Beta-hydroxybutyric acid (BHB) is the most abundant of the three compounds known as ketone bodies, which the body produces during specific metabolic states. BHB acts as an alternative, highly efficient energy source for the brain and other tissues when the body’s primary fuel, glucose, is in short supply. This shift in energy use, known as ketosis, typically occurs during periods of prolonged exercise, fasting, or when following a very low-carbohydrate, high-fat diet. Beyond its function as a fuel, BHB is now understood to be an important signaling molecule that communicates the body’s energy status to its cells.
How the Body Produces Beta Hydroxybutyric Acid
The production of beta-hydroxybutyric acid, a process called ketogenesis, takes place primarily in the mitochondria of liver cells. This process is triggered when the body enters a state of low carbohydrate availability, leading to low insulin levels and a corresponding rise in hormones like glucagon. These hormonal signals promote the breakdown of stored fat into fatty acids, which are then transported to the liver.
Inside the liver mitochondria, these fatty acids undergo beta-oxidation, breaking down into acetyl-coenzyme A (acetyl-CoA) molecules. When carbohydrate stores are depleted, the liver lacks the necessary components to process all the acetyl-CoA through the normal energy cycle. This excess acetyl-CoA is then diverted to produce acetoacetate, one of the other ketone bodies.
Acetoacetate is subsequently reduced to form beta-hydroxybutyric acid through the action of the enzyme \(\beta\)-hydroxybutyrate dehydrogenase. Although BHB contains a hydroxyl group instead of a ketone group, it is grouped with acetoacetate and acetone due to its close metabolic relationship. Once synthesized, BHB is released from the liver and circulated through the bloodstream to serve as fuel for other tissues.
BHB’s Role as a Primary Energy Source
BHB acts as an effective substitute for glucose, supplying energy to tissues that require a constant fuel source. The brain, which typically relies almost exclusively on glucose, is a major beneficiary of BHB during times of carbohydrate restriction. BHB is efficiently transported across the blood-brain barrier via specialized monocarboxylic acid transporters, ensuring that the brain can maintain cognitive function even when glucose is scarce.
Once BHB reaches a target cell, such as a neuron or a muscle cell, it is converted back into acetoacetate and then into acetyl-CoA. This acetyl-CoA enters the citric acid cycle within the cell’s mitochondria, where it is oxidized to produce adenosine triphosphate (ATP), the cell’s main energy currency. Burning ketones for energy is a clean process, potentially leading to a lower production of reactive oxygen species, which are normal but potentially damaging byproducts of metabolism.
BHB is a valuable fuel for skeletal muscle and the heart, as these organs also readily utilize it for energy. In a state of nutritional ketosis, BHB can supply a significant portion of the body’s overall energy needs. The brain alone is capable of deriving up to two-thirds of its energy from ketone bodies during prolonged fasting.
BHB as a Signaling Molecule and Gene Regulator
Modern research has revealed that BHB is not merely an energy substrate but also functions as an important signaling molecule that connects the body’s metabolic state to changes in gene expression. This regulatory role allows BHB to influence cellular functions far beyond simple energy production. One of its key signaling mechanisms involves acting as an endogenous inhibitor of a class of enzymes called histone deacetylases (HDACs).
HDACs normally remove acetyl groups from histone proteins, which are structural components of DNA, typically leading to the suppression of gene activity. By inhibiting these HDACs, BHB promotes a state of increased histone acetylation, which generally “opens up” the DNA structure and allows for the transcription of certain genes. This epigenetic effect allows BHB to regulate the expression of genes involved in processes like oxidative stress resistance and inflammation.
For example, BHB has been shown to increase the expression of genes such as FOXO3a and Mt2, which are involved in cellular protection against oxidative damage. BHB can also act as a substrate for a unique post-translational modification called histone \(\beta\)-hydroxybutyrylation. This specific modification on histone proteins directly links the presence of BHB to the regulation of genes involved in the starvation response and lipid catabolism.
Exogenous Ketones and Monitoring BHB Levels
For individuals seeking to raise their blood BHB levels without prolonged fasting or strict carbohydrate restriction, commercial supplements known as exogenous ketones are available. These supplements typically come as BHB salts or BHB esters, which, when ingested, are metabolized to quickly increase the concentration of BHB circulating in the blood. Exogenous ketones provide a rapid boost in BHB but bypass the full metabolic shift associated with endogenous ketogenesis, such as the increased breakdown of stored body fat.
Monitoring BHB concentration is commonly done to confirm a state of nutritional ketosis, which is generally defined by a blood BHB level at or above 0.5 millimolar (mM). Blood meters that measure BHB directly from a finger prick are considered the most accurate method for tracking this specific ketone body. Optimal nutritional ketosis is often cited as a range between 1.5 mM and 3.0 mM, though levels can fluctuate throughout the day.
Alternative methods include breath analyzers, which measure acetone, a breakdown product of acetoacetate, and urine strips, which measure acetoacetate levels. While these methods are non-invasive and convenient, they are less precise for measuring BHB, which is the most stable and abundant ketone body in circulation.