degradation and receptor-ligand dissociation during receptor-mediated endocytosis (RME) of 125I-asialoorosomucoid (ASOR) by hepatocytes isolated from rats fed ethanol for 4-6 weeks. In the present study, we investigated the effect of ethanol feeding on RME by using the intact perfused liver as a model. Male, Sprague-Dawley rats were fed a liquid diet containing either ethanol (36% of calories) or isocaloric carbohydrate. Receptor-mediated endocytosis of 125I-ASOR was then examined over a time course of perfusion. In all cases, clearance of the labeled glycoprotein was followed by a slower but steady appearance of acid-soluble products in the medium. Ethanol-fed animals had a significantly (P less than 0.01) slower rate of clearance of the labeled ligand from the circulating perfusate than did control animals. Impairment of ASOR surface binding and degradation in ethanol-fed animals was also demonstrated in this model. When we examined the subcellular distribution of labeled ligand after various times of perfusion, we found that in control livers, a shift of radiolabeled ligand from the subcellular fractions containing endosomes and plasma membranes to fractions containing lysosomes occurred, while significantly less ligand was shifted to the lysosomes of ethanol-treated rats. These results show that ethanol administration inhibits RME of ASOR in the isolated perfused liver model, thus confirming our earlier reported defects in isolated hepatocytes. In addition, transport of ligand along the intracellular RME pathway was also shown to be altered by ethanol treatment as indicated by the impaired movement of ASOR from the endosomal to the lysosomal compartment.

Administration, Oral↗
PubMed1990

Effect of chronic ethanol administration on total asialoglycoprotein receptor content and intracellular processing of asialoorosomucoid in isolated rat hepatocytes.

Chronic ethanol administration markedly impairs the process of receptor-mediated endocytosis (RME) of a representative asialoglycoprotein, asialoorosomucoid (ASOR), by the liver (Casey et al. (1987) J. Biol. Chem. 262, 2704-2710). Decreased surface binding was the major defect reported in our initial study, along with impaired internalization and degradation of 125I-ASOR in chronically-fed ethanol animals. In this study, we further characterized these impairments by examining the content of intracellular receptors and by investigating ligand processing directed by these intracellular receptors. Ethanol administration for 5-7 weeks decreased intracellular ASOR receptor content by 40%, a result which was confirmed by using both a ligand-binding assay and an antibody-binding assay. In addition to a decreased number of intracellular receptors, an impairment in intracellular processing of receptor-ligand complexes was identified. In ethanol-fed animals, dissociation of receptor-ligand complexes was decreased during steady-state conditions of endocytosis at 37 degrees C. Impaired receptor-ligand dissociation did not alter the fate of the ligand which was to undergo diacytosis (ligand recycling), but did appear to impair degradation of intracellular ligand. These results indicate that chronic ethanol administration decreases ligand binding due to a decreased number of receptors and impairs intracellular processing of ASOR in hepatocytes.

Alcoholism↗
PubMed1990

Chronic ethanol administration impairs receptor-mediated endocytosis of epidermal growth factor by rat hepatocytes.

The effects of chronic ethanol administration on the receptor-mediated endocytosis of epidermal growth factor were studied in isolated rat hepatocytes. In initial experiments, it was demonstrated that significantly less ligand was bound by hepatocytes isolated from rats fed an ethanol liquid diet for 5 to 7 wk than by cells isolated from chow-fed or pair-fed controls. Reduced binding was shown to be primarily caused by a decreased number of surface receptors rather than by changes in receptor affinity. When hepatocytes were incubated at 37 degrees C in the presence of a large saturating concentration of epidermal growth factor (80 nmol/L), intracellular levels of the ligand were significantly lower in cells from the ethanol-fed animals. However, no effect on degradation of the ligand was observed under those conditions. A defect in the initial stages of receptor-ligand internalization was also indicated because less surface-bound ligand was internalized and subsequently degraded in cells from the ethanol-treated rats. When the endocytosis of a lower, more physiological concentration of the growth factor (0.5 nmol/L) was studied, both the uptake of ligand and its degradation were markedly impaired in hepatocytes from the ethanol-fed animals. These results indicate that chronic ethanol administration impairs the receptor-mediated endocytosis of epidermal growth factor by the liver. The major impairment appears to be a reduction of cell surface receptors; however, other steps of the endocytotic pathway also appear to be affected. These altered steps include defective receptor-ligand internalization and changes in intracellular processing of the ligand leading to decreased degradation.

