Medizinische Universität Graz - Research portal
Selected Publication:
Mueller, M.
Role of Bile Acid Signalling in
Non-alcoholic Fatty Liver Disease and Progression to
Non-alcoholic Steatohepatitis in Morbid Obesity
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2015. pp.
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- Authors Med Uni Graz:
- Müller Michaela
- Advisor:
- Höfler Gerald
- Trauner Michael
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- Abstract:
- Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. NAFLD represents a spectrum of disease ranging from simple steatosis, non-alcoholic steatohepatitis (NASH), fibrosis to cirrhosis or even hepatocellular carcinoma (HCC). Obesity and insulin resistance (IR), by mediating an elevated fatty acid (FA) flux from white adipose tissue (WAT) to the liver, play a central role in disease development and progression. Bile acids (BAs) are potent signalling molecules implicated in the regulation of multiple metabolic processes. Via the activation of the nuclear BA receptor farnesoid X receptor (FXR), BAs regulate a host of metabolic processes including lipid biosynthesis. Furthermore, Ursodeoxycholic acid (UDCA), a hydrophilic secondary BA with cytoprotective properties, improves IR and steatosis in mouse models. However, its efficacy in human NAFLD is under debate. Therefore, we endeavoured to uncover the mechanisms and efficacy of UDCA in treating morbid obesity in a randomized clinical study. In this study, serum and biopsies from liver and visceral WAT (vWAT) were obtained from NAFLD patients after three weeks of UDCA treatment. Patient groups were without significant differences in gender, age or body mass index. Histological investigations revealed a higher steatosis score and NAFLD activity score in UDCA treated patients. Liver injury was improved upon UDCA reflected by decreased concentrations of serum liver enzymes such as aspartate aminotransferase and gamma-glutamyl transferase. Further, UDCA, by decreasing FXR activity, increasd BA generation, thereby depleted liver cholesterol and subsequently induced cholesterol de novo biosynthesis and uptake from the periphery via LDLR. Deficient FXR activation increased the expression of stearoyl-CoA-desatruase (SCD), the enzyme catalysing the synthesis of mono-unsaturated fatty acids such as oleic acid. Induced SCD expression mediated the elevated formation and accumulation of hepatic triglycerides. Lipid-profiling of vWAT indicated an increase in the concentration of oleic acid, the preferential substrate for the incorporation into triglycerides. In addition free fatty acid species were decreased upon UDCA suggesting an elevated incorporation of free fatty acids into triglycerides. In general, induced SCD activity in liver and vWAT could depict a mechanism to prevent the accumulation of potentially toxic FA species.