53. Pathobiochemistry of LDL-metabolism. Primary and secondary hyperlipoproteinemia

Introduction

Before we begin this topic there are some basic concept about lipoproteins and lipids that you must understand.

Lipoproteins are comprised of a protein-component and a lipid component. The protein-component of the lipoproteins are called apolipoproteins, of which there are many different types. The lipid component is comprised of triglycerides, phospholipids and/or cholesterol. The function of lipoproteins is to transport hydrophobic lipids in the circulation.

There are four (or five, if you consider IDL) types of lipoproteins. They differ in their lipid/protein ratio and apolipoprotein type. The more lipid a lipoprotein has compared to protein, the lower the density. The table below compares the different types.

Chylomicrons VLDL LDL HDL
Protein content (%) 2 10 25 55
Triglyceride content (%) 86 52 10 4
Free cholesterol content (%) 2 7 8 1
Cholesteryl ester content (%) 3 13 37 16
Phospholipid content (%) 7 18 20 24
Density (g/mL) 0.95 0.96 – 1.006 1.019 – 1.063 1.063 – 1.21
Site of origin Intestine Liver Breakdown of VLDL in circulation Intestine, liver, breakdown of VLDL in circulation
Particle size (nm) 500 43 22 8
Apolipoprotein content B-48, (E, C-II) B-100, (E, C-II) B-100 A-I, (E)

Most of these numbers probably aren’t important to know, but it illustrates the composition of the different lipoproteins. See also the relevant biochemistry topic for more details.

Lipoproteins are metabolized on three different pathways:

Exogenous pathway: Lipids absorbed from foods are transported in chylomicrons via lymphatic vessels from the intestine to the liver. The enzyme lipoprotein lipase (LPL) cleaves some non-esterified fatty acids (“free fatty acids”) from the triglycerides in the chylomicrons to supply tissues that need them. As the chylomicron “sheds” some of its components in the circulation will the composition change, so that it contains more cholesteryl ester and less triglycerides. At this point is the lipoprotein known as a chylomicron remnant. This remnant binds to the remnant receptor on hepatocytes, which causes it to be endocytosed into the hepatocyte.

Endogenous pathway: Lipids synthesized in the liver are released into the circulation as VLDL particles. Like for chylomicrons will LPL “shed” non-esterified fatty acids. VLDL will eventually shed enough components that it will become an LDL instead. LDL binds to LDL-receptors on peripheral tissues and the liver, causing it to be endocytosed and metabolized.

Inside the peripheral cells will LDL be broken down into its components. Free cholesterol is esterified by the enzyme ACAT into cholesteryl ester, the intracellular storage form of cholesterol. Uptake of LDL also down-regulates the LDL-receptor, as the cell doesn’t need more cholesterol. HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, will be inhibited to prevent too much cholesterol from being synthesized.

Reverse cholesterol transport: Cholesterol (and not so much lipid) is transported from peripheral cells back to the liver as HDL particles. HDL is secreted from cells in a “nascent” (“immature”) form, which is later “matured” in the circulation. HDL then binds to scavenger receptors on hepatocytes, causing them to be endocytosed.

It should be mentioned that the liver is the only organ that can excrete cholesterol. It can do this in both free cholesterol form or by converting cholesterol into bile acids. Both forms are secreted into the bile. Some of the excreted cholesterol and bile acids are reabsorbed in the intestine as part of the enterohepatic circulation.

Dyslipidaemias

Disorders of lipoprotein metabolism are referred to as dyslipidaemias. They’re generally characterised by increased plasma levels of cholesterol, triglycerides or both, often also by decreased levels of HDL. Most people with these conditions have both a genetic predisposition and environmental contribution, like bad diet or lifestyle.

Patients with these conditions have increased risk for cardiovascular disease, and, if there is hypertriglyceridaemia, increased risk for acute pancreatitis as well.

We know of some primary hyperlipoproteinaemias, conditions that are caused by single gene mutations. Secondary hyperlipoproteinaemias are more common and are associated with metabolic syndrome.

