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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.

Author information

1
School of Animal and Comparative Biomedical Scieces, University of Arizona.
2
School of Animal and Comparative Biomedical Science, University of Arizona.
3
School of Animal and Comparative Biomedical Scieces, U. Arizona, United States.

Abstract

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.

KEYWORDS:

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

PMID:
30767679
DOI:
10.1152/ajpgi.00415.2017

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