Biomedical subjects

Michael Trauner

Publications and source records attributed to Michael Trauner.

46 records · Page 3Linked to original sources

PubMed2003

Successful conservative management of acute hepatic failure following exertional heatstroke.

Acute hepatic failure is a rare complication of exertional heatstroke with poor prognosis. We herein report a 24-year-old man presenting with acute hepatic failure and rhabdomyolysis following exertional heatstroke during hard physical work on a construction site. Acute hepatic failure occurred after 2 days and led to massive impairment of coagulation parameters. On day 3 after heatstroke the patient fulfilled standard criteria for emergency liver transplantation (i.e. the 'London criteria' and the 'Clichy criteria') but was not transplanted. Nevertheless liver function improved spontaneously thereafter and the patient recovered completely within 12 days. In contrast, the outcome of emergency liver transplantation was dismal in three cases of exertional heatstroke in the literature. Thus conservative management appears to be justified in heatstroke-associated liver failure even in the presence of accepted criteria for emergency liver transplantation.

Adult↗

PubMed2003

Bile salt transporters: molecular characterization, function, and regulation.

Molecular medicine has led to rapid advances in the characterization of hepatobiliary transport systems that determine the uptake and excretion of bile salts and other biliary constituents in the liver and extrahepatic tissues. The bile salt pool undergoes an enterohepatic circulation that is regulated by distinct bile salt transport proteins, including the canalicular bile salt export pump BSEP (ABCB11), the ileal Na(+)-dependent bile salt transporter ISBT (SLC10A2), and the hepatic sinusoidal Na(+)- taurocholate cotransporting polypeptide NTCP (SLC10A1). Other bile salt transporters include the organic anion transporting polypeptides OATPs (SLC21A) and the multidrug resistance-associated proteins 2 and 3 MRP2,3 (ABCC2,3). Bile salt transporters are also present in cholangiocytes, the renal proximal tubule, and the placenta. Expression of these transport proteins is regulated by both transcriptional and posttranscriptional events, with the former involving nuclear hormone receptors where bile salts function as specific ligands. During bile secretory failure (cholestasis), bile salt transport proteins undergo adaptive responses that serve to protect the liver from bile salt retention and which facilitate extrahepatic routes of bile salt excretion. This review is a comprehensive summary of current knowledge of the molecular characterization, function, and regulation of bile salt transporters in normal physiology and in cholestatic liver disease and liver regeneration.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Bile acid-induced Mallory body formation in drug-primed mouse liver.

Chronic cholestasis is associated with retention of bile acids and profound cytoskeletal alterations in hepatocytes including Mallory body (MB) formation. The mechanisms responsible for MB formation in cholestatic liver diseases are unclear. The aim of our study was to determine the relevance of cholestasis and bile acids for MB formation. For this purpose mice received a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-supplemented diet for 2.5 months to induce MB formation. After recovery from DDC intoxication for 4 weeks followed by disappearance of MBs, these drug-primed mice were subjected to DDC refeeding, common bile duct ligation (CBDL), and feeding of a cholic acid (CA)-supplemented diet for 7 days, respectively. Cytokeratin (CK) 8 and CK 18 expression was studied by competitive reverse transcriptase-polymerase chain reaction and Western blot analysis. Cytoskeletal alterations of hepatocytes and MB formation were monitored by immunofluorescence microscopy and immunohistochemistry using CK-, ubiquitin-, and MB-specific antibodies. Like DDC refeeding, both CBDL and CA feeding of drug-primed mice significantly increased CK 8 and CK 18 mRNA and protein levels (with excess of CK 8) and resulted in ubiquitination and abnormal phosphorylation of CKs. Furthermore, CBDL and CA feeding resulted in rapid neoformation of MBs in drug-primed mice. It is concluded that MB formation in cholestatic liver diseases may be triggered by the action of potentially toxic bile acids.

Animals↗

PubMed2002

Cytokeratins as targets for bile acid-induced toxicity.

