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Am J Physiol Gastrointest Liver Physiol. 2019 Feb 15. doi: 10.1152/ajpgi.00415.2017. [Epub ahead of print]

The Role of Ketone Signaling in the Hepatic Response to Fasting.

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School of Animal and Comparative Biomedical Scieces, University of Arizona.
School of Animal and Comparative Biomedical Science, University of Arizona.
School of Animal and Comparative Biomedical Scieces, U. Arizona, United States.


Ketosis is a metabolic adaptation to fasting, non-alcoholic fatty liver disease (NAFLD), and prolonged exercise. β-OH butyrate acts as a transcriptional regulator and at G-protein coupled receptors to modulate cellular signaling pathways in a hormone-like manner. While physiological ketosis is often adaptive, chronic hyperketonemia may contribute to the metabolic dysfunction of NAFLD. To understand how β-OH butyrate signaling affects hepatic metabolism we compared the hepatic fasting response in control and 3-hydroxy-3-methylglutaryl-CoA Synthase II (HMGCS2) knockdown mice that are unable to elevate β-OH butyrate production. To establish that rescue of ketone metabolic/endocrine signaling would restore the normal hepatic fasting response, we gave intraperitoneal injections of β-OH butyrate (5.7mmol/kg) to HMGCS2 knockdown and control mice every 2 hours for the final 9 hours of a 16 hour fast. In hypoketonemic, HMGCS2 knockdown mice, fasting more robustly increased mRNA expression of uncoupling protein 2 (UCP2), a protein critical for supporting fatty acid oxidation and ketogenesis. In turn, exogenous β-OH butyrate administration to HMGCS2 knockdown mice decreased fasting UCP2 mRNA expression to that observed in control mice. Also supporting feedback at the transcriptional level, β-OH butyrate lowered the fasting induced expression of HMGCS2 mRNA in control mice. β-OH butyrate also regulates the glycemic response to fasting. The fast-induced fall in serum glucose was absent in HMGCS2 knockdown mice but was restored by β-OH butyrate administration. This data proposes that endogenous β-OH butyrate signaling transcriptionally regulates hepatic fatty acid oxidation and ketogenesis, while modulating glucose tolerance.


Beta-oxidation; Fasting; Gluconeogenesis; Ketogenesis; beta-hydroxy butyrate


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