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., ). Lifestyle changes also play an important role.
- Definition: organic molecules that are soluble in nonpolar solvents but do not dissolve in polar solvents (e.g., water)
- Substrates for:
- Digestion and absorption: Ingested fats (lipids) are cleaved by enzymes (e.g., pancreatic lipase) and absorbed in the small intestine.
- Absorbed lipids are transported in chylomicrons via the lymphatic system into the bloodstream, where they reach the liver, peripheral tissues (which have LDL receptors) and adipose tissue (storage).
- Lipids circulating in the bloodstream are transported in hydrophilic apolipoproteins) (contain because the hydrophobic lipids are insoluble in plasma.
Digestion and absorption of lipids
Dietary lipids: TAGs, phospholipids, and cholesterol esters
- Not readily absorbed by enterocytes due to:
- Hydrophobic properties
- Large molecular size
- First broken down by lipases; in the mouth, stomach, and intestinal lumen and packaged into micelles
- 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
- Formation of chylomicrons
- Secretion of chylomicrons into lymph → thoracic duct → bloodstream
Enzymes in lipid digestion
Lipases are enzymes that catalyze the breakdown of fats into glycerol and fatty acids.
|Lingual lipase|| |
- Consist of a hydrophobic core and a hydrophilic shell
- Core and shell are composed of different lipids, depending on the specific lipoprotein
- Main function:
|Overview of lipoproteins|
|Lipoproteins (in order of descending density)||Composition||Function||Apolipoproteins|
|High-density lipoprotein (HDL)|| || |
|Low-density lipoprotein (LDL)|
|Intermediate-density lipoprotein (IDL)|
|Very low-density lipoprotein (VLDL)|
|Overview of apolipoproteins|
|Apo E|| || |
|Apo A-I|| |
|Apo C-II|| |
Particles originating from the LIVer: LDL, IDL, VLDL.
Two Cs of apolipoprotein C-II (two) function: Catalyzes Cleavage.
Enzymes in lipid transport
|Hepatic lipase|| |
|Hormone-sensitive lipase|| |
|Lecithin-cholesterol acyltransferase (LCAT)|
|Lipoprotein lipase (LPL)|
|Cholesteryl ester transfer protein|| |
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.
- Carboxylic acid with an unbranched chain of carbon atoms differing in length (from 1–24 carbon atoms)
- 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 via releases energy.
- 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: contains an odd number of carbon atoms
- Essential fatty acid: cannot be synthesized by humans and need to be ingested (e.g., linoleic acid)
An increased concentration of triglycerides in the blood is called hypertriglyceridemia. It can be hereditary (lack of lipoprotein lipase), acquired (obesity, chronic alcohol use), 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
|Main goal|| || |
|Rate-determining enzyme|| |
Fatty acids travel to their site of degradation by CARnitine.
Fatty acid synthesis
- 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.
- Insulin, ↑ glucose, ATP, and citrate activate acetyl-CoA carboxylase (these substances indicate an energy excess).
Fatty acid degradation 
- Definition: : the process by which fatty acids are catabolized by the pathway of beta oxidation
- Aims: energy generation
- Metabolism site: mitochondria; of several tissues, including liver, muscle, and adipose tissue; erythrocytes and the brain are not able to utilize fatty acid
- Primary end-products: acetyl-CoA, ketone bodies, NADH, and FADH2
- Rate-limiting enzyme: carnitine palmitoyltransferase 1 (carnitine shuttle)
Fatty acid transport (into the 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 (also known as carnitine acyltransferase I; ) transfers the fatty acyl group to carnitine on the outer mitochondrial membrane → forming a fatty acylcarnitine
- Fatty acylcarnitine is then shuttled into the mitochondria.
- SCFA and MCFA: diffuse freely into mitochondria
- LCFA: enter via carnitine-dependent shuttle
Beta oxidation (in mitochondrial matrix): a catabolic process in which a fatty acid chain is cleaved (oxidized) at the beta carbon (every second 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
- Beta 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.
- Acyl-CoA dehydrogenase catalyzes the initial step of beta oxidation: fatty acyl-CoA + NAD+ + FAD+ → acetyl-CoA + NADH + FADH2
- Upregulation: glucagon indirectly upregulates beta oxidation by inhibiting acetyl CoA-carboxylase and decreasing the malonyl-CoA concentration.
- Primary carnitine deficiency
- Medium-chain acyl-CoA dehydrogenase deficiency
- Jamaican vomiting sickness
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)
- Beta oxidation occurs in both mitochondria and peroxisomes.
Degradation of fatty acids with an odd number of carbon atoms (propionic acid pathway)
- 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.
- Triglyceride synthesis occurs mainly in the liver and adipose tissue.
- Both glycerol and fatty acids have to be activated for triglyceride synthesis.
- Rate-determining enzyme: glycerol-3-phosphate acyltransferase (links glycerol-3-phosphate with two acyl-CoA molecules)
- Lipases split triglycerides into glycerol and three fatty acids.
- Water-soluble molecules that are produced by the liver and used by peripheral tissues (e.g., heart, brain, skeletal muscle) as an energy source when glucose is not readily available (e.g., during prolonged starvation, in diabetic ketoacidosis, or chronic heavy drinking)
- Three ketone bodies: acetoacetate, β-hydroxybutyrate, and acetone (acetone is a breakdown product of acetoacetate and β-hydroxybutyrate; has a fruity smell)
- Metabolism site: mitochondria of hepatocytes
- Starting substance: acetyl-CoA
- Two molecules of acetyl-CoA, catalyzed by thiolase, condense to form acetoacetyl-CoA.
- Acetoacetyl-CoA combines with another molecule of acetyl-CoA, catalyzed by rate-determining enzyme HMG-CoA synthase, to produce HMG-CoA.
- HMG-CoA lyase subsequently breaks down HMG-CoA into ketone bodies; acetoacetate and acetyl-CoA
- Acetoacetate can then be reduced to β-hydroxybutyrate or undergo spontaneous decarboxylation to form acetone (which gives the breath a fruity smell).
- In prolonged fasting and diabetic ketoacidosis
- In alcoholism
Two molecules of acetyl-CoA → acetoacetyl-CoA → HMG-CoA → acetoacetate → β-hydroxybutyrate. Acetone is formed by spontaneous decarboxylation of acetoacetate. The body has no use for acetone, which is excreted primarily via the lungs (gives breath a fruity odor). A small fraction is also exerted in the urine.
- Metabolism site: Mitochondria of extrahepatic tissues (cardiac and skeletal muscle and the renal cortex) can metabolize acetoacetate and β-hydroxybutyrate, producing acetyl-CoA, which means that RBCs are unable to use ketone bodies for energy (due to lack of mitochondria).
- β-hydroxybutyrate → acetoacetate, catalyzed by β-hydroxybutyrate dehydrogenase
- Acetoacetate plus succinyl-CoA → acetoacetyl-CoA plus succinate, catalyzed by thiophorase (succinyl-CoA:3-ketoacid CoA transferase)
- Acetoacetyl-CoA → two molecules of acetyl-CoA, catalyzed by thiolase
- Finally, acetyl-CoA can be metabolized in 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, estrogen
- Inhibited by: glucagon, cholesterol (feedback inhibition via SREBP)
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 structure similar to that of mevalonate). They are also referred to as statins.
- 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 “ ” for optimal and pathological levels.
|Laboratory parameter||Elevated in ||Reduced in||Prognostic correlations|
|Cholesterol||HDL|| || |
|LDL|| || |
- (e.g., )