Cholestasis is associated with retention of potentially toxic bile acids and profound cytoskeletal alterations of hepatocytes. Given the well-established cytoprotective role of hepatocyte keratins this study aimed to determine the effects of cholestasis on the cytokeratin (CK) intermediate filament network in mouse liver. Mice were subjected to common bile duct ligation or sham operation. Mice were also fed a cholic acid or ursodeoxycholic acid (UDCA)-supplemented diet (0.1%, 0.5%, and 1%) or control diet for 7 days. CK 8 and CK 18 expression was studied by competitive reverse transcriptase-polymerase chain reaction, in situ hybridization, Western blot analysis, and immunofluorescence microscopy. Common bile duct ligation and cholic acid feeding significantly stimulated CK 8 and CK 18 mRNA and protein levels compared to controls, whereas UDCA had no effect. CK overexpression was accompanied by pronounced phosphorylation. Our results show that potentially toxic bile acids induce hepatocytic CK 8 and CK 18 expression and phosphorylation whereas nontoxic UDCA has no effect on CKs. Thus, increased hepatocellular CK expression and phosphorylation in cholestasis may be caused by retention of toxic bile acids and reflect a hepatocellular stress response with potential beneficial effects.

Animals↗

PubMed2002

Hepatic transport systems.

The identification of the genes responsible for various genetic liver disorders lead to a better understanding of basic physiology of hepatic transport systems. In this review we focus on transport systems involved in the generation of bile and in the maintenance of copper homeostasis. Abnormal function of these transporters results in diseases like Wilson's disease, progressive familial cholestasis syndromes, Dubin-Johnson syndrome and cystic fibrosis. Beyond these well defined diseases, functional impairments of transport proteins may predispose to non-genetic diseases ranging from intrahepatic cholestasis of pregnancy to neurodegenerative disorders including Alzheimer's disease.

Adenosine Triphosphatases↗

PubMed2002

Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles.

BACKGROUND & AIMS: The effects of ursodeoxycholic acid (UDCA) in biliary obstruction are unclear. We aimed to determine the effects of UDCA in bile duct-ligated and in Mdr2 knockout (Mdr2(-/-)) mice with biliary strictures. METHODS: Mice fed UDCA (0.5% wt/wt) or a control diet were subjected to common bile duct ligation (CBDL), selective bile duct ligation (SBDL), or sham operation. UDCA was also fed to 2-month-old Mdr2(-/-) mice. Serum biochemistry, liver histology, and mortality rates were investigated. The biliary tract was studied by plastination, India ink injection, and electron microscopy. The effects of UDCA on biliary pressure were determined by cholangiomanometry. RESULTS: UDCA feeding in CBDL mice increased biliary pressure, with subsequent rupture of cholangioles and aggravation of hepatocyte necroses, resulting in significantly increased mortality. UDCA feeding in SBDL mice aggravated liver injury exclusively in the ligated lobe. Mdr2(-/-) mice developed liver lesions resembling sclerosing cholangitis characterized by biliary strictures and dilatations. UDCA induced bile infarcts in these animals. CONCLUSIONS: UDCA aggravates bile infarcts and hepatocyte necroses in mice with biliary obstruction via disruption of cholangioles as a result of increased biliary pressure caused by its choleretic action.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2002

Cholestatic syndromes.

Further insights into the molecular regulation of bile acid transport and metabolism have provided the basis for a better understanding of the pathogenesis of cholestatic liver diseases. Novel insights into the mechanisms of action of ursodeoxycholic acid should advance our understanding of the treatment of cholestatic liver diseases. Mutations of transporter genes can cause hereditary cholestatic syndromes in both infants and adults as well as cholesterol gallstone disease. Important studies have been published on the pathogenesis, clinical features, and treatment of primary biliary cirrhosis, drug-induced cholestasis, and cholestasis of pregnancy.

Journal Article↗

PubMed2002

Induction of short heterodimer partner 1 precedes downregulation of Ntcp in bile duct-ligated mice.

