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Selected Publication:
Fuchs, C.
Lipases and bile acids are novel key players in the pathogenesis of hepatic lipotoxicity
[ Dissertation ] Medical University of Graz; 2012. pp. 121
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- Authors Med Uni Graz:
- Fuchs Claudia
- Advisor:
- Höfler Gerald
- Moustafa Tarek
- Trauner Michael
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- Abstract:
- The pathogenic hallmark of non-alcoholic fatty liver disease (NAFLD) is the accumulation of lipids in the liver, also known as steatosis. Relatively 'benign' steatosis can progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and liver cancer. In contrast to adipose tissue, non-adipose cells such as hepatocytes have a limited capacity to store lipids in excess. When this capacity is exceeded, the resultant cellular dysfunction is called lipotoxicity. Lipases and bile acids are known to be important metabolic regulators of the hepatic lipid metabolism. Therefore, this study was designed to identify the role of lipases, and bile acids in the pathogenesis of hepatic lipotoxicity and progression to NASH. Part 1 aimed to identify the role of ATGL in hepatic lipotoxicity. Several studies have demonstrated that endoplasmic reticulum (ER) stress is induced via free saturated fatty acids and is observed in different animal models for steatosis and in NAFLD patients. Therefore, ER stress may appear as an important event in lipotoxicity. Since adipose triglyceride lipase (ATGL) is the main lipase in triglyceride (TG) breakdown, we hypothesized that lack of ATGL and subsequent reduction of free fatty acid availability may attenuate hepatic ER stress. As experimental model, WT and total body ATGL KO mouse were injected with Tunicamycin (TM) (a known ER stress inducer) for 48h hours. Indeed, ATGL KO TM injected mice were protected from hepatic ER stress. This protection was based on the differences in hepatic fatty acid composition between WT and ATGL KO mice. At baseline, WT mice consisted of more (potential toxic) Palmitic acid (PA) than non-toxic Oleic acid (OA), whereas ATGL KO mouse displayed the same levels of PA and OA. Moreover, mRNA expression of stearoyl-coenzym A desaturase (Scd1) ¿ the enzyme responsible for PA modification into OA ¿ was markedly decreased under TM challenging. Previous studies showed that in a ratio of at least 1:1, OA is able to protect from PA induced toxicity. Due to the basal higher amounts of hepatic PA compared to OA and the decrease in Scd1 mRNA expression, WT TM challenged mice were not protected from hepatic ER stress induction, in contrast to ATGL KO TM mouse. Part 2 describes the role of the nuclear receptor FXR in hepatic lipotoxicity. It has been shown previously that FXR is involved in hepatic lipid metabolism. To test the hypothesis that FXR play a key role in progression to NASH, WT and FXR KO mice were challenged with a methionine choline deficient (MCD) diet ¿ as a model for NASH ¿ for 5 weeks. Interestingly, we found a more pronounced lipid accumulation in WT mice upon MCD compared to challenged FXR KO mice. We could establish that under MCD challenge ¿ which leads to low serum glucose and high bile acid levels ¿ FXR negatively regulates C/ebp¿- a key player in hepatic lipid metabolism ¿ in a Chop dependent manner. The decrease in c/ebp¿ mRNA expression led to impaired very low densitiy lipoprotein (VLDL) secretion in WT MCD challenged mice, therefore explaining the increased hepatic lipid accumulation. Part 3 focuses on the role of bile salt export pump (BSEP) in the development of hepatic lipotoxicity. Bile acids are the end product of cholesterol catabolism and thus bile secretion represents the ultimate step in reverse cholesterol transport. BSEP is the main canalicular bile acid transporter, excreting bile acids into the bile. Hence we hypothesized that lack of BSEP could protect from NAFLD and progression to NASH. We were able to show that alterated expression of hepatic bile acid transporters together with modifications in bile acid composition, protected MCD fed BSEP KO mice a from hepatic inflammation and lipotoxicity. In summary, the metabolic keyplayers ATGL, FXR and BSEP are potentialpharmacological targets in the defense against the progression of NAFLD and lipotoxicity.