The role of hepatocellular autophagy in non-alcoholic fatty liver disease
22 December 2016
UAntwerpen, Campus Drie Eiken, Building Q, Promotiezaal - Universiteitsplein 1 - 2610 WILRIJK (route: UAntwerpen, Campus Drie Eiken
Prof P. Michielsen & Prof S. Francque
PhD defence Wilhelmus Kwanten - Faculty of Medicine and Health Sciences
Non-alcoholic fatty liver disease (NAFLD), which describes a spectrum of disease hallmarked by fat accumulation within hepatocytes, is a growing health problem in the Western society. The pathophysiology of NAFLD and its progression, e.g. the development of NASH (non-alcoholic steatohepatitis, i.e. the development of necro-inflammation with progressive fibrosis), is not fully understood. Amongst others autophagy might be one of the driving mechanisms.
Autophagy is a cellular process that secures cellular homeostasis and plays a role in lipid and glucose metabolism and is as such involved in the pathophysiology of NAFLD. However, the role of autophagy in lipid metabolism is still under debate with evidence supporting both lipid breakdown and lipid build-up. After the implementation of a hepatocellular-specific autophagy-deficient mice model, via targeted knockout of Atg7, the effects of this autophagy-deficiency were investigated on mice fed a control diet and in two different models of NAFLD.
We demonstrated that hepatocellular autophagy-deficiency prevents diet-induced obesity, reduces peripheral fat tissue mass, improves glucose-tolerance and prevents the development of lipid droplet accumulation in hepatocytes (i.e. prevents steatosis). However, this is at the expense of severe hepatocellular injury with the activation of other homeostatic cellular pathways and the development of adenomata (benign liver tumours). The unfolded protein response (UPR), one of the homeostatic mechanisms, was pathway-selectively modulated by autophagy-deficiency which might in part explain the observed effects on liver cell death and the absence of lipid droplet accumulation in these mice.
The occurrence of lipid droplet containing autophagy-competent cell groups was observed within the liver parenchyma of autophagy-deficient mice, reinforcing the close relationship of Atg7 (i.e. autophagy) and lipid metabolism. Moreover, this finding confirms the existence of an extrahepatic source for liver cell renewal.
Finally, gene-arrays of adult obese patients without and with NAFLD revealed that autophagy and the UPR play a rather minor role compared to metabolic pathways.