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Lipids and fat metabolism

Last updated: November 19, 2020


After ingested fats (lipids) are cleaved by enzymes, lipids are absorbed in the small intestine and transported via the lymphatic system into the bloodstream. During this transport process, lipids are bound to special hydrophilic apolipoproteins. These lipoproteins control fat metabolism and have different proportions of bound fat as well as different functions. Elevated low-density lipoprotein (LDL) and triglycerides are associated with an increased risk of atherosclerosis; however, an increase in high-density lipoprotein (HDL) has a positive effect on the vessels. Treatment of elevated lipid levels usually involves the administration of lipid‑lowering agents (e.g., statins). Lifestyle changes also play an important role.



Fat metabolism


Digestion and absorption of lipids

Lipid digestion

Acyl-CoA and acetyl-CoA should not be confused with each other! Acyl-CoA is a collective name for all activated fatty acids. Acetyl-CoA is the acyl-CoA of acetic acid (also known as acetate).

There is a very small amount of lipid in the stool of healthy individuals. Defects in lipid digestion result in steatorrhea (i.e., fatty stool).

Enzymes in lipid digestion

Lipases: enzymes that catalyze the breakdown of fats into glycerol and fatty acids

Enzyme Site Function
Lingual lipase
Gastric lipase
Pancreatic lipase

Lipid resorption

The decomposition products of lipid digestion form mixed micelles with bile acids.


Lipid transport

Lipoproteins [5]

Abnormalities in the structure or metabolism of lipoproteins result in an increased risk of atherosclerosis.

Lipoproteins (in order of descending density) Composition Function Apolipoproteins
High-density lipoprotein (HDL)
  • ApoE
  • ApoA-I
  • ApoC-II
Low-density lipoprotein (LDL)
Intermediate-density lipoprotein (IDL)
Very low-density lipoprotein (VLDL)

The lipoproteins in order of increasing triglycerides are HDL, LDL, IDL, VLDL, and chylomicrons.

Free fatty acids in the blood are not transported by lipoproteins but are instead bound to albumin!

HDL is Healthy (protective against atherosclerosis) and LDL is Lethal (cholesterol plaque formation in peripheral arteries → cardiac disease and stroke).


Apolipoprotein Function Component of
Apo E Mediates remnant uptake by the liver
  • All except for LDL
Apo A-I Activates LCAT
Apo C-II Cofactor for lipoprotein lipase
Apo B-48 Mediates the secretion of chylomicron particles that originate from the intestine into the lymphatics
Apo B-100 Mediates endocytosis of LDL by binding to LDL receptors on hepatic and extrahepatic tissues
  • Particles originating from the liver

To remember the particles originating from the LIVer, think: LDL, IDL, VLDL.

Enzymes in lipid transport

Enzyme Site Function
Hepatic lipase
  • Released by the liver and activated in the bloodstream
Hormone-sensitive lipase
Lecithin-cholesterol acyltransferase (LCAT)
  • Found on the surface of HDL (synthesized by the liver)
Lipoprotein lipase

Lipoprotein lipase is activated by binding to its cofactor apo C-II!


Fatty acid metabolism

Fatty acids and triacylglycerols (TAGs) are important energy carriers. They are stored in the adipose tissue and can be mobilized from there if necessary and degraded (via beta oxidation) while releasing energy in the form of ATP. TAGs are the storage form of fatty acids in the body. They consist of one molecule of glycerine esterified with three fatty acids. TAG metabolism is subject to strict regulation by the hormone-sensitive lipase of adipose tissue.

Fatty acids

A carboxylic acid with an unbranched chain of carbon atoms differing in length (from 1–24 carbon atoms).

  • Definitions
    • Short-chain fatty acid (SCFA): total carbon-chain length between 1–6
    • Medium-chain fatty acid (MCFA): total carbon-chain length between 7–12
    • Long-chain fatty acids (LCFA) total carbon-chain length between 13–20
    • Very long-chain fatty acid (VLCFA): total carbon-chain length 20
    • Odd-chain fatty acid: contain an odd number of carbon atoms
    • Essential fatty acid: cannot be synthesized by humans and need to be ingested (e.g., linoleic acid)
  • Can be unsaturated (with C=C double bonds) or saturated (without C=C double bonds)
  • Typically found as esters (in triglycerides, phospholipids, or cholesterol esters)
    • Triglyceride
      • A lipid composed of one glycerol linked to three fatty acids
      • Storage form of fatty acids, mainly in adipocytes
      • Serves as an energy reserve
      • Monoglyceride and diglyceride: Only one or two of the hydroxyl groups of glycerol are esterified with fatty acids.
  • Degradation via beta oxidation releases energy.