Cholestasis is associated with retention of bile acids and reduced expression of the Na(+)/taurocholate cotransporter (Ntcp), the major hepatocellular bile acid uptake system. This study aimed to determine whether downregulation of Ntcp in obstructive cholestasis 1) is a consequence of bile acid retention and 2) is mediated by induction of the transcriptional repressor short heterodimer partner 1 (SHP-1). To study the time course for the changes in serum bile acid levels as well as SHP-1 and Ntcp steady-state mRNA levels, mice were subjected to common bile duct ligation (CBDL) for 3, 6, 12, 24, 72, and 168 h and compared with sham-operated controls. Serum bile acid levels were determined by radioimmunoassay. SHP-1 and Ntcp steady-state mRNA expression were assessed by Northern blotting. In addition, Ntcp protein expression was studied by Western blotting and immunofluorescence microscopy. Increased SHP-1 mRNA expression paralleled elevations of serum bile acid levels and was followed by downregulation of Ntcp mRNA and protein expression in CBDL mice. Maximal SHP-1 mRNA expression reached a plateau phase after 6-h CBDL (12-fold; P < 0.001) and preceded the nadir of Ntcp mRNA levels (12%, P < 0.001) by 6 h. In conclusion, bile acid-induced expression of SHP-1 may, at least in part, mediate downregulation of Ntcp in CBDL mice. These findings support the concept that downregulation of Ntcp in cholestasis limits intracytoplasmatic accumulation of potentially toxic bile acids.

Animals↗

PubMedDate not supplied

Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations.

Cholestasis results in intrahepatic accumulation of cytotoxic bile acids which cause liver injury ultimately leading to biliary fibrosis and cirrhosis. Cholestatic liver damage is counteracted by a variety of intrinsic hepatoprotective mechanisms. Such defense mechanisms include repression of hepatic bile acid uptake and de novo bile acid synthesis. Furthermore, phase I and II bile acid detoxification is induced rendering bile acids more hydrophilic. In addition to "orthograde" export via canalicular export systems, these compounds are also excreted via basolateral "alternative" export systems into the systemic circulation followed by renal elimination. Passive glomerular filtration of hydrophilic bile acids, active renal tubular secretion, and repression of tubular bile acid reabsorption facilitate renal bile acid elimination during cholestasis. The underlying molecular mechanisms are mediated mainly at a transcriptional level via a complex network involving nuclear receptors and other transcription factors. So far, the farnesoid X receptor FXR, pregnane X receptor PXR, and vitamin D receptor VDR have been identified as nuclear receptors for bile acids. However, the intrinsic adaptive response to bile acids cannot fully prevent liver injury in cholestasis. Therefore, additional therapeutic strategies such as targeted activation of nuclear receptors are needed to enhance the hepatic defense against toxic bile acids.

Adaptation, Biological↗

PubMedDate not supplied

Transcriptional regulation of hepatobiliary transport systems in health and disease: implications for a rationale approach to the treatment of intrahepatic cholestasis.

Hepatobiliary transport systems mediate hepatic uptake and biliary excretion of bile acids, bilirubin and other biliary constituents. Hereditary or acquired defects of these transporters may cause or maintain cholestasis and jaundice under various clinical conditions including progressive familial intrahepatic cholestasis (PFIC) 1-3 or its milder forms, benign recurrent intrahepatic cholestasis (BRIC) 1 and 2 , Dubin-Johnson syndrome, drug and inflammation-induced cholestasis and intrahepatic cholestasis of pregnancy. Moreover, induction of alternative efflux pumps for bile acids/bilirubin and phase I/II detoxifying enzymes may counteract hepatic accumulation of potentially toxic biliary constituents in cholestasis by providing alternative escape routes. Transcriptional and post-transcriptional regulation of hepatobiliary transporters in health and disease is mediated by multiple factors such as bile acids, proinflammatory cytokines, drugs and hormones. Ligand-activated nuclear receptors (NR) and hepatocyte-enriched transcription factors play a critical role in transcriptional transporter regulation. Many hepatobiliary transporter alterations in cholestatic liver disease can now be explained by ligand binding of accumulating cholephiles to NRs. Moreover, NR-mediated actions may be targeted by pharmacological ligands. Understanding the transcriptional mechanisms leading to transporter changes therefore not only represents a key for understanding the pathophysiology of the cholestatic liver disease, but also represents a prerequisite for designing novel therapeutic strategies.

Animals↗