Lipids and lipid disorders

Lipids

• Composed mostly of carbon-hydrogen (C-H) bonds
• Serve as energy storage for excess calories
• Function as precursors for various biomolecules:
  • Steroid hormones
  • Prostaglandins
  • Leukotrienes
  • Lipoxins

Fatty Acids

• Chains of carbon-hydrogen bonds terminating with a carboxyl (-COOH) group
• In plasma, mostly non-covalently bound to albumin

Classification of Fatty Acids by Length

• Fatty acids with 4 to 6 carbon atoms are classified as short-chain fatty acids
• Medium-chain fatty acids have 8 to 12 carbon atoms
• Long-chain fatty acids have more than 12 carbon atoms

Classification of Fatty Acids by Bonding

• Unesterified fatty acids are bound to albumin
• Esterified fatty acids are constituents of triglycerides or phospholipids

Classification of Fatty Acids

• Classified according to the number of C=C double bonds present
• Three categories: Saturated, Monounsaturated, and Polyunsaturated

Saturated Fatty Acids

• Have no double bonds

Monounsaturated Fatty Acids

• Contain one double bond

Polyunsaturated Fatty Acids

• Contain 2 or more double bonds

Triglycerides

• Composed of 3 fatty acids attached to 1 molecule of glycerol
• Held together by ester bonds
• No charged groups, making them water insoluble
• Classified as neutral lipids

Phospholipids

• Consist of 2 fatty acids attached to 1 molecule of glycerol
• 3rd position contains phospholipid head groups
• Amphipathic, meaning they have:
  • Hydrophobic (water-repelling) tails
  • Hydrophilic (water-attracting) heads

Cholesterol

• Unsaturated steroid alcohol
• Composed of 4 rings
• Has a single C-H side chain tail
• Also an amphipathic lipid

Classification of Cholesterol

• Cholesterol exists in two forms: unesterified (free cholesterol) and esterified (cholesteryl ester)
• Cholesteryl ester is a neutral lipid

Lipoprotein Characteristics

• Lipoproteins are typically spherical in shape
• Lipoproteins range in size from 10-1200 nm
• Lipoproteins are composed of two main components: lipids and proteins

Lipoproteins: Chylomicrons

• Chylomicrons are the largest lipoproteins and have the lowest density.
• They are formed in the intestines and transport triglycerides after a meal, giving serum a turbid appearance.
• Due to their low density, chylomicrons will float to the top and form a creamy layer when plasma is stored overnight.
• Composition of chylomicrons:
  • 86% triglyceride
  • 5% cholesterol
  • 7% phospholipid
  • 2% apolipoprotein
• Apoproteins present on the surface of chylomicrons:
  • Mainly apoprotein B-48
  • Lesser amounts of apoproteins A-I, C-I, C-II, and C-III

VLDL Composition and Function

• VLDL (Very Low-Density Lipoprotein) carries endogenous triglycerides synthesized in the liver.
• VLDL molecules consist of:
  • 55% triglycerides
  • 19% cholesterol
  • 18% phospholipid
  • 8% apolipoprotein
• VLDLs have the following apolipoproteins on their surface:
  • Apolipoprotein B-100 (mainly)
  • Apolipoprotein C-I
  • Apolipoprotein C-II
  • Apolipoprotein C-III
  • Apolipoprotein E
• Normal lipid metabolism: VLDLs are secreted into the blood by the liver for metabolism in peripheral tissues.

IDL (Intermediate-Density Lipoprotein)

• A transitional form of lipoprotein formed from VLDL (Very-Low-Density Lipoprotein)
• Modified in the liver to form LDL (Low-Density Lipoprotein)
• Carries endogenous triglycerides and cholesterol esters
• Composed of:
  • 23% triglycerides
  • 38% cholesterol
  • 19% phospholipid
  • 19% apolipoprotein
• Surface apolipoproteins include:
  • Mainly B-100
  • Some E

Low-Density Lipoprotein (LDL)

• LDL is the body's major cholesterol carrier, transporting a large amount of endogenous cholesterol.
• LDL is commonly known as "bad cholesterol" due to its association with increased risk for atherosclerosis when levels are elevated.
• LDLs are composed of:
  • 50% cholesterol
  • 22% phospholipids
  • 6% triglycerides
  • 22% protein
• LDLs have apoprotein B-100 on their surface.

High-Density Lipoprotein (HDL)

• Also known as "good cholesterol"
• Synthesized in the intestine and liver cells
• HDL molecules are recycled from chylomicron and VLDL molecules
• Composed of 50% protein, 28% phospholipids, 19% cholesterol, and 3% triglycerides
• Has apoproteins A-I, mainly, and A-II on its surface

Lipoprotein (a) [Lp(a)]

• Primarily composed of cholesterol esters, phospholipids, and apolipoprotein (a) and B-100
• Elevated levels of Lp(a) are associated with increased risk for: • Coronary heart disease • Myocardial infarction • Cerebrovascular disease

Lipoprotein Physiology & Metabolism

• Lipoprotein metabolism involves the transport of lipids in the bloodstream, playing a crucial role in maintaining cellular lipid homeostasis.

