期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 322, 期 4, 页码 F460-F467出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00447.2021
关键词
circulating ketones; fasting ketogenesis; hydroxymethylglutaryl-coenzyme A synthase 2; kidney; liver
资金
- George M. O'Brien Kidney Center at Yale [National Institutes of Health (NIH)] [P30DK079310]
- NIH [R35GM137984]
- American Society of Nephrology Carl W. Gottschalk Research Scholar Grant
- NIH T32 Training Grant [T32DK007257]
- Yale Diabetes Research Center-Molecular Genetics Core (NIH) [P30DK045735]
- George M. O'Brien Kidney Research Core at the University of Texas Southwestern Medical Center (NIH) [P30DK079328]
HMGCS2 is the rate-limiting enzyme in ketogenesis and the liver is the main organ for this process. Previous studies suggested that the kidney also contributes to fasting ketosis, but our research shows that renal HMGCS2 does not significantly contribute to circulating ketones, and the increase in circulating ketones during fasting is solely dependent on hepatic HMGCS2.
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-alpha dependent. Mice with kidney-specific Hmgcs2 deletion showed a minor, likely physiologically insignificant, decrease in circulating ketones during fasting. Conversely, liver-specific Hmgcs2 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. NEW & NOTEWORTHY 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.
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