Lipids and fat metabolism

Abstract

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 are typically differentiated in their function and proportion of bound fat. 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.

Overview

Lipids

Fat metabolism

  • Digestion and absorption: ingested fats (lipids) are cleaved by enzymes (e.g., pancreatic lipase), absorbed in the small intestine, and then transported in chylomicrons via the lymphatic system into the bloodstream, where they reach the liver, peripheral tissues (with LDL receptors) and adipose tissue (storage)
  • Lipid transport: circulating lipids are transported in lipoproteins (contain hydrophilic apolipoproteins) because the hydrophobic lipids are insoluble in plasma

Digestion and absorption of lipids

Lipid digestion

Acyl-CoA and acetyl-CoA must 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 ("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 splitting of fats into glycerol and fatty acids.

Enzyme Site Function
Lingual lipase
Gastric lipase
  • Hydrolyzes dietary TGs into a monoglyceride and a diglyceride
Pancreatic lipase
  • Hydrolyzes dietary TGSs in small intestine into monoglycerides and free fatty acids.

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

Lipid resorption

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

[1][2]

Lipid transport

Lipoproteins

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

Lipoproteins (in descending density) Composition Function Structure
High-density lipoprotein (HDL)
  • ApoE
  • ApoA-I
  • ApoC-II
Low-density lipoprotein (LDL)
Intermediate-density lipoprotein (IDL)
Very-low-density lipoprotein (VLDL)
Chylomicron
  • Secreted by the intestinal epithelial cells into lymphatics
  • Transport dietary triglycerides from the intestine to peripheral tissues
  • Transport cholesterol to the liver in the form of chylomicron remnants
  • ApoE
  • ApoC-II
  • ApoB-48

The TG content of lipoproteins increases in the order HDL < LDL < IDL < VLDL < chylomicrons!

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

Apolipoproteins

Apolipoprotein Function Part of
ApoE Mediates remnant uptake by the liver
  • All except for LDL
ApoA-I Activates LCAT
  • HDL
ApoC-II Cofactor for lipoprotein lipase
  • Chylomicron
  • VLDL
  • HDL
ApoB-48 Mediates the secretion of chylomicron particles that originate from the intestine into the lymphatics
  • Chylomicron
  • Chylomicron remnant
ApoB-100 Mediates endocytosis of LDL by binding to LDL receptor on hepatic and extrahepatic tissues
  • Particles originating from the liver:
    • LDL
    • IDL
    • VLDL

Enzymes in lipid transport

Enzyme Site Function
Hepatic lipase
  • Released by the liver and activated in the bloodstream
Hormone-sensitive lipase
  • Hydrolyzes TGs and diglycerides stored in adipocytes into monoglycerides (lipolysis)
Lecithin-cholesterol acyltransferase (LCAT)
  • Found on the surface of HDL (synthesized by the liver)
  • Catalyzes esterification of plasma cholesterol (i.e., converts free cholesterol into cholesteryl ester)
  • Nascent HDL → mature HDL
Lipoprotein lipase
  • Secreted in vascular endothelial surface of extrahepatic tissues (esp. adipose tissue, heart, and skeletal muscle)
  • Hydrolyzes TGs circulating in chylomicrons and VLDLs into fatty acids and glycerin, which can be taken up by cells
  • Upregulated by insulin

Fatty acid metabolism

:Fatty acids and triacylglycerols (TAGs) are important energy carriers of the organism. They are stored in the adipose tissue and can be mobilized from there if necessary and degraded (ß-oxidation) while releasing energy in the form of ATP. TAGs are the storage form of fatty acids in the organism. They consist of one molecule of glycerine esterified with three fatty acids. The 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).

An increased concentration of TGs in the blood is called hypertriglyceridemia. It can be caused genetically (lack of lipoprotein lipase) or be acquired (obesity, alcoholism). Like hyperlipoproteinemia, hypertriglyceridemia increases the risk for vascular disease (atherosclerosis, coronary heart disease, peripheral vascular disease).

Overview of fatty acid metabolism

The breakdown of fatty acids is not a reversal of fatty acid synthesis. The following important differences are present:

Breakdown of fatty acids Synthesis of fatty acids
Site
  • Mitochondrium
Rate-determining enzyme
Cofactors
  • NAD+ und FAD
Components

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 a 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)

Regulation of fatty acid oxidation

Triglyceride synthesis

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

Triglyceride degradation

[1][2]

Ketone body metabolism

Ketone bodies

  • Water-soluble molecules that are produced by the liver to be used by peripheral tissues (e.g., heart, brain, skeletal muscle) as an energy source when glucose is not readily available
  • Three ketone bodies: acetoacetate, β-hydroxybutyrate, and acetone (acetone is a breakdown product of acetoacetate and beta-hydroxybutyrate)

Ketogenesis

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)!

Acetyl-CoAacetoacetyl-CoAHMG-CoAacetoacetateβ-hydroxybutyrate! Acetone is formed by spontaneous decarboxylation of acetoacetate. The organism has no use for acetone, which is excreted through the lungs and a small fraction in the urine.

Ketogenolysis

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

[1][2]

Cholesterol metabolism

Cholesterol

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-CoA → acetoacetyl-CoA → HMG-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 similar structure to mevalonate). They are also referred to as statins.

Clinical significance

Laboratory considerations

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

Laboratory parameter Elevated in Reduced in Prognostic correlations
Cholesterol HDL
  • Healthy lifestyle (physical activity)
  • Moderate alcohol consumption
LDL
  • Healthy lifestyle (calorie restriction, physical activity)
Triglyceride

Associated conditions

[1][2][3][4][5]