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M Malavolti

Publications and source records attributed to M Malavolti.

At least 19 recordsLinked to original sources
PubMed2000

Effect of ursodeoxycholic acid on hepatic LDL binding and uptake in dietary hypercholesterolemic hamsters.

Administration of ursodeoxycholic acid (UDCA) has been shown to decrease serum total and low density lipoprotein (LDL) cholesterol in hypercholesterolemic patients with primary biliary cirrhosis. Results of previous studies prompted us to postulate that the cholesterol-lowering effect of UDCA may be due, at least in part, to a direct increment in hepatic LDL receptor binding [Bouscarel et al., Biochem J, 1991;280:589; Bouscarel et al., Lipids 1995;30:607]. The aim of the present investigation was to determine the ability of UDCA to enhance hepatocellular LDL receptor recruitment, as determined by its effect in vivo on LDL uptake, and its effect in vitro on LDL binding, under conditions of moderately elevated serum cholesterol. Study groups consisted of male golden Syrian hamsters fed either a standard chow diet (control), a 0.15% cholesterol-containing diet, or a 0.15% cholesterol-containing diet supplemented with either 0.1% UDCA, or 0.1% chenodeoxycholic acid (CDCA). Cholesterol feeding increased (P<0.01) total serum cholesterol by 44%, and was associated with a 10-fold accumulation of cholesteryl esters in the liver (P<0.01). In vivo, hepatic uptake of [U-(14)C]sucrose-labeled hamster LDL was increased (P<0.05) to a level of 454+/-101 microl in animals fed a cholesterol-containing diet supplemented with UDCA, compared to that either without UDCA (337+/-56 microl), or with CDCA (240+/-49 microl). The hepatic uptake of [U-(14)C]sucrose-labeled methylated human LDL, a marker of LDL receptor-independent LDL uptake, was unaffected by bile acid feeding. In vitro, specific binding of [125I]hamster LDL to isolated hepatocytes was determined at 4 degrees C, in presence and absence of 700 micromol/l UDCA. The K(D) ranged from 25 to 31 microg/ml, and was not affected by either cholesterol feeding or UDCA. In the presence of UDCA, the B(max) was increased by 19% (P<0.05) in cells isolated from control animals and by 29% (P<0.01) in cells isolated from hamsters fed a cholesterol-supplemented diet. In conclusion, in dietary hypercholesterolemic hamsters, both chronic in-vivo and acute in-vitro treatments with UDCA resulted in restoration of hepatic LDL binding and uptake to levels observed in control hamsters.

Animals↗
PubMed1999

Effect of dietary oils containing different amounts of precursor and derivative fatty acids on prostaglandin E2 synthesis in liver, kidney and lung of rats.

The availability of the fatty acids which are precursors of prostaglandins is affected by dietary intake. We have studied, in particular, the effects of dietary intake of lipids with different amounts of precursor and derivative fatty acids on the synthesis of prostaglandin E2 (PGE2) in rat liver, kidney and lung. Fifteen-month-old rats were fed for 3 months diets containing different amounts of oleic, linoleic, alpha linolenic, gamma linolenic and stearidonic acids. The fatty acid compositions of total phospholipids and prostaglandin E2 levels of liver, kidney and lung were investigated. In the organs studied, the intake of lipids at different amount of precursor/derivative fatty acids caused variations in the fatty acid composition of phospholipids. PGE2 showed different values which did not seem directly affected by tissue availability of arachidonate but by the effect of dietary lipids on the metabolic pool of polyunsaturated fatty acids (PUFAs).

Animals↗
PubMed1998

Extrahepatic deposition and cytotoxicity of lithocholic acid: studies in two hamster models of hepatic failure and in cultured human fibroblasts.

