Energy Production from Fats—The Citric Acid Cycle and Ketogenesis

Dear BLOG readers, dear PEAK customers,

Some time ago, I already addressed the topic of obesity and its far-reaching effects on health.

Obesity—Not Just a Cosmetic Issue

In another blog post, I took a closer look at adipocytes—the fat cells in our bodies—and examined the processes involved in their formation and breakdown.

Fat Breakdown and Fat Accumulation / Adipocyte Metabolism – Part I

Fat Breakdown and Fat Synthesis / Adipocyte Metabolism – Part II

These processes take place, as needed, via a series of enzymes and signaling molecules. Excess dietary fat is stored in adipocytes as triglycerides. When the body signals a need for energy, stored fat must be released and converted into energy that the body can utilize. Fat, in its natural form, cannot be used directly as an energy source—for example, to power muscle contraction or supply our brain with energy. This requires a series of conversion steps.

It is precisely these steps that I would like to address today and provide readers with insight into the fundamental metabolic processes of our cells as they handle fats.

Fats

Fats (also called lipids) are organic substances that are poorly soluble in water but highly soluble in organic solvents. The term “fats” encompasses fatty acids, triglycerides (neutral fats), cholesterol, phospholipids, waxes, terpenes, eicosanoids, glycolipids, cerebrosides, and gangliosides.

Functions

The various fats have a wide range of different functions.

Fatty acids serve as a relatively rapidly available energy substrate for the body in aerobic metabolism (oxygen-dependent).

Triglycerides are our body’s most important energy store. As storage or structural fats, they also protect us from cold and mechanical stress.

Phospholipids and glycolipids (fats that contain a carbohydrate component in their molecule) serve as building blocks for the synthesis of membrane components in our cells.

Cholesterol serves as a precursor for the synthesis of steroid hormones and is necessary for the formation of bile for fat digestion.

Eicosanoids improve communication between a messenger substance and the target cell.

Digestion and Absorption of Fats

The digestion of fats begins in the stomach. However, the majority of the process takes place in the duodenum and the jejunum (part of the small intestine).

Stomach

The enzyme lipase breaks down triglycerides into monoglycerides, free fatty acids, and glycerol. The enzyme cholesterol esterase hydrolyzes cholesterol compounds. Phospholipases and phosphatases break down phospholipids. All of these enzymes originate in the pancreas.

Duodenum

The liver produces the bile needed for fat digestion. This bile is stored in the gallbladder and released into the duodenum as needed. The active components of bile are bile salts. With the help of bile acids, phospholipids, and pre-existing β-monoacylglycerides, the fats arriving from the stomach are emulsified (intensive mixing of fatty and aqueous liquids) and formed into micelles (transport units).

Micelles consist of approximately 35% bile acids, 45% free fatty acids, 5% lipophospholipids, 2% cholesterol, and 1% fat-soluble vitamins.

Small Intestine

In the small intestine, micelles are absorbed by the mucosal cells located in the small intestinal mucosa. The bile acids contained in the micelles are required for this absorption. Short-chain free fatty acids can cross the small intestinal mucosa even without binding and enter the bloodstream directly, proceeding on to the liver.

Before absorption, the micelle components are reconstructed, and chylomicrons are formed, which are then absorbed via the small intestine into the lymphatic/bloodstream. Chylomicrons are lipoproteins. They serve as transport units for water-insoluble substances (see BLOG: Cholesterol).

Absorption

Absorption generally refers to the uptake of dietary components through the intestine. A distinction can be made between active and passive absorption.

Passive

In the small intestine, the lumen (inner cavity) has a high concentration of lipid components, while the cells of the intestinal mucosa have a low concentration, leading to passive transport via osmosis. Osmosis requires a concentration gradient as described.

Active

Active absorption also occurs against a concentration gradient. This process requires transport molecules and energy in the form of ATP.

Formation of Energy Reserves via Fats (Lipogenesis)

Replenishing energy stores is one of the main functions of fats. The exact process of lipogenesis has already been discussed in detail in my BLOG about adipocytes.

Fat Breakdown and Fat Synthesis / Metabolism of Adipocytes – Part I

Fat Breakdown and Fat Synthesis / Adipocyte Metabolism – Part II

It is clear that fats not needed for immediate energy requirements (lipogenesis), as well as excess glucose from the blood (liponeogenesis), are used to replenish adipocytes as energy stores.

After the uptake of excess fats, several conversion steps lead to the formation of triglycerides, the storage form within adipocytes.

Triglyceride synthesis takes place in the cell’s cytoplasm. The following are involved in the synthesis:

• acyl-CoA
• glycerol phosphate
• acyltransferase enzymes (ATF)

Energy supply via free fatty acids

Free fatty acids can:

• either be used directly for aerobic energy production via beta-oxidation, the citric acid cycle, and the respiratory chain,
• or be broken down in the liver and converted into ketone bodies

Which pathway is chosen depends on the overall energy supply situation (primarily glucose). Through ketone body metabolism, the body creates an alternative energy substrate that can replace glucose during periods of fasting.

Citric Acid Cycle – ATP Production from Fatty Acids

The Path from Fatty Acids to the Citric Acid Cycle

The citric acid cycle is one of the most important metabolic pathways in human cells and plays a central role in aerobic energy production.

During glucose metabolism, pyruvate is formed in the step described above, which is then converted to acetyl-CoA, which subsequently enters the citric acid cycle.

In the case of fatty acids, acetyl-CoA is produced through beta-oxidation (described in more detail in the section on ketogenesis).

Within the citric acid cycle itself, a number of complex processes take place, the explanation of which would go beyond the scope of this blog. Effectively, once acetyl-CoA is available, there are 8 synthesis steps:

NAD+ is produced during all of these degradation steps; it then combines with hydrogen—which is also released during the reaction steps described—to form NADH/H+.

Illustration: Citric Acid Cycle

Respiratory Chain

The goal of the citric acid cycle is to produce as much NADH/H+ as possible. This ultimately enters the respiratory chain and reacts with oxygen from the air we breathe. The final reaction in the respiratory chain is the formation of water, during which a large amount of energy is released in the form of ATP.

ATP is the primary energy source for the reactions occurring within cells. It is used for all energy-intensive metabolic processes. These naturally include, to a large extent, muscle contractions.

Illustration: Respiratory chain during ATP production

Ketogenesis – Alternative Energy Production in the Absence of Glucose

Interrelationships Between Carbohydrate and Fat Metabolism – Metabolic Processes

Our metabolism triggers specific metabolic processes depending on the caloric phase. In the absence of food intake, it distinguishes between:

• Post-resorption phase A or starvation (no nutrient intake for less than 24 hours)
• Post-resorption phase B or fasting (no nutrient intake for more than 36 hours).

The primary goal of our body is to maintain a constant blood sugar level in order to adequately supply the brain, the renal medulla, the CNS (central nervous system), and the red blood cells with glucose.

During the transition from starvation to fasting, our body switches