Autophagy:Circadian Regulation and Role in Non-Alcoholic Fatty Liver Disease.

Autophagy;Circadian Clock;Nonalcoholic Steatohepatitis;Molecular;Cellular and Developmental Biology;Science;Cell and Developmental Biology

Ma, DiInoki, Ken ;

University of Michigan

关键词: Autophagy;    Circadian Clock;    Nonalcoholic Steatohepatitis;    Molecular;    Cellular and Developmental Biology;    Science;    Cell and Developmental Biology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/98023/dimapku_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Metabolic syndrome has become a global health care challenge characterized by increased risk for type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Recent studies have strongly implicated circadian rhythms as an integral aspect of metabolic homeostasis. Despite this, how the biological clock controls the temporal events of nutrient and energy metabolism remains largely unknown. My dissertation investigates the regulation of circadian autophagy rhythm and defines the role of autophagy in lipid metabolism and the pathogenesis of non-alcoholic steatohepatitis. Earlier electron microscopy analyses suggest that autophagy, a lysosome-dependent degradation process, might be rhythmically activated in mammalian tissues. Using a comprehensive set of molecular markers and assays, we show that autophagy exhibits a robust circadian rhythm in mouse liver with peak in light phase and trough in dark phase. This circadian autophagy rhythm is accompanied by cyclic induction of the autophagy gene program. Functional analyses of transcription factors and cofactors identified C/EBPb as a potent activator of autophagy in hepatocytes. C/EBPb is rhythmically expressed in the liver and is regulated by both circadian and nutritional signals. Adenoviral-mediated RNAi knockdown of C/EBPb in vivo abolishes diurnal autophagy rhythm in the liver. Furthermore, circadian regulation of C/EBPb and autophagy is disrupted in mice lacking a functional liver clock. These studies identified C/EBPb as a key factor that links autophagy to the biological clock and maintains nutrient homeostasis throughout light/dark cycles.Autophagy has been proposed to play a potentially important role in mobilizing triglycerides stored in lipid droplets. I focused the second part of my studies on defining the role of autophagy in hepatic lipid metabolism and the development of non-alcoholic steatohepatitis. By analyzing mice with liver-specific autophagy deficiency caused by conditional deletion of FIP200, we found that defective autophagy per se is not sufficient to cause fatty liver. Instead, acute suppression of autophagy results in increased liver injury, whereas chronic inhibition leads to liver fibrosis and inflammation, hallmarks of steatohepatitis. These findings raise the possibility that compromised autophagy may serve as a potential ;;second hit” that drives the progression from relatively benign fatty liver to steatohepatitis.