Animals↗
PubMed1990

Effects of ethanol on hepatic protein trafficking: impairment of receptor-mediated endocytosis.

Ethanol administration disorders protein trafficking in the liver. The protein secretory and plasma membrane assembly pathways have been shown to be impaired in the liver of ethanol-treated animals; however, traffic along the receptor-mediated endocytosis pathway appears to be especially susceptible to alterations by ethanol. Using asialoglycoproteins as model ligands for studying receptor-mediated endocytosis, we have identified at least three steps of this multi-step pathway that are affected by ethanol treatment. These altered steps are recycling of the receptor, internalization of the receptor-ligand complex and dissociation of the ligand from its receptor in endosomes. Ethanol-induced derangements of endocytosis are more severe in the perivenule region, where alcoholic liver injury starts and predominates, than in the periportal region of the liver. In addition, recent studies have shown that the endocytosis of other ligands, including epidermal growth factor and insulin, are also altered by ethanol treatment. Mechanisms which have been proposed to explain faulty endocytosis include: acetaldehyde adducts to tubulin resulting in impaired microtubule function, improper acidification of endosomes and defective receptor clustering in coated pits. Since receptor-mediated endocytosis by the liver represents an important process by which levels of various hormones, growth factors and other ligands are regulated, and since endocytosis may also be an integral process by which the biological effects of various ligands are elicited, changes in this important process could disrupt numerous metabolic and homeostatic events in the liver and total organism.

Alcohol Drinking↗
PubMed1989

Ethanol-induced impairments in receptor-mediated endocytosis of asialoorosomucoid in isolated rat hepatocytes: time course of impairments and recovery after ethanol withdrawal.

Chronic ethanol administration markedly impairs the process of receptor-mediated endocytosis (RME) of a representative asialoglycoprotein, asialoorosomucoid (ASOR), by the liver. In this study, we further characterized these impairments by identifying the time of onset for ethanol-induced changes in RME as well as establishing the time course for recovery to normal endocytotic values after ethanol withdrawal. Ethanol administration for 3 days did not alter any aspect of endocytosis examined in this study. After feeding ethanol to rats for 7 days, however, significant decreases in amounts of ligand bound, internalized, and degraded were apparent. These impairments persisted throughout the 5-week feeding study although the effects were somewhat attenuated with more prolonged ethanol feeding. In addition, an accumulation of intracellular receptors was observed in ethanol-fed animals relative to controls after 7 days of ethanol feeding. In all cases, recovery of endocytotic values to control levels was partially completed after 2 to 3 days of refeeding control diet and was fully completed after 7 days of refeeding. These results indicate that ethanol feeding for as little as 7 days profoundly impairs the process of RME by the liver. These impairments can be reversed after refeeding control diet for 7 days.

Animals↗
PubMed1988

Soft splinting with neoprene: the thumb abduction supinator splint.

Thermoplastics are useful for many types of splints, but most splints made from them position the hand statically and have the disadvantage of limiting the sensory feedback that occurs during normal use and movement. Neoprene is an alternative to thermoplastics when dynamic mobility in splinting is the goal. Neoprene is soft, stretchable, lightweight, durable, nontoxic, machine-washable, and has a good memory. The TASS uses the Bobaths' key point of forearm supination and thumb abduction to position the upper extremity more functionally without the patient having to use effort. Thus sensory feedback can occur while the limb is moving within a prescribed range. The TASS can be used as an extra "hand" during the occupational therapy treatment session, or it can be applied immediately after treatment to continue to facilitate functional positioning of the limb.