Effects of bile acids on tissues outside of the enterohepatic circulation may be of major pathophysiological significance under conditions of elevated serum bile acid concentrations, such as in hepatobiliary disease. Two hamster models of hepatic failure, namely functional hepatectomy (HepX), and 2-day bile duct ligation (BDL), as well as cultured human fibroblasts, were used to study the comparative tissue uptake, distribution, and cytotoxicity of lithocholic acid (LCA) in relation to various experimental conditions, such as binding of LCA to low-density lipoprotein (LDL) or albumin as protein carriers. Fifteen minutes after i.v. infusion of [24-(14)C]LCA, the majority of LCA in sham-operated control animals was recovered in liver, bile, and small intestine. After hepatectomy, a significant increase in LCA was found in blood, muscle, heart, brain, adrenals, and thymus. In bile duct-ligated animals, significantly more LCA was associated with blood and skin, and a greater than twofold increase in LCA was observed in the colon. In the hepatectomized model, the administration of LCA bound to LDL resulted in a significantly higher uptake in the kidneys and skin. The comparative time- and concentration-dependent uptake of [14C]LCA, [14C]chenodeoxycholic acid (CDCA), and [14C]cholic acid (CA) in cultured human fibroblasts was nonsaturable and remained a function of concentration. Initial rates of uptake were significantly increased by approximately tenfold, with decreasing hydroxylation of the respective bile acid. After 1 hour of exposure of fibroblasts to LCA, there was a significant, dose-dependent decrease in mitochondrial dehydrogenase activity from 18% to 34% of the control, at LCA concentrations ranging from 1 to 20 micromol/L. At a respective concentration of 100 and 700 micromol/L, CDCA caused a 35% and 99% inhibition of mitochondrial dehydrogenase activity. None of the bile acids tested, with the exception of 700 micromol/L CDCA, caused a significant release of cytosolic lactate dehydrogenase into the medium. In conclusion, we show that bile acids selectively accumulate in nonhepatic tissues under two conditions of impaired liver function. Furthermore, the extrahepatic tissue distribution of bile acids during cholestasis may be affected by serum lipoprotein composition. At a respective concentration of 1 and 100 micromol/L, LCA and CDCA induced mitochondrial damage in human fibroblasts, after just 1 hour of exposure. Therefore, enhanced extrahepatic uptake of hydrophobic bile acids during liver dysfunction, or disorders of lipoprotein metabolism, may have important implications for bile-acid induced cytotoxic effects in tissues of the systemic circulation.

Alanine Transaminase↗
PubMed1997

Serum lipid and lipoprotein patterns in patients with liver cirrhosis and chronic active hepatitis.

BACKGROUND: An impaired lipid metabolism is often found in patients with chronic liver diseases. Unfortunately, few studies are available concerning serum lipid and lipoprotein levels in patients with liver cirrhosis and chronic active hepatitis (CAH). OBJECTIVES: To evaluate low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and total cholesterol serum levels in patients with cirrhosis and CAH and control patients and to relate the findings to the severity of the cirrhosis (Child classification). METHODS: We measured the serum lipid pattern in 34 consecutive patients with liver cirrhosis (15 men and 19 women; mean [+/-SD] age, 55 +/- 14 years; Child classes: 14 in A, 9 in B, 11 in C; patients with biliary cirrhosis were excluded), 34 patients with CAH, and 34 control patients. The 3 groups were matched for sex and age. Total serum, HDL cholesterol, and triglyceride levels were measured by enzymatic methods; serum LDL and VLDL levels were calculated. RESULTS: In patients with cirrhosis, there was a significant decrease in LDL, HDL, and total cholesterol serum levels compared with both the patients with CAH and the control patients, while the VLDL cholesterol level in patients with cirrhosis was significantly lower compared with the control patients alone. A significant decrease in total cholesterol levels was also observed in the CAH group when compared with the control patients. In patients with cirrhosis, levels of LDL, HDL, and total serum cholesterol were progressively lower when comparing patients in Child class A with patients in class C. CONCLUSIONS: In this study, the striking decrease in the level of serum LDL cholesterol in patients with liver disease was related to the increasing severity of the disease. Accordingly, the assessment of the serum LDL cholesterol level is important for an effective treatment and prognostic evaluation of patients with chronic liver disease.

Adult↗
PubMed1996

Flutamide-induced toxic hepatitis. Potential utility of ursodeoxycholic acid administration in toxic hepatitis.

Flutamide is a nonsteroidal antiandrogen commonly used in the treatment of prostate cancer. Hepatic toxicity associated with flutamide has been reported with an incidence from less than 1% to about 5%. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, has been widely used in the treatment of cholesterol gallstones and of several liver diseases, but few data are now available concerning its use in the management of drug-induced hepatitis. The case of a patient who presented severe hepatitis with jaundice following use of flutamide is reported. UDCA treatment was started on admission and, contemporaneously, flutamide was withdrawn. Clinical and biochemical improvement was progressively observed, and the patient was discharged six weeks after the admission. Since fatal flutamide-related hepatitis has been reported, monitoring of serum liver tests is advocated during flutamide administration, and the effectiveness of UDCA in the treatment of drug-induced hepatotoxicity requires further study.

