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., ). Lifestyle changes also play an important role.
- Definition: hydrophobic organic molecules
- 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 (contain hydrophilic apolipoproteins) because the hydrophobic lipids are insoluble in plasma
Dietary lipids: TAGs, phospholipids, and cholesterol esters
- Not readily absorbed by enterocytes due to:
- Hydrophobic properties
- Large molecular size
- They are first broken down by lipases in the mouth, stomach, and intestinal lumen and packaged into micelles
- A spherical-shaped aggregation of surfactant molecules in a colloid
- Composed of an outer layer of hydrophilic (polar) heads and an inner hydrophobic (nonpolar) core
- Encloses lipids and , acting like a “package”
- Are readily absorbed by the membranes of enterocytes → deliver internal contents to the cell
- Not readily absorbed by enterocytes due to:
- Bile release: Once a lipid enters the intestinal lumen, bile is secreted into the lumen to emulsify the lipid contents.
- Pancreas secretion: The pancreas secretes pancreatic lipase, colipase, and cholesterol esterase, which hydrolyze the lipid into cholesterol, fatty acids, and 2-monoglyceride molecules.
- Absorption of short-chain and medium-chain fatty acids: pass the enterocytes → released to the hepatic portal vein → liver → enter the general circulation and bind albumin
Absorption of long-chain fatty acids: absorbed by enterocytes and activated → re-esterified to triglycerides and cholesterol esters
- Activation: takes place at the cytosolic side of the outer mitochondrial membrane
- Esterification: takes place in ER
Formation of chylomicrons: takes place in Golgi apparatus
- Apolipoproteins B-48 and phospholipids are added
- Chylomicrons are secreted into lymph → thoracic duct → bloodstream
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
|Lingual lipase|| || |
|Gastric lipase|| |
- Structure: consists of a hydrophobic core and a hydrophilic shell of varying lipids
- Main function: transport of hydrophobic lipids in blood
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)|| |
|Low-density lipoprotein (LDL)|
|Intermediate-density lipoprotein (IDL)|
|Very-low-density lipoprotein (VLDL)|
The TG content of lipoproteins increases in the order HDL < LDL < IDL < VLDL < chylomicrons!
|ApoE||Mediates remnant uptake by the liver|| |
|ApoA-I||Activates LCAT|| |
|ApoC-II||Cofactor for|| |
|ApoB-48||Mediates the secretion of chylomicron particles that originate from the intestine into the lymphatics|| |
|ApoB-100||Mediates endocytosis of LDL by binding to on hepatic and extrahepatic tissues|| |
Enzymes in lipid transport
|Hepatic lipase|| || |
|Hormone-sensitive lipase|| || |
|Lecithin-cholesterol acyltransferase (LCAT)|| |
: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.
A carboxylic acid with an unbranched chain of carbon atoms differing in length (from 1–24 carbon atoms).
- 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).
- Degradation by releases energy.
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
|Breakdown of fatty acids||Synthesis of fatty acids|
|Cofactors|| || |
- Definition: The creation of fatty acids from acetyl-CoA and NADPH through the action of fatty acid synthases.
- Metabolism site: cytoplasm of liver (mainly), adipose tissue, and lactating mammary glands
- Primary end-product: palmitic acid (palmitate), a 16-carbon fatty acid (only fatty acid that humans can synthesize de novo)
- Rate-limiting enzyme: acetyl CoA carboxylase
- Acetyl-CoA groups (from glycolysis) are transported from the mitochondria to the cytoplasm through the citrate shuttle
- In the cytoplasm, ATP citrate lyase hydrolyzes citrate back into acetyl-CoA and oxaloacetate
- Acetyl CoA carboxylase activates acetyl-CoA and converts it into malonyl-CoA
Regulation of fatty acid synthesis: via phosphorylation (= inhibition) of acetyl-CoA carboxylase
- Insulin, ↑ glucose, ATP, and citrate activate acetyl-CoA carboxylase (these substances indicate an energy excess)
- Definition: The process in which fatty acids are catabolized by the pathway of β-oxidation.
- Aims: energy generation
Metabolism site: mitochondria of several tissues including liver, muscle, and adipose tissue
Fatty acid transport into the mitochondria depends on its length.
- SCFA and MCFA: diffuse freely into mitochondria
LCFA: enter via carnitine-dependent shuttle
- Fatty acyl-CoA synthetase on the outer mitochondrial membrane activates the fatty acid by attaching CoA → forming a fatty acyl group
- Carnitine palmitoyltransferase 1 transfers the fatty acyl group to carnitine on the outer mitochondrial membrane → forming a fatty acylcarnitine
- Fatty acylcarnitine is then shuttled into the mitochondria
- Fatty acid transport into the mitochondria depends on its length.
