Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis

Autor: Anja Beilfuss, Lars P. Bechmann, Jan-Peter Sowa, Alpaslan Kilicarslan, Frieder Berr, Andreas Geier, Guido Gerken, Christian Rust, Rebekka A. Hannivoort, Johannes Schmitt, Ali Canbay, Martin Schlattjan, Peri Kocabayoglu, Scott L. Friedman, Oliver Tschopp, Svenja Sydor, Jan Best
Přispěvatelé: Liver Cell Biology, University of Zurich, Canbay, Ali
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Male
Medizin
10265 Clinic for Endocrinology and Diabetology
Receptors
Cytoplasmic and Nuclear
Fatty Acids
Nonesterified
Severity of Illness Index
DISEASE
Liver disease
0302 clinical medicine
HEPATOCYTE APOPTOSIS
HEPATOCELLULAR-CARCINOMA
Nonalcoholic fatty liver disease
Cholesterol 7-alpha-Hydroxylase
0303 health sciences
INSULIN-RESISTANCE
Symporters
Research Support
Non-U.S. Gov't
Fatty liver
FATTY LIVER
Middle Aged
3. Good health
Obesity
Morbid
SALT TRANSPORTERS
comorbidity
OBESITY
Small heterodimer partner
Disease Progression
030211 gastroenterology & hepatology
Female
hormones
hormone substitutes
and hormone antagonists
Adult
medicine.medical_specialty
CHOLESTASIS
Organic Anion Transporters
Sodium-Dependent
610 Medicine & health
Biology
Cholesterol 7 alpha-hydroxylase
liver
digestive system
MECHANISMS
Bile Acids and Salts
03 medical and health sciences
Internal medicine
medicine
Journal Article
Humans
Comparative Study
fas Receptor
030304 developmental biology
Hepatology
Adiponectin
adiponectin
nutritional and metabolic diseases
non-alcoholic fatty liver disease
medicine.disease
digestive system diseases
MICE
Endocrinology
Farnesoid X receptor
2721 Hepatology
Steatohepatitis
NUCLEAR RECEPTORS
Zdroj: Hepatology (Baltimore Md.)
Hepatology, 57(4), 1394-1406. Wiley
ISSN: 0270-9139
Popis: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and may proceed to steatohepatitis (NASH). Apoptosis and free fatty acid (FFA)-induced lipotoxicity are important features of NASH pathogenesis. We have shown a hepatoprotective effect of adiponectin in steatotic livers of hepatitis C virus (HCV) patients and recent data links bile acid (BA) metabolism to the pathogenesis of NAFLD. The aim of this study was to identify potential interactions between BA and FFA metabolism in NAFLD. Liver biopsies and serum samples from 113 morbidly obese patients receiving bariatric surgery, healthy individuals, and moderately obese NAFLD patients were studied. Serum FFA, BA, and M30 were increased in NASH versus simple steatosis, while adiponectin was significantly decreased. The NAFLD activity score (NAS) score correlated with BA levels and reversely with adiponectin. Adiponectin reversely correlated with CD95/Fas messenger RNA (mRNA) and hepatocellular apoptosis. The BA transporter high-affinity Na+/taurocholate cotransporter (NTCP) and the BA synthesizing enzyme cholesterol 7 alpha-hydroxylase (CYP7A1) were significantly up-regulated in obese patients and hepatoma cells exposed to FFA. Up-regulation of NTCP and CYP7A1 indicate failure to activate small heterodimer partner (SHP) upon farnesoid X receptor (FXR) stimulation by increasing BA concentrations. In line with the NAS score, adiponectin levels were reversely correlated with BA levels. Adiponectin correlated with NTCP and affects Cyp7A1 expression both in vivo and in vitro. Conclusion: BA synthesis and serum BA levels correlated with disease severity in NAFLD, while adiponectin is reversely correlated. FFA exposure prevented SHP-mediated repression of NTCP and Cyp7A1 expression, which lead to increased BA synthesis and uptake. In NASH, BA accumulation induced hepatocyte cell death and late FXR activation failed to prevent hepatocyte injury due to decreased adiponectin levels. Early treatment with FXR ligands and/or adiponectin-receptor agonists might prevent NASH. (HEPATOLOGY 2013;57:13941406)
Databáze: OpenAIRE
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