Adenocarcinoma↗
PubMed1993

Formation, absorption, and biotransformation of delta 6-lithocholenic acid in humans.

delta 6-Lithocholenic acid was identified in small amounts in fecal samples in vitro after incubation with ursodeoxycholic acid and in vivo in controls and after chenodeoxycholic and ursodeoxycholic acid ingestion. Fourteen to 45.0% of delta 6-[24-14C]lithocholenic acid was biotransformed in vitro in feces within 30 s. After colonic instillation of delta 6-[24-14C]lithocholenic acid, 50% of the radioactivity appeared in bile acids, most of it in lithocholic acid, within 3 h. Jejunal perfusions with delta 6-[24-14C]lithocholenic acid showed 33-92% absorption. One hour after jejunal instillation of 1 mmol, 4.4-27.5% of the biliary radioactivity was found in ursodeoxycholic, chenodeoxycholic, lithocholic, and 7-ketolithocholic acids. A sulfated glycine conjugate of delta 6-lithocholenic acid was identified in bile. One hour after intravenous injection of delta 6-[24-14C]lithocholenic acid, 40.1-42.6% of biliary radioactivity appeared in 7-ketolithocholic, chenodeoxycholic, lithocholic/isolithocholic, and ursodeoxycholic acids. The studies show that delta 6-lithocholenic acid is 1) formed in colonic lumen from chenodeoxycholic and ursodeoxycholic acids, 2) well absorbed in small intestine, and 3) biotransformed in both the colonic lumen and liver. The studies also identified delta 6-lithocholenic acid as a new intermediate in formation of lithocholic acid. Finally, the studies showed that a small portion of delta 6-lithocholenic acid is excreted as a sulfated glycine conjugate in bile.

Bile↗
PubMed1992

Bile acid dissolution therapy of gallbladder stones.

Oral cholelitholytic bile acid therapy has become established treatment for selected patients with cholesterol gallstones. The treatment finds its clinical application both alone and in combination with ESWL. UDCA alone or, less commonly, a combination of this bile acid with CDCA is used. Optimal results can be expected only in carefully selected patients. Bile acid dissolution therapy is most successful in patients with radiolucent gallstones which are < or = 0.5 cm in diameter or are shown by OCG to be floating. Dissolution is seldom seen when the stones are > 1 cm in size. Cholelitholytic treatment in combination with ESWL yields optimal results in single radiolucent gallstones which are not greater than 2 cm. ESWL thus makes it possible to use medical treatment effectively in single 1-2 cm gallstones when bile acids alone would not be successful. Bile acid treatment is extremely safe, especially if UDCA is given without the addition of CDCA.

Chenodeoxycholic Acid↗
PubMed1991

Cerebral low-density lipoprotein (LDL) uptake is stimulated by acute bile drainage.

Although the cholesterol pool in the central nervous system is considered to be relatively stable, few studies have tested this assumption. The aim of the study was to gain further information on the communication between the extracerebral organs and the brain as far as cholesterol and lipoprotein transport are concerned. Receptor-dependent as well as receptor-independent LDL uptake in the brain were measured, by established methods, after constant 1-h intravenous infusions of [14C]sucrose-labelled hamster LDL and methylated human LDL, both in hamsters with an acute bile fistula and in control animals with an intact enterohepatic circulation. The receptor-dependent LDL uptake in the brain promptly showed a significant increase after the construction of the bile fistula. However, there was no difference in the receptor-independent LDL uptake between the bile fistula and control animals. The studies indicate the presence of close communications between extracerebral and brain cholesterol. Changes in the extracerebral compartments of cholesterol are, apparently, readily sensed by the LDL receptor in the brain and promptly evoke appropriate modifications in its activity.

Animals↗
PubMed1990

Effects of bile acid depletion and of ursodeoxycholic and chenodeoxycholic acids on biliary protein secretion in the hamster.

The effect of changes of both the rate of secretion and the composition of bile acids on biliary proteins was studied in a bile fistula hamster model. Biliary protein secretion as well as bile flow and bile acid secretion were studied in response to intravenous infusions of low, medium and high doses of ursodeoxycholic acid and chenodeoxycholic acid in comparison to the infusion of the normal saline carrier (control) solution. The control-infused animals showed a marked and statistically significant increase in both the concentration and total excretion of biliary proteins. All three doses of ursodeoxycholic acid either prevented the increase of protein concentration or led to its decrease. The low and medium doses of chenodeoxycholic acid had similar effects. However, the high dose of this bile acid was cholestatic and increased the biliary protein concentration. The results of the study indicate that decreases in bile acid secretion, as they occur after an interruption of the enterohepatic circulation, may lead to major increases in biliary protein concentration. The study also shows that these changes in protein secretion, which may promote nucleation, are reversed by the cholelitholytic bile acids, ursodeoxycholic acid and chenodeoxycholic acid.