Lipid Absorption

• Lipid absorption occurs in the small intestine, where dietary fats are broken down into fatty acids and cholesterol.
• Fatty acids are taken up by enterocytes, re-esterified into triglycerides, and packaged into chylomicrons.
• Chylomicrons are then transported to the lymphatic system, ultimately entering the bloodstream.

Endogenous Pathway

• The endogenous pathway involves the synthesis of lipids in the liver, which are then transported to peripheral tissues.
• The liver produces very-low-density lipoproteins (VLDLs), which are rich in triglycerides.
• VLDLs are converted into low-density lipoproteins (LDLs) in the bloodstream, which are then taken up by peripheral tissues.

Exogenous Pathway

• The exogenous pathway involves the uptake of dietary lipids from the small intestine, which are then transported to the liver.
• Chylomicrons are converted into chylomicron remnants in the bloodstream, which are then taken up by the liver.

Reverse Cholesterol Transport

• Reverse cholesterol transport is a process by which excess cholesterol from peripheral tissues is transported back to the liver for excretion.
• High-density lipoproteins (HDLs) play a crucial role in this process, taking up excess cholesterol from peripheral tissues and transporting it to the liver.
• The liver then excretes the cholesterol into the bile, which is eventually eliminated from the body.

Lipid Metabolism

• Lipid metabolism involves releasing fatty acids to cells for energy, then recycling glycerol into triglycerides.
• Enzymes involved in breaking down triglycerides include lipase, lipoprotein lipase, epinephrine, and cortisol.

Clinical Significance of Lipids

• Abnormal lipid metabolism can be due to genetic defects or can be acquired.
• Abnormal lipid metabolism is associated with an increased risk of coronary heart disease and other disorders.

ATP III Classification

• The National Cholesterol Education Program (NCEP) established the Adult Treatment Panel III Classification (ATP III).
• ATP III sets cutoff values for cholesterol and triglyceride levels based on a 9- to 12-hour fast.

Blood Disorders

• Hypoproteinemia: a condition characterized by very low protein levels in the blood
• Hyperlipoproteinemia: high levels of lipoproteins in the blood

Cholesterol-related Disorders

• Hypercholesterolemia: high cholesterol, characterized by increased levels of cholesterol in the blood
• Hypertriglyceridemia: high amounts of triglycerides in the blood

Combined Lipid Disorder

• Combined hyperlipidemia: elevated levels of fats in the blood, including low-density lipoprotein (LDL) cholesterol ("bad" cholesterol) and triglycerides

Dyslipidemia

• Abnormally high levels of lipids (fats) in the blood
• Typically asymptomatic, but can lead to cardiovascular diseases
• Can cause coronary artery disease, a common heart condition

Coronary Artery Disease

• Occurs when major blood vessels (coronary arteries) struggle to supply enough blood, oxygen, and nutrients to the heart muscle
• A common heart condition that can lead to cardiovascular disease

Peripheral Vascular Disease (PVD)

• A slow and progressive disorder of the blood vessels
• Caused by narrowing, blockage, or spasms in a blood vessel
• A type of cardiovascular disease

Cardiovascular Disease

• A class of diseases involving the heart or blood vessels
• May include conditions such as coronary artery disease, peripheral vascular disease, and arteriosclerosis

Arteriosclerosis

• Characterized by deposition of esterified cholesterol in the artery wall
• A type of cardiovascular disease that can lead to narrowing or blockage of blood vessels

Hypercholesterolemia and Familial Hypercholesterolemia

• Elevated cholesterol levels are associated with increased LDL (Low-Density Lipoprotein) due to genetic abnormalities.
• Despite normal intracellular cholesterol levels, individuals with Familial Hypercholesterolemia have a deficiency in active LDL receptors.

Hypertriglyceridemia

• Characterized by an imbalance between the synthesis and clearance of VLDL (Very-Low-Density Lipoprotein) in the circulation.
• Can be caused by familial or hormonal abnormalities.

Combined Hyperlipoproteinemia

• Characterized by elevated levels of serum total cholesterol and triglycerides
• Caused in part by excessive hepatic synthesis of apo B
• Leads to increased VLDL secretion
• Results in increased LDL production from VLDL
• Can be associated with Familial Dysbetalipoproteinemia

Familial Dysbetalipoproteinemia

• Caused by accumulation of cholesterol-rich VLDL and chylomicrons remnants

Lp(a) and its Impact on Plaque Formation

• Lp(a) is a variant of LDL (low-density lipoprotein) with an additional apolipoprotein (a)
• Apolipoprotein (a) has a high degree of homology with plasminogen, a coagulation factor
• Due to this homology, apo(a) competes with plasminogen for binding sites on fibrin
• This competition leads to increased plaque formation

Hypoalphalipoproteinemia

• Characterized by an isolated decrease in circulating high-density lipoprotein (HDL) cholesterol
• Defined as HDL levels less than 40 mg/dL or 1.0 mmol/L
• Not associated with hypertriglyceridemia
• Can result from mutations in genes involved in HDL metabolism
• Specifically, mutations in LCAT, apo A-I, and ABCA1 transporter genes can cause hypoalphalipoproteinemia

Tangier's Disease

• An extreme form of hypoalphalipoproteinemia
• Caused by mutations in the ABCA1 transporter gene