Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease.
Level 5 - mechanism / opinion, no new human data
Narrative review of ketone body biology and HMGCS2 regulation with no original human trial data.
PubMed 40305364 · doi:10.3390/biom15040580
What was done
This narrative review synthesized literature on the biological functions of ketone bodies (chiefly β-hydroxybutyrate) and the regulatory mechanisms and clinical significance of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the rate-limiting enzyme of ketogenesis.
What was found
The abstract reports no quantitative values or statistical metrics. It describes ketogenesis as occurring primarily in the liver, kidney, colon, and retina, triggered by fasting, exercise, ketogenic diets, diabetes, and SGLT2 inhibitor therapy. β-hydroxybutyrate acts as an energy substrate for extrahepatic tissues, an agonist for the GPR109A receptor, and an epigenetic modifier with protective effects against inflammation, cancer, and neurodegeneration. HMGCS2 is transcriptionally and post-translationally regulated by insulin, glucagon, and glucocorticoids. Loss-of-function mutations in human HMGCS2 present in the first year of life with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, hepatic steatosis, hyperammonemia, and neurological complications.
Why it matters
The review summarizes the shift in understanding ketone bodies from simple metabolic fuels to signaling and epigenetic regulators, while outlining the clinical presentation of rare congenital HMGCS2 deficiency.
Limits
The abstract provides no systematic search strategy, quality appraisal, or quantitative data. As a narrative review, it presents mechanistic and clinical summaries without new primary experimental or clinical evidence. Long-term outcomes for patients with HMGCS2 loss-of-function mutations remain entirely uncharacterized.
Cited by
- supports Ketones are produced by mitochondria in the liver, with a minor amount produced by the kidneys, and the biochemical pathway from ketones to mitochondrial metabolism involves fewer enzymes than that of glucose.
- supports Ketone bodies can replace glucose as an energy source for the brain, muscles, and most cells in the body, except for erythrocytes.