Animals↗
PubMed1989

Interaction of potentially toxic bile acids with human plasma proteins: binding of lithocholic (3 alpha-hydroxy-5 beta-cholan-24-oic) acid to lipoproteins and albumin.

The binding of lithocholic acid to different plasma fractions was studied. When whole plasma was incubated for 8 hr, approximately 25% of the incubated [14C]lithocholic acid was bound to the lipoprotein and lipoprotein-free, albumin-rich fractions. An average of 87.6% of the bound-lithocholic acid was present in the lipoprotein-free, albumin-rich fraction, 7.2% in high density lipoproteins, 2.2% in low density lipoproteins, 1.0% in intermediate density lipoproteins and 2.0% in very low density lipoproteins. Expressed as binding per microgram protein, considerably less [14C]lithocholic acid was bound to the lipoprotein-free, albumin-rich fraction, than to the lipoproteins. The binding of [14C]lithocholic acid after the incubation of the isolated plasma fractions was similar to that found after the incubation of whole plasma. The highest transfer of [14C]lithocholic acid occurred from the lipoprotein-free, albumin-rich fraction to the lipoprotein fractions. The studies indicate, that, although the largest amount of lithocholic acid is bound to the lipoprotein-free, albumin-rich fraction, per microgram protein, the binding of lithocholic acid to lipoproteins is more pronounced and stable than that bound to the lipoprotein-free, albumin-rich fraction. Since lipoproteins, in contrast to albumin, are internalized by most tissues, they may be important carriers into cells of lithocholic acid and other potentially toxic or tumorigenic bile acids.

Humans↗
PubMed1987

Absence of significant role of bile acids in diarrhea of a heterogeneous group of postcholecystectomy patients.

Twenty-five postcholecystectomy (PC) patients who underwent a diagnostic work-up for persistent diarrhea and six control subjects were studied. Fourteen of the 25 patients were also characterized by conditions other than PC which could play a role in the pathogenesis of the diarrhea. However, none of the patients had evidence of ileal disease or resection. The average follow-up of the patients after the study was approximately 4.4 years. Excretion, composition, and aqueous-phase concentrations of fecal bile acids were analyzed using gas-liquid chromatography. Eleven of the 25 PC patients showed an increased fecal bile acid excretion. In three of the 11 patients, the magnitude of the bile acid loss, which ranged from 2.26 to 3.34 mmol/24 hr, indicated the presence of severe bile acid malabsorption. The fecal bile acid composition showed a significant shift from secondary to primary bile acids. In spite of the presence of marked bile acid malabsorption, the aqueous-phase concentrations of the dihydroxy bile acids, chenodeoxycholic and deoxycholic acids, did not, with one exception, reach the secretory level of 1.5 mM. The relatively low aqueous concentrations were the result of low bile acid solubility, due to an acidic fecal pH. Only two of nine patients, one with severe, and the other with equivocal bile acid malabsorption, who were treated with cholestyramine, showed an improvement of the diarrhea. The findings of subsecretory bile acid concentrations in the fecal aqueous phase and of inconsistent therapeutic responses to cholestyramine indicate that, in spite of the presence of bile acid malabsorption, the diarrhea was, with few exceptions, not bile acid-induced. The results of the study also suggest that the diarrhea in many PC patients is multifactorial in origin.

Adult↗
PubMed1987

Modulation of bile secretion by hepatic low-density lipoprotein uptake and by chenodeoxycholic acid and ursodeoxycholic acid treatment in the hamster.

