Products Cited in Publications Worldwide Identification of a novel mechanism driving NAFLD progression and therapeutic strategies

Identification of a novel mechanism driving NAFLD progression and therapeutic strategies

Myllys, Maiju

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries with an increasing prevalence of approximately 25%. NAFLD comprises several stages, starting as benign steatosis and progressing to non-alcoholic steatohepatitis (NASH), and in some cases to liver cirrhosis and hepatocellular carcinoma (HCC). Although several emerging therapies are currently in clinical trials, so far there are no approved drugs for treatment of NASH. This is mainly because the driving mechanisms behind NAFLD progression are rather poorly understood. Consequently, NAFLD represents the second most common cause for liver transplantation. The overarching goal of this thesis was to investigate the mechanisms of NAFLD stage transitions, and to establish preventive measures for the progression from benign steatosis to NASH. For this purpose, a mouse model of NAFLD progression was first established by long-term feeding of male C57Bl/6N mice with western-style diet (WD) up to 54 weeks. The disease progression was evaluated time-dependently by biochemical, histopathological, and immunohistochemical analyses as well as by intravital two-photon-based imaging. This comprehensive analyses revealed six stages in NAFLD progression:(1) benign steatosis,(2) macrophage crown-like structure formation,(3) macropinocytosis of bile,(4) ductular reaction,(5) dedifferentiation and functional shutdown, and (6) tumor nodule formation. Particularly, the novel finding of this thesis was the identification of stage 3, macropinocytosis of bile, where a retrograde vesicular uptake of bile from bile canaliculi to hepatocytes led to toxic accumulation of bile acids in the liver tissue, providing a link between NAFLD and cholestasis. The phenomenon was further identified as macropinocytosis by treating the mice with a macropinocytosis-specific inhibitor imipramine. As a result, a single application of imipramine efficiently blocked macropinocytosis in WD-fed mice. Interestingly, a long-term application of imipramine for 8 weeks decreased the bile acid concentrations in the liver tissue and led to significant NAFLD amelioration. To study whether these findings are also relevant for human NAFLD, liver biopsies from patients at different stages of NAFLD were also analysed. Interestingly, bile macropinocytosis was also relevant in the NAFLD patients as detected by the presence of fragments of bile canaliculi within steatotic hepatocytes. In conclusion, an NAFLD mouse model recapitulating the different stages of human NAFLD progression to NASH and eventually to HCC was successfully established. Moreover, a novel mechanism possibly driving NALFD progression was identified as macropinocytosis of bile from bile canaliculi back to hepatocytes. Inhibition of macropinocytosis may represent an attractive therapeutic target to prevent NAFLD progression in human patients.

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