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.
β-oxidation (in mitochondrial matrix): A catabolic process in which a fatty acid chain is cleaved (oxidized) at the β carbon (every 2nd carbon) by dehydrogenase enzymes in several cycles
- Breaks down acetyl-CoA and propionyl CoA (see ) and even-chain fatty acids into acetyl-CoA only. into
- β-oxidation of VLCFA occurs in peroxisomes (see ).
- For every cleaved acetyl-CoA, one molecule of FAD, H2O, and NAD+ each are required.
- Acetyl-CoA enters the citric cycle.
- Rate-determining enzyme: acyl-CoA dehydrogenase catalyzes the initial step of β-oxidation: fatty acyl-CoA + NAD+ + FAD+ → acetyl-CoA + NADH +FADH2
Jamaican vomiting sickness:
- Acyl-CoA dehydrogenase is inhibited by the toxin hypoglycin,; contained in unripe ackee, the fruit of the ackee tree found in West Africa and Jamaica.
- Intoxication results in severe vomiting, coma, and possibly death.
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)
- β-oxidation occurs in both mitochondria and peroxisomes
Degradation of fatty acids with an odd number of carbon atoms (propionic acid pathway)
- In the final cycle of fatty acid oxidation:
In the mitochondria, propionyl-CoA is converted into succinyl-CoA (a citric acid cycle intermediate) in a two-step pathway
- Propionyl-CoA carboxylase converts propionyl-CoA into methylmalonyl-CoA
- Methylmalonyl-CoA mutase converts methylmalonyl-CoA into succinyl-CoA
Regulation of fatty acid oxidation
- Fatty acid oxidation is mainly regulated by malonyl-CoA; , which inhibits carnitine palmitoyltransferase 1 (the rate-limiting step in β-oxidation).
- Insulin indirectly inhibits β-oxidation by activating the fatty acid synthesis pathway and thus increasing ; the malonyl-CoA level in the cytoplasm.
- Glucagon does the opposite
Synthesized TGs are either stored in adipose tissue or transported to the muscle for energy utilization.
- TG synthesis occurs mainly in the liver and adipose tissue.
- Both glycerol and fatty acids have to be activated for it:
- Rate-determining enzyme: glycerol-3-phosphate acyltransferase (links glycerol-3-phosphate with two acyl-CoA molecules)
- Lipases split TGs into glycerol and three fatty acids.
- 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)
- Metabolism site: mitochondria of hepatocytes
- Starting substance: acetyl-CoA
- In prolonged fasting and diabetic ketoacidosis:
- In alcoholism:
- Sites: Cardiac and skeletal muscles and the renal cortex can metabolize acetoacetate and 3-hydroxybutyrate, producing acetyl-CoA.
Acetyl-CoA → acetoacetyl-CoA → HMG-CoA → acetoacetate → β-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.
- Metabolism site: mitochondria of extrahepatic tissues
- Process: : (β-hydroxybutyrate → acetoacetate →) acetoacetate is activated by the succinyl-CoA acetoacetyl-CoA transferase (thiophorase) enzyme → acetoacetyl-CoA is broken down into two acetyl-CoA → acetyl-CoA enters the TCA cycle
- Clinical relevance
- Definition: A polycyclic steroid alcohol absorbed through food but also synthesized in the body.
- Resorption: Cholesterol combines with bile salts to form absorbable bile salt micelles.
Transport: Since cholesterol is apolar, it must be rendered into a water-soluble form for its transport within the body.
- Transport in bile:
- Transport in blood via lipoproteins:
- Excretion: via bile as a whole molecule or modified in the form of bile acids
- Starting substance: acetyl-CoA
- Metabolism site: cytoplasm
- Rate-determining enzyme: HMG-CoA reductase in the membrane of smooth ER (catalyzes the reaction: HMG-CoA → mevalonate; requires two NADPH)
Regulation: of HMG-CoA reductase
- Stimulated by: insulin, thyroxine
- Inhibited by: glucagon, cholesterol (feedback inhibition)
Sterol regulatory element-binding proteins (SREBPs): transcription factors that can bind to intracellular cholesterol via the SCAP protein.
- Cholesterol deficiency: SREBP does not bind intracellular cholesterol but migrates to the nucleus and binds to the sterol regulatory element (SRE) of the LDL receptor gene and to enzymes of cholesterol synthesis → increased transcription of LDL receptors and enzymes → increased uptake and synthesis of cholesterol
- Cholesterol excess: SCAP-SREBP complex binds to cholesterol → no transportation to the nucleus
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.
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 for associated levels.
|Laboratory parameter||Elevated in||Reduced in||Prognostic correlations|
|Cholesterol||HDL|| || |
|LDL|| || |
- (e.g., )