The effects of both apolipoprotein B,E receptor-dependent and receptor-independent uptake of low-density lipoprotein (LDL) in the liver on bile secretion were studied in bile fistula hamsters. Three groups of animals were studied after 4 wk of feeding either a control, chenodeoxycholic acid-, or ursodeoxycholic acid-containing diet. The hepatic receptor-dependent and receptor-independent uptake of LDL was related to both bile flow and biliary lipid secretion. The correlation with bile flow and biliary lipid secretion was positive for the receptor-dependent, but negative for the receptor-independent uptake of LDL. Although the receptor-mediated LDL uptake appeared to exert a strong influence on bile acid-independent bile flow, the receptor-independent uptake showed a significant relation with biliary bile acid excretion. Differences between the two mechanisms of LDL uptake were also evident in the biliary bile acid-cholesterol coupling, which was significantly stronger during receptor-independent than during receptor-dependent uptake of LDL. The effects of LDL uptake on bile secretion were modulated by the experimentally induced changes in both the content and composition of bile acids in the enterohepatic circulation.

Animals↗
PubMed1987

Modulation of low density lipoprotein receptor activity by bile acids: differential effects of chenodeoxycholic and ursodeoxycholic acids in the hamster.

Hamsters were fed chenodeoxycholic acid (CDC), ursodeoxycholic acid, (UDC), or no bile acid. [14C]Sucrose-labeled hamster low density lipoprotein (LDL) and methylated human LDL were infused intravenously to study LDL receptor-dependent and LDL receptor-independent organ uptake, respectively, of LDL. Biliary CDC increased during both CDC and UDC treatment. The UDC enrichment of bile after UDC feeding was relatively small. Bile acid synthesis was suppressed after both bile acid treatments. Under the condition of an acute bile fistula, the hamster LDL uptake increased in the liver, heart, and adrenals in the CDC-treated animals. During an intact enterohepatic circulation, the hepatic uptake of hamster LDL, which accounted for a major portion of the total uptake, was increased after UDC treatment. The hamster LDL uptake in the colon, which represented only a small fraction of the total uptake, increased after CDC treatment. When hamster LDL was infused at increasing concentrations, its uptake was significantly higher in the UDC-treated than in the control and CDC-treated animals. The methylated human LDL uptake showed no significant changes in the different treatment groups under either experimental condition. The study shows significantly different effects of CDC and UDC on LDL receptor activity. Since these differences are expressed in spite of a similar suppression of bile acid synthesis, UDC may directly influence LDL receptor activity.

Albumins↗
PubMed1986

Gallstone dissolution treatment with a combination of chenodeoxycholic and ursodeoxycholic acids. Studies of safety, efficacy and effects on bile lithogenicity, bile acid pool, and serum lipids.

Sixteen patients with radiolucent gallstones were treated with a combination of chenodeoxycholic and ursodeoxycholic acids for an average of 19 months. Liver tests remained normal in all patients. In nine of 15 patients (60%), in whom the gallbladder visualized during an oral cholecystogram, gallstones dissolved after one year, in eight of them, partially, and in the remaining one, completely. After two years, partial dissolution became complete in three patients, and partial dissolution occurred in 1 additional patient. Changes in lithogenic index and bile acid pool size were statistically not significant. Biliary content of chenodeoxycholic acid increased significantly from 25.7 +/- 3.53 to 45.2 +/- 3.31 (mean +/- SE)% and that of ursodeoxycholic acid from 2.6 +/- 0.52 to 34.6 +/- 2.45%. There were no discernible changes in serum triglycerides, total cholesterol, and HDL cholesterol. The findings suggest that the chenodeoxycholic-ursodeoxycholic acid combination provides a safe and efficacious treatment for some cholesterol gallstones.

Bile↗
PubMed1986

Bile acid-induced diarrhoea.

Three types of bile acid-induced diarrhoea can be distinguished. The best documented and most common entity is represented by type I bile acid malabsorption, which occurs as the result of a pathologically, anatomically defined ileopathy. Type II bile acid malabsorption is found in the setting of a morphologically completely normal ileum. This primary disorder of bile acid transport, which has been described in only a few paediatric and adult patients, appears to be rare. The third variety of bile acid malabsorption is characterized by the history of a previous cholecystectomy and/or by the presence of other gastroenterological conditions. Severe bile acid malabsorption is relatively uncommon in the type III syndrome. Even in the presence of severe bile acid malabsorption, patients with this condition are rarely found to have secretory concentrations of faecal bile acids, and/or rarely respond satisfactorily to cholestyramine. Present data suggest that bile acids play no significant role in the pathogenesis of idiopathic diarrhoea. A careful history, the measurement of stool weight and pH, a therapeutic trial of cholestyramine and the performance of a bile acid test, such as a bile acid breath test, can be used to establish the diagnosis of bile acid diarrhoea. Cholestyramine is the treatment of choice and is virtually always effective in this syndrome.

Bile Acids and Salts↗