Child↗
PubMed1987

Chronic ethanol administration impairs the binding and endocytosis of asialo-orosomucoid in isolated hepatocytes.

We have examined the effect of ethanol administration on receptor-mediated endocytosis of asialo-orosomucoid by isolated hepatocytes. Significantly less ligand was bound, internalized, and degraded by hepatocytes isolated from rats fed an ethanol diet for 5-7 weeks than by cells isolated from chow-fed or pair-fed controls. Reduced binding was shown to be primarily due to a decreased number of cell surface receptors rather than to a lowered affinity of the receptor for its ligand. This reduction in cell surface receptors resulted in a marked inhibition of internalization and degradation of ligand by hepatocytes from the ethanol-fed rats. In addition, a defect in the initial stages of receptor-ligand internalization was also indicated, since less surface-bound ligand was internalized and subsequently degraded in cells from the ethanol-treated animals as compared to controls. Rates of internalization and degradation of internalized ligand were, however, similar for all three groups, suggesting that neither degradation per se nor rate of delivery of internalized ligand to the lysosomes was affected by ethanol feeding. Receptor recycling was impaired in ethanol-fed rats, as indicated by a decrease in the binding site number after stimulation of endocytosis for 120 min when compared to initial binding capacity. Receptor recycling was not impaired in hepatocytes from control animals. These results indicate that chronic ethanol feeding impairs the process of receptor-mediated endocytosis by the liver; the major cause of this impairment appears to be due to a decreased number of cell surface asialoglycoprotein receptors in the ethanol-fed animals, along with a decreased ability of these cells to internalize all of the surface-bound ligand.

Animals↗
PubMed1987

Chronic ethanol administration alters hepatic surface membranes as evidenced by decreased concanavalin A binding.

The effects of chronic ethanol administration on the hepatic surface membrane were examined. The binding of the lectin, concanavalin A (Con A), to isolated hepatocytes was used to ascertain changes in the hepatic plasma membrane, especially in regard to glycoprotein composition, due to chronic ethanol feeding. Hepatocytes, isolated from rats fed ethanol for 5 to 7 weeks, had a decreased ability to bind Con A when compared to hepatocytes from either the pair-fed controls or ad libitum chow-fed rats. Since decreased Con A binding was more apparent at high Con A concentrations, reduced lectin binding likely reflected changes in the composition of surface membrane glycoproteins in the livers of the ethanol-fed rats. When ethanol (50 mM) was added to the incubation medium containing hepatocytes from ethanol-fed rats, pair-fed controls, or chow-fed rats, no effects on Con A binding were observed. These results indicate that chronic ethanol administration induces changes in the oligosaccharide chains of plasma membrane glycoproteins in the liver. Such alterations may play a role in the pathogenesis of alcoholic liver disease.

Alcoholism↗
PubMed1986

Ethanol-induced alterations of plasma membrane assembly in the liver.

The effects of acute ethanol administration on the assembly of glycoproteins into the hepatic plasma membrane were studied in the rat. When [14C]fucose and N-acetyl[3H]mannosamine, a sialic acid precursor, were injected following an acute dose of ethanol, the incorporation of these precursors into the total pool of membrane glycoproteins was minimally affected. This finding indicated that ethanol treatment did not appreciably alter the glycosylation of proteins in the Golgi apparatus. However, the assembly of labeled fucoproteins and sialoproteins into the plasma membrane was markedly inhibited in the ethanol-treated animals. This inhibition of plasmalemmal glycoprotein assembly was accompanied by a corresponding accumulation of labeled glycoproteins in the cytosolic fraction of the hepatocyte. The content of labeled glycoproteins in the Golgi complex was not significantly altered by ethanol treatment. These results indicate that ethanol administration impairs the late stages of hepatic plasma membrane assembly and further suggest that ethanol administration interferes with the flow of membrane components from the Golgi apparatus to the surface membrane.

Animals↗