Fats as cellular energy sources
Fats (lipids) are stored in adipose tissue, usually as triglycerides. They are composed of glycerol and fatty acids which can be broken down in a process known as lipogenesis. Eating excess calories leads to more fats being made and stored between muscles and under the skin. Conversely, when we eat less, levels of both blood glucose and insulin fall, and production of a hormone called glucagon increases. This stimulates the release of triglycerides from the adipose stores and its breakdown into glycerol and free fatty acids (FFA). Glycerol then enters glycolysis to produce pyruvic acid which, if oxygen is present, then enters the Krebs cycle. Fatty acids are changed, via a series of reactions called beta-oxidation, into ketones. The enzyme carnitine is important in this process, as it is also increased by glucagon and enhances the utilisation of FFA by increasing their transport into the mitochondria of cells where the conversion to ketones then acetyl CoA occurs. Cells can happily utilise sugar or fatty acid throughout the day depending on the timing of meals and the amount of sugar in the bloodstream.
Proteins as cellular energy sources
When protein is eaten, the body breaks it down into individual amino acids before it can be used by the cells. Most of the time, amino acids are recycled and used to make new proteins, rather than being oxidised for fuel. However, if there are more amino acids than the body needs, or if cells are starving, some amino acids will be broken down for energy. In order to enter cellular respiration, most amino acids must first have their amino group removed in a process called deamination. A toxic by-product of this step is ammonia, which the liver converts to urea and uric acid by adding carbon dioxide before it is then filtered and excreted by the kidneys. Once the amino acids have been deaminated, some glucogenic products can enter glycolysis while others are degraded directly into acetyl CoA and ketone bodies.
Ketones as energy sources
Ketones are produced when the body burns fats or proteins to produce energy molecules. They are also produced when there is not enough insulin to help your body use sugar for energy, such as during an uncontrolled type 1-diabetic crisis. As mentioned above, fatty acids are changed via a series of reactions called beta-oxidation into ketones, then acetyl CoA molecules, which enter the Krebs cycle to produce energy molecules. The three main ketones are; Acetone, B-hydroxybutyrate and acetoacetate.
Acetone is volatile and excreted in the breath, while B-hydroxybutyrate is converted to acetoacetate. To understand why this mechanism is a survival advantage, it is important to note that liver cells lack the enzyme (Succinyl CoA transferase) which concerts ketones to acetyl CoA. Instead, ketones are released into the bloodstream, enabling them to feed other tissues such as the brain, muscles and heart. In these tissues (which have the enzyme) the ketones are converted back to acetyl CoA, which then enters the Krebs cycle to produce energy.
The difference between normal and cancer cell energy utilisation
Normal cells fluctuate between using sugars or fatty acids depending on blood sugar levels, degree of oxygenation and rate of proliferation required. Usually cells slow glycolysis in the presence of oxygen and low blood sugars, and favour oxidative phosphorylation (OXPHOS). Likewise, when blood sugars drop, they switch to fatty acid metabolism, which by-passes glycolysis. In normal conditions, the cell metabolism consumes energy, of which 70% is supplied by OXPHOS. In hypoxia, however, glycolysis becomes enhanced to compensate for the weakened function of OXPHOS. Glycolysis and OXPHOS essentially cooperate to maintain the cellular energetic balance. Cancer cells appear to lose this regulation and favour glycolysis, despite falling blood sugars. This aerobic glycolysis was first observed by Otto Warburg in the 1920s and was initially thought to be an Achilles heel for cancer cells and a target for drugs and nutritional strategies such as the ketogenic diet. This view, however, has been challenged by recent investigations, which found that the function of mitochondrial OXPHOS in many cancers is intact and cancer cells can switch from one to another with ease depending on the level of oxygen and other cellular conditions.