Pathways
Ketolysis is the process of catabolizing ketones, the opposite of ketogenesis which is the process of synthesizing ketones. Ketolysis provides more energy for ATP synthesis than fatty acid oxidation (beta oxidation). [1]
Ketogenesis occurs primarily in the liver, whereas ketolysis occurs in non-liver cells, especially in the heart, brain, and skeletal muscle. [2] The SCOT enzyme is required for ketolysis, [3] and is present in the mitochondria of all mammalian cells except for hepatocytes. [2]
Although type II cells of the pulmonary alveolus possess monocarboxylate transporters to transport of beta hydroxybutyrate precursors into the cytoplasm, the absence of ketolytic enzymes results in the cells being unable to catabolize the beta hydroxybutyrate. [4]
The cardioprotective effects of SGLT2 inhibitors have been attributed to the elevated ketone levels and increased ketolysis. [1]
Ketone bodies are water-soluble molecules or compounds that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA —which then enters the citric acid cycle and is oxidized for energy. These liver-derived ketone groups include acetoacetic acid (acetoacetate), beta-hydroxybutyrate, and acetone, a spontaneous breakdown product of acetoacetate.
Ketosis is a metabolic state characterized by elevated levels of ketone bodies in the blood or urine. Physiological ketosis is a normal response to low glucose availability, such as low-carbohydrate diets or fasting, that provides an additional energy source for the brain in the form of ketones. In physiological ketosis, ketones in the blood are elevated above baseline levels, but the body's acid–base homeostasis is maintained. This contrasts with ketoacidosis, an uncontrolled production of ketones that occurs in pathologic states and causes a metabolic acidosis, which is a medical emergency. Ketoacidosis is most commonly the result of complete insulin deficiency in type 1 diabetes or late-stage type 2 diabetes. Ketone levels can be measured in blood, urine or breath and are generally between 0.5 and 3.0 millimolar (mM) in physiological ketosis, while ketoacidosis may cause blood concentrations greater than 10 mM.
Acetyl-CoA is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle to be oxidized for energy production. Coenzyme A consists of a β-mercaptoethylamine group linked to the vitamin pantothenic acid (B5) through an amide linkage and 3'-phosphorylated ADP. The acetyl group of acetyl-CoA is linked to the sulfhydryl substituent of the β-mercaptoethylamine group. This thioester linkage is a "high energy" bond, which is particularly reactive. Hydrolysis of the thioester bond is exergonic (−31.5 kJ/mol).
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.
Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under specific scenarios including fasting, caloric restriction, sleep, or others.
Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms.
Ketoacidosis is a metabolic state caused by uncontrolled production of ketone bodies that cause a metabolic acidosis. While ketosis refers to any elevation of blood ketones, ketoacidosis is a specific pathologic condition that results in changes in blood pH and requires medical attention. The most common cause of ketoacidosis is diabetic ketoacidosis but can also be caused by alcohol, medications, toxins, and rarely, starvation.
Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.
In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycle, and NADH and FADH2, which are co-enzymes used in the electron transport chain. It is named as such because the beta carbon of the fatty acid undergoes oxidation to a carbonyl group. Beta-oxidation is primarily facilitated by the mitochondrial trifunctional protein, an enzyme complex associated with the inner mitochondrial membrane, although very long chain fatty acids are oxidized in peroxisomes.
Ketonuria is a medical condition in which ketone bodies are present in the urine.
β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid or BHB, is an organic compound and a beta hydroxy acid with the chemical formula CH3CH(OH)CH2CO2H; its conjugate base is β-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxybutyric acid is a chiral compound with two enantiomers: D-β-hydroxybutyric acid and L-β-hydroxybutyric acid. Its oxidized and polymeric derivatives occur widely in nature. In humans, D-β-hydroxybutyric acid is one of two primary endogenous agonists of hydroxycarboxylic acid receptor 2 (HCA2), a Gi/o-coupled G protein-coupled receptor (GPCR).
Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In animals, these fats are obtained from food and are synthesized by the liver. Lipogenesis is the process of synthesizing these fats. The majority of lipids found in the human body from ingesting food are triglycerides and cholesterol. Other types of lipids found in the body are fatty acids and membrane lipids. Lipid metabolism is often considered as the digestion and absorption process of dietary fat; however, there are two sources of fats that organisms can use to obtain energy: from consumed dietary fats and from stored fat. Vertebrates use both sources of fat to produce energy for organs such as the heart to function. Since lipids are hydrophobic molecules, they need to be solubilized before their metabolism can begin. Lipid metabolism often begins with hydrolysis, which occurs with the help of various enzymes in the digestive system. Lipid metabolism also occurs in plants, though the processes differ in some ways when compared to animals. The second step after the hydrolysis is the absorption of the fatty acids into the epithelial cells of the intestinal wall. In the epithelial cells, fatty acids are packaged and transported to the rest of the body.
Starvation response in animals is a set of adaptive biochemical and physiological changes, triggered by lack of food or extreme weight loss, in which the body seeks to conserve energy by reducing the amount of calories it burns.
Acyl-CoA is a group of coenzymes that metabolize fatty acids. Acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way, fats are converted to ATP, the universal biochemical energy carrier.
3-Hydroxy-3-methylglutaryl-CoA lyase is an enzyme (EC 4.1.3.4 that in human is encoded by the HMGCL gene located on chromosome 1. It is a key enzyme in ketogenesis. It is a ketogenic enzyme in the liver that catalyzes the formation of acetoacetate from HMG-CoA within the mitochondria. It also plays a prominent role in the catabolism of the amino acid leucine.
Acetoacetyl CoA is the precursor of HMG-CoA in the mevalonate pathway, which is essential for cholesterol biosynthesis. It also takes a similar role in the ketone bodies synthesis (ketogenesis) pathway of the liver. In the ketone bodies digestion pathway, it is no longer associated with having HMG-CoA as a product or as a reactant.
The Randle cycle, also known as the glucose fatty-acid cycle, is a metabolic process involving the competition of glucose and fatty acids for substrates. It is theorized to play a role in explaining type 2 diabetes and insulin resistance.
In enzymology, 3-hydroxybutyrate dehydrogenase (EC 1.1.1.30) is an enzyme that catalyzes the chemical reaction:
Exogenous ketones are a class of ketone bodies that are ingested using nutritional supplements or foods. This class of ketone bodies refers to the three water-soluble ketones. These ketone bodies are produced by interactions between macronutrient availability such as low glucose and high free fatty acids or hormone signaling such as low insulin and high glucagon/cortisol. Under physiological conditions, ketone concentrations can increase due to starvation, ketogenic diets, or prolonged exercise, leading to ketosis. However, with the introduction of exogenous ketone supplements, it is possible to provide a user with an instant supply of ketones even if the body is not within a state of ketosis before ingestion. However, drinking exogenous ketones will not trigger fat burning like a ketogenic diet.
Metabolic flexibility is the capacity to alter metabolism in response to exercise or available fuel. Metabolic inflexibility was first described as the ability to generate energy through either aerobic or anaerobic respiration or as the inability of muscle to increase glucose oxidation in response to insulin. An organism can also be said to have metabolic flexibility if it is capable of metabolizing either carbohydrate or fat efficiency, depending on availability of those fuels.