Part of the TeachMe Series

Lipid Metabolism in the Liver

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Original Author(s): Dr. Danny Stevens
Last updated: 13th May 2022
Revisions: 13

Original Author(s): Dr. Danny Stevens
Last updated: 13th May 2022
Revisions: 13

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The liver is the second largest organ in the body and has a variety of important functions relating to metabolism and detoxification. Information on the anatomy of the liver can be found here.

In this article, we will consider the role of the liver in the metabolism of lipids, and we will discuss the clinical relevance of lipid metabolism in relevant disease states.


Lipids in the body include triglycerides, phospholipids and cholesterol. Triglycerides and phospholipids are composed of fatty acids, whereas cholesterol is not.

Triglycerides are mainly used for as an energy store for times of increased energy demand, whereas cholesterol and phospholipids are used for functions such as the synthesis of the cell membrane and the synthesis of steroid hormones.

We will now consider the processes of lipolysis and lipogenesis in detail:


When energy is needed from the fat stored in adipose tissue, triglycerides are hydrolysed into fatty acids and glycerol by triglyceride lipase, which is stimulated by adrenaline and glucagon. These fatty acids then enter the circulation where they bind immediately to albumin. When conjugated to albumin, the fatty acids are soluble in blood and so can be transported to tissues including the liver.

Upon entering hepatocytes, glycerol is immediately converted into glycerol-3-phosphate, which then enters the glycolysis pathway. However, fatty acids need to be oxidised and degraded, and this occurs in the mitochondria by a series of reactions known as beta-oxidation.

In beta-oxidation, two carbon segments are progressively released from the fatty acid chain until acetyl co-A is generated. NADH and FADH2 are generated as byproducts. Acetyl-co-A then binds immediately with oxaloacetate to form citrate and then enters the TCA cycle to release energy in the form of ATP.


A large proportion of fatty acid degradation by beta-oxidation occurs in the liver, but only a small amount is used for the liver’s own metabolism. Excess acetyl-coA is converted into acetoacetic acid using HMG-coA as an intermediate, and then transported to other tissues.

Some of the acetoacetic acid is converted to beta-hydroxybutyric acid, and small amounts to acetone in the following equation. Acetoacetic acid is a keto acid, and together with beta-hydroxybutyric acid and acetone the three compounds are known as ketone bodies.

Ketone bodies can travel in the blood to other tissues where they are then used for energy. However, they can also play a significant role in disease states. This will be discussed at the end of the article.

Figure 1 – Schematic diagram of ketogenesis


Lipogenesis is an essential mechanism that provides an energy store which can be used at times when the body’s energy requirement cannot be met by glucose alone. The body can only store ~15g/kg of glycogen; this can soon become depleted during times of starvation or high activity. In contrast, much more fat can be stored within adipose tissue, and fat contains 2.5x the energy as the same quantity of glycogen.

Fatty acid synthesis

Fatty acids are synthesised within the cytoplasm of hepatocytes, following maximal conversion of glucose to glycogen. The remaining glucose is then converted to pyruvate via the glycolysis pathway, and transported into the mitochondria where it is converted to acetyl Co-A.

If not entering the TCA cycle, acetyl-CoA needs to leave the mitochondria and enter the cytosol. However, the inner mitochondrial membrane is impermeable to acetyl-coA, and therefore it must traverse the membrane in an altered form; as citrate. This is the citrate shuttle.

  • Acetyl-CoA joins with oxaloacetate to form citrate
  • Citrate is able to cross the mitochondria membrane
  • Citrate is then converted back into acetyl-CoA and oxaloacetate within the cytosol

Once acetyl-CoA is in the cytosol, it can be converted to malonyl-CoA by acetyl-CoA carboxylase. This step is important in the regulation of lipogenesis as it is allosterically activated by citrate and inhibited by AMP.

Fatty acid synthase then creates an elongated fatty acid chain from the malonyl-CoA molecules, adding two carbon atoms for each molecule of malonyl-coA. As the malonyl-CoA molecules are added they lose a carbon atom creating CO2.

Figure 2 – Simplified equations of lipogenesis where c = number of carbon atoms in fatty acid chain


Three fatty acid molecules can then combine with a molecule of glycerol to become triglycerides. In the liver, very low density lipoprotein (VLDL) is synthesised; this transports triglycerides from the liver to their destination in adipose tissue.


Glucagon and adrenaline are the hormones that inhibit lipogenesis, alongside negative feedback from the presence of lipoproteins in the blood. Insulin is the main hormone to stimulate lipogenesis.

Clinical Relevance – Diabetic Ketoacidosis

Ketosis is a build-up of ketone bodies in the blood. It can arise through a range of circumstances, including diabetic ketoacidosis (DKA), alcoholic ketoacidosis and starvation. Diabetic ketoacidosis occurs primarily in type 1 diabetics, and can be the initial presenting complaint or a consequence of intercurrent illness.


Due to the lack of insulin in type 1 diabetics, glucose cannot enter cells, and so cannot be used for glycogenesis or for glycolysis. Simultaneously, levels of circulating glucagon are high due to the perceived cellular need for glucose. Therefore, fatty acids are needed for energy production and thus beta-oxidation is stimulated by hormones such as glucagon, adrenaline and cortisol.

The large turnover of fatty acids yields large amounts of acetyl-coA, which in excess is converted into ketones, leading to ketosis. As the levels of ketones rise in the blood, acidosis occurs, and the patient becomes very ill.

A VBG and a finger-prick ketone test will confirm DKA if the following three criteria are all met.

Diabetic Keto Acidosis
Glucose >11mmol/L Serum ketones >3mmol/L pH<7.30

As acetoacetic acid accumulates, some is converted to acetone. Acetone is volatile and is blown off on a patients’ breath, giving them the sweet pear drop breath associated with DKA.


Treatment for DKA is a fixed-rate insulin infusion and aggressive IV rehydration to restore circulating volume, correct acidosis and to glucose into cells. It is important to note that potassium will need to be added to much of the infusion fluid, as insulin will drive potassium into the cells.

Without treatment, DKA will eventually be fatal.