Upregulation of hepatic autophagy under nutritional ketosis

J Nutr Biochem. 2021 Jul:93:108620. doi: 10.1016/j.jnutbio.2021.108620. Epub 2021 Mar 8.


Many of the metabolic effects evoked by the ketogenic diet mimic the actions of fasting and the benefits of the ketogenic diet are often attributed to these similarities. Since fasting is a potent autophagy inductor in vivo and in vitro it has been hypothesized that the ketogenic diet may upregulate autophagy. The aim of the present study was to provide a comprehensive evaluation of the influence of the ketogenic diet on the hepatic autophagy. C57BL/6N male mice were fed with two different ketogenic chows composed of fat of either animal or plant origin for 4 weeks. To gain some insight into the time frame for the induction of autophagy on the ketogenic diet, we performed a short-term experiment in which animals were fed with ketogenic diets for only 24 or 48 h. The results showed that autophagy is upregulated in the livers of animals fed with the ketogenic diet. Moreover, the size of the observed effect was likely dependent on the diet composition. Subsequently, the markers of regulatory pathways that may link ketogenic diet action to autophagy were measured, i.e., the activity of mTORC1, activation of AMPK, and the levels of SIRT1, p53, and FOXO3. Overall, observed treatment-specific effects including the upregulation of SIRT1 and downregulation of FOXO3 and p53. Finally, a GC/MS analysis of the fatty acid composition of animals' livers and the chows was performed in order to obtain an idea about the presence of specific compounds that may shape the effects of ketogenic diets on autophagy.

Keywords: AMPK; Autophagy; Beta-hydroxybutyrate; FOXO3; Fatty acids; Ketogenic diet; Ketosis; LC3; SIRT1; SQSTM1/p62; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Autophagy / physiology*
  • Diet, Ketogenic*
  • Dietary Fats / analysis
  • Dietary Fats / pharmacology*
  • Forkhead Box Protein O3 / genetics
  • Forkhead Box Protein O3 / metabolism
  • Gene Expression Regulation / drug effects
  • Ketosis / metabolism*
  • Liver / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Plants
  • Signal Transduction
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation / drug effects*


  • Dietary Fats
  • Forkhead Box Protein O3
  • FoxO3 protein, mouse
  • Tumor Suppressor Protein p53
  • AMP-Activated Protein Kinases
  • Sirt1 protein, mouse
  • Sirtuin 1