Although the ketone body β-hydroxybutyrate (BHB) is commonly associated with the pathologic condition diabetic ketoacidosis, its most recognized physiologic function is as an alternative fuel source produced by the liver when glucose is sparse.  More recently, evidence has emerged that BHB also serves as a signaling and regulatory molecule that is associated with protection against the effects of aging, inflammation, and neuronal excitotoxicity.BHB released from the liver is taken up by muscle, brain, and other peripheral tissues, where it is trafficked to the mitochondria.  BHB is reversibly converted to acetoacetyl-CoA (Figure 1), which can then be processed through β-oxidation.  Because BHB is processed in the mitochondria, the cytosolic NAD+ pool is preserved.  In addition to its use as a redox cofactor, cytosolic NAD+ also acts as a substrate for the sirtuin and poly(ADP-ribose) polymerase (PARP) enzymes; by preserving the cytosolic NAD+ pool, increased BHB levels enhance the anti-aging and anti-apoptotic effects of the sirtuin and PARP enzymes.Figure 1  Conversion of BHB to acetoacetyl-CoABHB acts directly as an agonist for several receptors, including the hydroxycarboxylic acid receptor 2 (HCAR2), a Gi-coupled G protein–coupled receptor (GPCR) that upon activation inhibits adenylyl cyclase and its downstream effectors.  In adipocytes, BHB-mediated activation of HCAR2 reduces lipolysis, decreasing serum levels of proinflammatory free fatty acids.  In the colonic epithelium, HCAR2 activation is critical in the maintenance of gut membrane integrity.  In this way, BHB acts similarly to the short-chain fatty acids (eg, butyric acid), produced from fermentation of dietary fiber, in protecting gut health.Several mechanisms have been proposed to explain BHB's action as a neuroprotectant against excitotoxicity.  In glutamatergic neurons, BHB inhibits vesicular glutamate transporter 2 (VGLUT2), inhibiting the packaging of the excitatory neurotransmitter glutamate.  In GABAergic neurons, BHB infusion stimulates production of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and decreases α-ketoglutarate levels. Question 40Based on the passage, hepatocytes (ie, liver cells) that are producing BHB are also most likely to have:A.downregulated phosphofructokinase-2 (PFK2) activity.B.downregulated phosphorylase kinase activity.C.upregulated acetyl-CoA carboxylase (ACC) activity.D.upregulated glycogen synthase activity.

The primary ketone found in the body:Group of answer choicessuccinatecitratebeta-hydroxybutyratemaltate

The liver plays a central role in maintaining blood glucose homeostasis.  It contains the highest concentration of glycogen of any organ in the body and is one of the few organs that can regenerate glucose from metabolic byproducts.  The liver can replenish glucose in muscle and brain tissue during times of fasting, and it can help prevent lactate accumulation during intense physical activity.Von Gierke disease is a rare autosomal recessive disorder that arises from inactivating mutations in the liver enzyme glucose 6-phosphatase (G6Pase).  It affects roughly 1 in 100,000 individuals, and the resulting loss of enzymatic activity leads to hypoglycemia (low blood sugar) that cannot be counteracted by catabolic hormones like glucagon.  Von Gierke can also cause an increase in blood acidity concurrent with lactate build-up.  Patients typically become symptomatic shortly after birth with convulsions, hyperventilation, and tremors.  Left untreated, patients may develop gout, osteoporosis, and life-threatening complications such as kidney failure and liver tumors.In an effort to examine the biochemical consequences of this disorder, scientists generated a genetically engineered mouse model with liver G6Pase expression under the control of the Tet-Off system at both alleles.  Under this system, addition of the small molecule tetracycline in the water source of the mouse rapidly shuts off G6Pase gene expression and therefore can recapitulate von Gierke disease.  Blood glucose and pH levels were measured daily in two groups of genetically engineered mice over 20 days: group A mice received no tetracycline and group B mice were given tetracycline starting at day 10.  All mice were fed identical low-sugar diets throughout the experiment.Adapted from Froissart R, Piraud M, Boudjemline AM, et al. Glucose-6-phosphatase deficiency. Orphanet J Rare Dis. 2011;6:27. Question 7Treatment with which of the following could help counteract hypoglycemia in patients with von Gierke disease?A.InsulinB.Vitamin AC.EpinephrineD.Starch

In addition to being metabolized for energy, the ketone body β-hydroxybutyrate (BHB) can also react with lysine residues of histone proteins.Which statement best explains the general upregulation of gene expression following histone β-hydroxybutyrylation?  β-Hydroxybutyrylation:A.decreases the binding interaction between histones and the DNA backbone.B.increases the binding interaction between histones and the nitrogenous bases of DNA.C.increases the binding interaction between histones and the RNA backbone.D.decreases the binding interaction between histones and the nitrogenous bases of RNA.

In the adaptive phase of fasting (between 2 and 7 days without food), the body is said to have similarities with untreated type I diabetes mellitus because:Question 9Answera.Ketone bodies are being generated from blood urea raising serum H+ levels while fatty acids form the main energy fuelb.Glucose is being generated from glycogenolysis and fatty acids are rising in the serumc.Ketone bodies are being generated as an alternative fuel to glucose although some gluconeogenesis continues using amino acids and also generating uread.Glucose is being generated from gluconeogenesis and fatty acids are falling in the serume.Most fat stores have been used and urea nitrogen is high due to gluconeogenesis

Diabetic ketoacidosis