Abstract
Hepatic autophagy has been shown to be regulated by acute exercise and exercise training. Moreover, high‐fat diet‐induced steatosis has been reported to be associated with impaired hepatic autophagy. In addition, autophagy has been shown to be regulated by acute exercise and exercise training in a PGC‐1α dependent manner in skeletal muscle. The aim of this study was to test the hypotheses that high‐fat high‐fructose (HFF) diet changes hepatic autophagy and mitophagy, that exercise training can restore this through a PGC‐1α‐mediated mechanism, and that acute exercise regulates autophagy and mitophagy in the liver. Liver samples were obtained from liver‐specific PGC‐1α KO mice and their littermate Lox/Lox mice fed a HFF diet or a control diet for 13 weeks. The HFF mice were either exercise trained (ExT) on a treadmill the final 5 weeks or remained sedentary (UT). In addition, half of each group performed at the end of the intervention an acute 1 h exercise bout. HFF resulted in increased hepatic BNIP3 dimer and Parkin protein, while exercise training increased BNIP3 total protein without affecting the elevated BNIP3 dimer protein. In addition, exercise training reversed a HFF‐induced increase in hepatic LC3II/LC3I protein ratio, as well as a decreased PGC‐1α mRNA level. Acute exercise increased hepatic PGC‐1α mRNA in HFF UT mice only. In conclusion, this indicates that exercise training in part reverses a HFF‐induced increase in hepatic autophagy and capacity for mitophagy in a PGC‐1α‐independent manner. Moreover, HFF may blunt acute exercise‐induced regulation of hepatic autophagy.
Highlights
The liver is an essential organ with key functions in whole-body glucose and lipid metabolism
The aim of this study was to test the hypotheses that (1) High-fat high-fructose (HFF) diet changes autophagy and mitophagy in the liver and exercise training performed after several weeks of HFF diet can restore hepatic autophagy regulation, (2) Hepatic autophagy is regulated by acute exercise in a proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a)-dependent manner and (3) PGC-1a influences basal regulation of hepatic autophagy when on HFF and liver PGC-1a is required for exercise training-induced adaptations in hepatic autophagy and mitophagy when on HFF
The present finding that LC3II/LC3I protein ratio increased and LC3I decreased in the liver with HFF is corroborated by several other studies reporting increased LC3II/LC3I protein ratios in the liver with high-fat diet (HFD) feeding (Gonzalez-Rodriguez et al 2014, Hsu et al 2016, Wang et al 2017a)
Summary
The liver is an essential organ with key functions in whole-body glucose and lipid metabolism. Previous studies have shown that high-fat diet is associated with hepatic triglyceride accumulation and disturbed liver metabolism (Delgado et al 2009, Koonen et al 2007, Schults et al 2012). Several processes have been suggested to be affected, including recent indications that high-fat diet changes the regulation of autophagy in the liver. Autophagy is a catabolic process targeting damaged proteins and cell organelles for lysosomal degradation, thereby supporting cellular survival and maintenance of homeostasis (Klionsky et al 2016). The energy sensors mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) are important checkpoints in the regulation of autophagy, exerting inhibitory (ULKSer757) or activating (ULKSer317) phosphorylation of Unc-51-like kinase 1 (ULK1), respectively (Komatsu 2012).
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