Dyslipidaemias are classified according to the Frederickson classification:

Frederickson phenotype Condition Relative frequency Mode of inheritance Pathogenesis Increased lipoproteins
I Hyperchylomicronaemia Rare Autosomal recessive Deficiency of LPL Chylomicrons
IIa Familial hypercholesterolaemia 10% Autosomal dominant Defective LDL receptor or defective ApoB-100 LDL
IIb Combined hyperlipidaemia 1 – 15% Autosomal dominant LDL and VLDL
III Remnant hyperlipidaemia 5% Autosomal recessive Defective ApoE VLDL remnants and chylomicron remnants
IV Hypertriglyceridaemia 70% Autosomal dominant Hepatic overproduction of VLDL VLDL
V Mixed hyperlipidaemia Rare Unknown Various VLDL and chylomicrons
Primary hyperlipidaemias

Primary hyperlipidaemias are rare causes of dyslipidaemia. Depending on the specific type the incidence varies from less than 1 per 1,000,000 to 1 per 500. The most important types are:

Familial hypercholesterolaemia, the type IIa dyslipidaemia, occurs in 1 per 500 persons (in heterozygote form). It occurs due to a defect in the LDL receptor gene, which prevents LDL from being cleared from the circulation, causing its level to increase in the blood. There is no hypertriglyceridaemia. Patients can be either heterozygous, where they have some LDL receptor, or homozygous, where there are no LDL receptors at all.

The diagnosis is based on substantial hypercholesterolaemia without a secondary cause, and a family history of hypercholesterolaemia and/or premature coronary artery disease.

Homozygotes and heterozygotes show similar symptoms; xanthomas develop on the skin and coronary artery disease is more prevalent. The difference between these two is that homozygotes develop these symptoms already in their teenage years, while heterozygotes don’t develop symptoms until around 30 years.

Familial combined hyperlipidaemia causes IIb or type V dyslipidaemia. Its inheritance is polygenic.

Secondary hyperlipidaemias

Many frequent conditions nowadays cause secondary or acquired hyperlipidaemias:

  • Obesity
  • Alcohol abuse
  • Liver disorders
  • Nephrotic syndrome
  • Chronic inflammation
  • Hypothyroidism
  • Old age
  • Glucocorticoid excess
  • Certain drugs
    • Beta blockers
    • Diuretics
    • Oral contraceptives

Obesity and/or metabolic syndrome and/or 2DM cause type I, IV or V hyperlipidaemia, involving increased levels of VLDL and decreased levels of HDL. This causes the levels of triglycerides and cholesterol to increase in blood. The production of VLDL is increased in these conditions as a large amount of non-esterified fatty acids are transported from the adipose tissue to the liver, where they are converted into triglycerides. Insulin resistance causes decreased activity of lipoprotein lipase, which would break down VLDL.

Alcohol abuse causes type IV or V hyperlipidaemia, involving increased levels of VLDL. Alcohol inhibits fatty acid oxidation and instead causes fatty acids to accumulate and be packaged into VLDL.

Liver disorders cause type III hyperlipidaemia, involving increased levels of lipoprotein remnants. These disorders impair the liver’s ability to clear lipoproteins.

Nephrotic syndrome causes increased VLDL and LDL. As proteins like albumin are lost in the urine will the liver ramp up the protein synthesis, however the organ cannot “uncouple” the albumin synthesis from the apolipoprotein synthesis, causing lipoprotein synthesis to increase as well.

Chronic inflammation causes hyperlipidaemia by not important mechanisms.

Hypothyroidism causes elevated LDL, as the decreased level of thyroid activity decreases the number of LDL receptors.

Old age: Hyperlipidaemias are more frequent in elderly. Oestrogen protects women from this condition until they reach menopause.

Glucocorticoid excess, like in Cushing’s syndrome, is associated with increased VLDL synthesis.

Elevated LDL Elevated VLDL Reduced HDL
Nephrotic syndrome Nephrotic syndrome Smoking
Hypothyroidism DM type 2 DM type 2
Cholestasis Obesity Obesity
Liver disorders
Alcohol
Glucocorticoid excess

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