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Lipids and their metabolism

Last updated: February 15, 2021

Summarytoggle arrow icon

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.

Lipids

Lipid metabolism

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 are enzymes that catalyze the breakdown of fats into glycerol and fatty acids.

Overview
Enzyme Site Function
Lingual lipase
Gastric lipase
Pancreatic lipase

Lipid resorption

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

Lipoproteins [1]

Abnormalities in the structure or metabolism of lipoproteins increase the risk of atherosclerosis.

Overview of lipoproteins
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)
Chylomicron

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 increases risk of cardiac disease and stroke).

Apolipoproteins

Overview of apolipoproteins
Apolipoprotein Function Component of
Apo E
  • Mediates remnant uptake by the liver
  • All except for LDL
Apo A-I
Apo C-II
Apo B-48
Apo B-100
  • Mediates endocytosis of LDL by binding to LDL receptors on hepatic and extrahepatic tissues
  • Particles originating from the liver

Particles originating from the LIVer: LDL, IDL, VLDL.

A-I is Activates LCAT and is only present on Alpha-lipoproteins (only HDL)

Two Cs of apolipoprotein C-II (two) function: Catalyzes Cleavage.

Enzymes in lipid transport

Overview
Enzyme Site Function
Hepatic lipase
  • Released by the liver and activated in the bloodstream
Hormone-sensitive lipase
  • Intracellular [2]
Lecithin-cholesterol acyltransferase (LCAT)
  • Found on the surface of HDL (synthesized by the liver)
Lipoprotein lipase (LPL)
Cholesteryl ester transfer protein
  • Synthesized by the liver, secreted into the blood stream
PCSK9

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

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

Characteristics

  • 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 beta oxidation releases energy.

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: contains an odd number of carbon atoms
  • Essential fatty acid: cannot be synthesized by humans and need to be ingested (e.g., linoleic acid)
  • Triglyceride
    • A lipid composed of one glycerol molecule linked to three fatty acid molecules
    • 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.

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

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

Overview
Synthesis Breakdown
Main goal
  • Energy generation
Site
Tissue
Precursor
Transporter
Rate-determining enzyme
  • Carnitine palmitoyltransferase I
Required substances
Upregulation
Downregulation
End products

The Sytrate (citrate) shuttle is essential for fatty acid Synthesis.

Fatty acids travel to their site of degradation by CARnitine.

Fatty acid synthesis

Overview

Procedure

  1. Acetyl-CoA groups (from glycolysis) are transported from the mitochondria to the cytoplasm through the citrate shuttle.
  2. In the cytoplasm, ATP citrate lyase hydrolyzes citrate back into acetyl-CoA and oxaloacetate.
  3. Acetyl CoA carboxylase activates acetyl-CoA and converts it into malonyl-CoA.

Regulation

Fatty acid synthesis is regularted via phosphorylation of acetyl-CoA carboxylase.

Fatty acid degradation [4]

Overview

Procedure

  1. Fatty acid transport (into the mitochondria)
  2. 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.

Regulation

Clinical significance

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 bodies

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).

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.

Ketogenolysis

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

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 cholesterol synthesis: acetyl-CoA acetoacetyl-CoA HMG-CoA mevalonate 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.

Laboratory considerations

Overview
Laboratory parameter Elevated in [5][6] Reduced in Prognostic correlations
Cholesterol HDL
LDL
  • Healthy lifestyle (calorie restriction, physical activity)
Triglyceride

Associated conditions

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  2. Feingold KR et al. Introduction to Lipids and Lipoproteins. Endotext [Internet]. 2000 .
  3. Kraemer FB, Shen W-J. Hormone-sensitive lipase. J Lipid Res. 2002; 43 (10): p.1585-1594. doi: 10.1194/jlr.r200009-jlr200 . | Open in Read by QxMD
  4. Persson E. Lipoprotein lipase, hepatic lipase and plasma lipolytic activity. Effects of heparin and a low molecular weight heparin fragment (Fragmin).. Acta Med Scand Suppl. 1988; 724 : p.1-56.
  5. The effect of endocrine disorders on lipids and lipoproteins.
  6. Attman P-O, Alaupovic P. Pathogenesis of hyperlipidemia in the nephrotic syndrome. Am J Nephrol. 1990; 10 (1): p.69-75. doi: 10.1159/000168197 . | Open in Read by QxMD
  7. De Oliveira e Silva ER, Foster D, McGee Harper M, et al. Alcohol Consumption Raises HDL Cholesterol Levels by Increasing the Transport Rate of Apolipoproteins A-I and A-II. Circulation. 2000; 102 (19): p.2347-2352. doi: 10.1161/01.cir.102.19.2347 . | Open in Read by QxMD
  8. Arnaldi G, Scandali VM, Trementino L, Cardinaletti M, Appolloni G, Boscaro M. Pathophysiology of dyslipidemia in Cushing’s syndrome. Neuroendocrinology. 2010; 92 (1): p.86-90. doi: 10.1159/000314213 . | Open in Read by QxMD