Week 2: Lipids and Metabolism

Question 1

What is the energy content per gram of carbohydrates, lipids and proteins?

Answer 1

Proteins: 4kcal/g

Lipids: 9kcal/g

Carbohydrates: 4kcal/g

Question 2

How is energy released from organic molecules?

Answer 2

Oxidation reactions (loss of electrons)

(For organic molecules, the more carbon/hydrogen and less oxygen they contain, the more scope there is for oxidising them)

Question 3

Why do lipids contain more energy?

Answer 3

They are oxygen poor and hydrogen and carbon rich

Question 4

What constitutes an ‘unsaturated’ fatty acid?

What is the significance of this?

Answer 4

Contains at least 1 double bond, meaning they contain less hydrogens. There is no rotation around the double bond, meaning they have fixed configuration at each double bond.

Double bond provides rigidity to the fatty acid- e.g. provides more rigidity to a cell membrane.

Question 5

What is meant by ‘trans’ and ‘cis’ configurations?

Answer 5

Trans configurations: carbon chain crosses the double bond

Cis configurations: carbon chain kinks back on itself

Question 6

What does the ‘omega’ nomenclature describe?

Answer 6

The position of the final double bond, counting from the hydrocarbon end.

Question 7

How are short chain fatty acids absorbed?

Answer 7

Simple diffusion across brush border of cell membrane and diffusion across basolateral membrane into blood.

Question 8

How are long chain fatty acids absorbed?

Answer 8

Fats (triglycerides) emulsified by bile salts and phospholipids into emulsion droplets.

Digested by pancreatic lipase to monoglycerides and fatty acids.

Held in micelles, combined with bile salts and phospholipids.

Micelles diffuse into an ‘unstirred layer’ next to the surface of epithelial cells.

Monoglycerides and fatty acids diffuse into cell membrane.

Inside the cell monoglycerides and fatty acids are reassembled into triglycerides and packaged into chylomicrons

Exported across the basolateral membrane and leave the intestinal villus via the lacteals of its lymph system and into the systemic circulation.

Question 9

Describe the structure of a lipoprotein

Answer 9

Lipids with a hydrophobic core containing triglycerides and cholesterol esters and a hydrophilic surface containing phopsholipids, free cholesterol and proteins.

Question 10

What releases fatty acids from chylomicrons and VLDLs into the tissues?

Answer 10

Lipoprotein lipase

Question 11

What are the main functions of chylomicrons?

Describe their composition

Answer 11

Deliver dietary (exogenous) triacylglycerols (TAG) to peripheral tissues.

High triacylglycerol, low cholesterol

Question 12

What are the main functions of VLDLs?

Describe their composition

Answer 12

Deliver endogenous triacylglycerols to peripheral tissues.

High triacylglycerols, low cholesterol (less TAG and more cholesterol however than chylomicrons)

Question 13

What is the main function of LDLs?

Describe their composition

Answer 13

Deliver cholesterol to peripheral tissues and liver

Low triacylglycerols, highest cholesterol (compared to chylomicrons, LDLs and HDLs)

Question 14

What is the function of HDLs?

Describe their composition

Answer 14

Deliver cholesterol from peripheral tissues to the liver for elimination.

Lowest tryacylglycerol content (compared with chylomicrons, LDLs and VLDLs) and high cholesterol

Question 15

Describe the exogenous lipid cycle

Answer 15

Dietary lipids absorbed in the GI tract and packaged into chylomicrons which enter the systemic circulation.

Broken down by lipoprotein lipase in the systemic circulation to remove lipid content.

Remnants of chylomicrons reach the liver via the systemic circulation.

Liver breaks down remnants of chylomicrons into cholesterol which is re-introduced to the GI tract via the biliary system.

Question 16

Describe the endogenous lipid cycle

Answer 16

Lipids and lipoproteins occurs largely in the liver

VLDLs released from liver into systemic circulation and broken down by lipoprotein lipase into IDLs→LDLs.

LDLs are transported back to the liver and also to extrahepatic tissues, where the majority of the triacylglycerols and triglycerides removed.

HDLs then transport cholesterol back to the liver.

Question 17

How is cholesterol synthesised?

Answer 17

de novo from acetyl-CoA in the liver (80%), intestine (10%) and skin (5%).

Question 18

What is the role of cholesterol?

Answer 18

Essential structural component of all cell membranes.

Precursor of steroid hormones (oestrogen, aldosterone, corticosterone, cortisol), bile acids and Vitamin D.

Question 19

Describe the composition of most cholesterol

Answer 19

Esterified form, with a fatty acid attached at carbon 3

Question 20

Describe the role of the liver in cholesterol homeostasis

Answer 20

De novo synthesis of cholesterol

HMG-CoA reductase regulation

LDL-receptor regulation

Conversion to bile acids/salts

Secretion of free cholesterol in bile

Secretion of HDLs and VLDLs

Question 21

Describe the process of cholesterol synthesis in hepatocytes

Answer 21

Acetyl-CoA → Acetoactyl-CoA → HMG-CoA

HMG-CoA broken down by HMG-CoA reductase into Mevalonate (irreversible, the rate-limiting step (slowest))

Mevalonate is transported into the hepatocyte to be converted into cholesterol:

• Mevalonate → C₅ → C₁₀ → C₁₅ → C₃₀ → Cholesterol

Question 22

How do Statins work to reduce cholesterol?

Answer 22

Competitively inhibit HMG-CoA reductase enzyme, therefore slowing down the synthesis of endogenous cholesterol.

A compensatory up-regulation of LDL receptors occurs in an attempt to capture more circulating LDL particles, resulting in decreased plasma LDL

Also lower hepatic VLDL production and increased HDL is sometimes observed

Question 23

What other beneficial cardiovascular effects do statins have?

What are the side effects and contraindications?

Answer 23

Other beneficial cardiovascular outcomes e.g. lowering plasma fibrinogen and enhancing fibrinolysis and anti-inflammatory effects

Adverse effects:

• GI (e.g. vomiting and diarrhoea)
• CNS (dizziness and blurred vision)
• Muscle (myositis, myalgia, myopathy)

Contraindications:

• Active liver disease
• Pregnancy
• Breast feeding

Question 24

Name a clinical example where statins would be indicated

Describe this condition

Answer 24

Familial hypercholesterolaemia

• Inherited disease (autosomal recessive) involving a mutation in the gene coding for LDL receptors
• This leads to excessively high levels of circulating LDL → high blood cholesterol
• Leads to increased risk of developing CV disease or stroke at an early age

Question 25

Name a side effect of statins affecting 1-5% of patients

Answer 25

Skeletal muscle toxicity:

• Myalgias
• Myopathy
• Rhabdomyolysis

Caused by common polymorphism is SLCOB1 gene causing the transporter responsible for the hepatic uptake of statins to work less effectively.