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Fasting-induced HMGCS2 expression in the kidney does not contribute to circulating ketones.

Citation
Venable, A. H., et al. “Fasting-Induced Hmgcs2 Expression In The Kidney Does Not Contribute To Circulating Ketones.”. American Journal Of Physiology. Renal Physiology, pp. F460-F467.
Center Yale University
Author Andrea H Venable, Lauren E Lee, Kyle Feola, John Santoyo, Tatyana Broomfield, Sarah C Huen
Keywords circulating ketones, fasting ketogenesis, hydroxymethylglutaryl-coenzyme A synthase 2, Kidney, liver
Abstract

Mitochondrial hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) is the rate-limiting enzyme in ketogenesis. The liver expresses high levels of HMGCS2 constitutively as the main ketogenic organ. It has been suggested that the kidney could be ketogenic as HMGCS2 is expressed in the kidney during fasting and diabetic conditions. However, definitive proof of the capacity for the kidney to produce ketones is lacking. We demonstrated that during fasting, HMGCS2 expression is induced in the proximal tubule of the kidney and is peroxisome proliferator activated receptor-α dependent. Mice with kidney-specific deletion showed a minor, likely physiologically insignificant, decrease in circulating ketones during fasting. Conversely, liver-specific knockout mice exhibited a complete loss of fasting ketosis. Together, these findings indicate that renal HMGCS2 does not significantly contribute to global ketone production and that during fasting, the increase in circulating ketones is solely dependent on hepatic HMGCS2. Proximal tubule HMGCS2 serves functions other than systemic ketone provision. The mitochondrial enzyme hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) catalyzes the rate-limiting step of ketogenesis. Although the liver constitutively expresses HMGCS2 and is considered the main ketogenic organ, HMGCS2 is induced in the kidney during fasting, leading to the proposal that the kidney contributes to fasting ketosis. We showed kidney HMGCS2 does not contribute to circulating ketones during fasting and cannot compensate for hepatic ketogenic insufficiency.

Year of Publication
2022
Journal
American journal of physiology. Renal physiology
Volume
322
Issue
4
Number of Pages
F460-F467
Date Published
04/2022
ISSN Number
1522-1466
DOI
10.1152/ajprenal.00447.2021
Alternate Journal
Am J Physiol Renal Physiol
PMID
35224990
PMCID
PMC9076412
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