An increased concentration of triglycerides in the blood is called hypertriglyceridemia. It can be hereditary (lack of lipoprotein lipase), acquired (obesity, alcoholism), or a combination of both. Like hyperlipoproteinemia, hypertriglyceridemia increases the risk of vascular disease (atherosclerosis, coronary heart disease, peripheral vascular disease).

Overview of fatty acid metabolism

The breakdown of fatty acids is not simply a reversal of fatty acid synthesis; there are a number of differences between the two processes.

Synthesis Breakdown
Main goal
  • Energy generation
Rate-determining enzyme
  • Carnitine palmitoyltransferase I
Required substances
End products

Say “Sytrate” to remember that the Citrate shuttle is essential for the synthesis of fatty acids.

Fatty acids use the CARnitine shuttle to travel to their site of degradation.

Fatty acid synthesis

Fatty acid degradation

Carnitine deficiency results in toxic accumulation of LCFA in the cytoplasm of myocytes and other cells. Patients present with hypoketotic hypoglycemia, fatty liver, myopathy, hypotonia, and fatigue. Treatment consists of oral supplementation of the amino acid carnitine.

MCAD deficiency is characterized by the defective breakdown of MCFA, which renders FAs an unusable alternative energy source in the case of carbohydrate deficiency. Because the liver cannot degrade FAs beyond C8–C10, acetyl-CoA and NADH are missing for ketone body production and gluconeogenesis. This deficiency results in nonketotic hypoglycemia, encephalopathy, and lethargy in fasting states. C8–C10 acylcarnitines can be found in the blood.

Degradation of very long-chain fatty acids (20 carbons)

Degradation of fatty acids with an odd number of carbon atoms (propionic acid pathway)

Triglyceride synthesis

Synthesized triglycerides are either stored in adipose tissue or transported to the muscle for energy utilization.

Triglyceride degradation


Ketone body metabolism

Ketone bodies


Ketone body synthesis takes place exclusively in the mitochondria of hepatocytes! Ketone bodies are then released into the blood and transported to their target tissues (mainly the brain and muscle)!

Two molecules of acetyl-CoAacetoacetyl-CoAHMG-CoAacetoacetateβ-hydroxybutyrate! Acetone is formed by spontaneous decarboxylation of acetoacetate. The body has no use for acetone, which is excreted primarily in the lungs (gives breath a fruity odor). A small fraction is also exerted in the urine.


RBCs do not have mitochondria and hepatocytes lack the thiophorase enzyme. Therefore, neither of them can utilize ketone bodies for energy.


Cholesterol metabolism


Excess cholesterol secretion into bile (e.g., in pregnancy, obesity) can lead to precipitation of cholesterol crystals and gallstone formation (cholelithiasis).

There is no intestinal absorption of cholesterol without bile salts! Bile salt deficiency can be caused by gallstones or a tumor of the biliary tract.

Cholesterol synthesis

Simplified depiction of cholesterol synthesis: acetyl-CoAacetoacetyl-CoAHMG-CoAmevalonate → squalene → cholesterol.

The enzyme HMG-CoA reductase is clinically important because it is the target for drugs that are designed to reduce the plasma concentration of cholesterol (i.e., HMG-CoA reductase inhibitors, which have a structure similar to that of mevalonate). They are also referred to as statins.

Clinical significance

Laboratory considerations

In laboratory tests, total cholesterol, triglycerides, HDL, and LDL are usually measured. If levels are elevated or reduced, testing should be repeated after at least 2 weeks. See parameters of fat metabolism for optimal and pathological levels.

Laboratory parameter Elevated in Reduced in Prognostic correlations
Cholesterol HDL
  • Healthy lifestyle (calorie restriction, physical activity)

Associated conditions



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