Abstract: The ketone body β-hydroxybutyrate (βOHB) is a convenient carrier of energy from adipocytes to peripheral tissues during fasting or exercise. However, βOHB is more than just a metabolite, having important cellular signaling roles as well. βOHB is an endogenous inhibitor of histone deacetylases (HDACs) and a ligand for at least two cell surface receptors. In addition, the downstream products of βOHB metabolism including acetyl-CoA, succinyl-CoA, and NAD+ (nicotinamide adenine dinucleotide) themselves have signaling activities. These regulatory functions of βOHB serve to link the outside environment to cellular function and gene expression, and have important implications for the pathogenesis and treatment of metabolic diseases including type 2 diabetes.
Alex’s Notes: I want to begin by stating that this is not an article about ketosis or ketogenic dieting. Rather, we are dealing with beta-hydroxybutyrate (BHOB), a ketone molecule that was long thought to be a simple carrier of energy from the liver to the rest of the body during times of prolonged fasting. Evolutionarily, BHOB is synthesized within the liver from the fatty acids of our adipose tissue and circulated to other tissues such as the muscle or brain where it is converted into acetyl-CoA. When food is prevalent, BHOB concentrations are very small, but they can reach 1-2 mM after two days of fasting and exceed 2mM with a ketogenic diet that is almost devoid of carbohydrates.
So why is BOHB special?
Perhaps most intriguing is that BOHB is an endogenous inhibitor of histone deacetylaes (HDACs), a family of proteins that broadly regulate gene expression.Histone hyperacetylation is generally associated with activation of gene expression, and so deacetylation often suppresses transcription. Therefore, inhibition of HDACs allows for gene transcription to continue. This is important because the histone hyperacetylation is similar to that seen after fasting or with caloric restriction (think lifespan extension and longevity).
HDACs have also been shown to regulate several factors of metabolic disease such as oxidative stress and glucose metabolism. It has been demonstrated that chronic treatment with butyrate – the short-chained fatty acid – to mice fed an obesogenic diet helps maintain their metabolic normality. That is, the mice had lower glucose and insulin levels, better glucose tolerance, prevention of weight gain, and improved respiratory efficiency; even mice that were fat pre-treatment demonstrated improvement with butyrate. Butyrate, like BOHB, is a HDAC inhibitor, and it stands to reason that these effects would be similar with BOHB. As a side note, this is also another reason to eat your veggies and have a healthy intake of prebiotic fiber.
As for oxidative stress, BOHB activates transcription of FOXO3 and downstream antioxidant genes via HDAC inhibition, and long-term treatment with an HDAC inhibitor attenuates kidney injury in a mouse model of diabetic nephropathy. BOHB also protects neurons from hypoxic stress in vitro, and a ketogenic diet is also protective from ischemic neuronal death. These similarities between BOHB and butyrate may be in part because they share at least two receptors (HCAR2 and FFAR3).
It should also be noted that many of BOHB effects on metabolism result from downstream metabolites within the peripheral tissues, such as acetyl-CoA, succinyl-CoA, and NAD.
“The first step in BOHB utilization in peripheral tissues is its conversion to acetoacetate by mitochondrial B-hydroxybutyrate dehydrogenase (BDH1), which uses NAD as a cofactor and generates NADH. Next, acetoacetate is converted to acetoacetyl-CoA by succinyl-CoA:3-ketoacid coenzyme A transferase (OXCT1, also known as SCOT), which uses succinyl-CoA as a CoA donor, releasing free succinate. Acetoacetyl-CoA is then split into two acetyl-CoA that are burned in the TCA cycle to generate ATP in peripheral tissues. Utilization of BOHB therefore might increases acetyl-CoA levels, decrease succinyl-CoA levels, and alter the NAD/NADH ratio in peripheral tissues such as muscle.”
Increasing the intracellular pools of acetyl-CoA should indirectly increase protein acetylation. This effect is complementary to HDAC inhibition by BOHB, but may have broader effects, especially in the mitochondria.For example, caloric restriction, fasting, and high-fat diets – states associated with increased lipid utilization and therefore high acetyl-CoA throughput – cause increased mitochondrial protein acetylation.The enzymes in many key mitochondrial pathways are heavily succinylated and include fatty acid oxidation, branched-chain amino acid catabolism, and the Krebs cycle. These pathways may be activated by a reduction in succinylation, and therefore consumption of succinyl-CoA during BOHB utilization and consequent reduction in mitochondrial protein succinylation may regulate many of these crucial mitochondrial pathways in peripheral tissues. Finally, the cytoplasmic and mitochondrial NAD pools are relatively distinct, so the preservation of cytoplasmic NAD+ by βOHB may have important cellular effects.
Thanks for the biochemistry lesson, but what the hell does it mean?
In a nutshell, BOHB may have a broad regulatory role in metabolic disease through alterations in histone acetylation and gene expression, post-translational protein function, and cell surface receptor activation. In other words, BOHB can no longer simply be viewed as an energy carrier during times of prolonged fasting or carbohydrate restriction.
Speaking of carbohydrate restriction, a commonality between ketogenic diets, prolonged fasting, and starvation is a rise in BOHB concentrations. While it was previously thought that caloric restriction was necessary for metabolic health benefits and “longevity,” new research suggests that it is more the fasting state, per se, that is important. For example, in a classic mouse experiment, mice fed only during eight hours at night were resistant to diet-induced obesity despite identical caloric intake to controls. Ketogenic diets have been used to treat epileptic children since Hippocrates time, and there is a growing interest in its use for diabetes and other chronic diseases. Nonetheless, these dramatic dietary interventions are not without side effects, and the new research into BOHB may provide yet another avenue to reap the benefits. Perhaps, supplementation would allow for the benefits without dietary changes.