Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease

Abstract

Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by "keto" diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is β-hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport/metabolism is impaired. Recent studies have identified new functions for β-hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin, and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans, resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease.

Keywords: GPR109A; HMGCS2; cancer; epigenetic modification; inflammation; ketoacidosis; ketone body transporters; loss-of-function mutations; neurodegeneration; β-hydroxybutyrate.

Figure 1

Reactions involved in ketogenesis and ketone utilization. ACAT1, acetyl CoA acetyltransferase 1; HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2; HMGCL, 3-hydroxy-3-methylglutaryl-CoA lyase; BDH1, β-hydroxybutyrate dehydrogenase 1; OXCT1, 3-oxoacid CoA transferase 1; FFA, free fatty acids; AAs, amino acids; MCT, monocarboxylate transporter; SMCT1, sodium-coupled monocarboxylate transporter 1; TCA, tricarboxylic acid.

Figure 2

Biochemical mechanisms underlying ketoacidosis under various physiological, pathologi-cal and pharmacological conditions. FFA, free fatty acids; CHO, carbohydrate; HMGCS2, 3-hydroxy-3-methylglutaryl-CoA 2; AMPK, AMP-activated kinase; mTOR, mechanistic target of rapamycin; PPARα, peroxisome proliferator-activated receptor α; SGLT2i, sodium-coupled glucose transporter 2 inhibitors.

Figure 3

Regulation of HMGCS2 at the transcriptional level. PKA, protein kinase A; CREB, cAMP-responsive element binding protein; CBP, CREB binding protein; FoxA2, forkhead box protein A2; PKB, protein kinase B; PI3K, phosphatidylinositol-3-kinase; PXR, pregnane X receptor; CAR, constitutive androstane receptor; PPARα, peroxisome proliferator-activated receptor α; PGC1α, peroxi-some proliferator-activated receptor gamma coactivator 1α; FGF21, fibroblast growth factor 21; P, phosphorylated; Ac, acetylated; H3, histone 3. The positions of the individual cis-elements in the HMGCS2 gene promoter that are responsible for the binding of the indicated transcription factors are simply schematic and do not represent the exact positions in relation to one another.

Figure 4

Regulation of the catalytic activity of HMGCS2 by post-translational modifications. HMGCS2, 3-hydroxy-3-methylglutaryl-CoA 2; Ac, acetylated; Suc, succinylated; P, phosphorylated; BHB, β-hydroxybutyrate; HDAC, histone deacetylase; PKA, protein kinase A; PPase, protein phosphatase 1; CBP, CREB binding protein.

Figure 5

Clinical symptoms of HMGCS2 deficiency and their molecular basis. HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2; FAs, fatty acids; ↑ and ↓ indicate an ‘increase’ or ‘decrease’, respectively.