Cholesterol and complex lipid biochemistry

Question 1

Sources of cholesterol

Answer 1

Diet: consume ~300-600 mg/day - half of which is absorbed

De Novo synthesis ~ 1 gm (1000mg)/d - mostly in the liver (highly regulated process)

Question 2

Possible fates of cholesterol

Answer 2

Steroid hormones
Bile acids - secrete about 300-600 mg of cholesterol in bile salts/day
Component of membranes
Vitamin D

Question 3

Steps in the de novo synthesis of cholesterol

Answer 3

In the hepatocyte cytoplasm:
Acetyl CoA (thiolase & HMG CoA synthase) → HMG CoA (HMG CoA reductase*) + NADPH → mevalonate → lots of complicated steps resulting in key intermediates geranyl pyrophosphate and farnesyl pyrophosphate → cholesterol
*Key regulated step, rate limiting

Question 4

What is the source of energy for cholesterol synthesis

Answer 4

NADPH

Question 5

What is the substrate for cholesterol synthesis?

Answer 5

Acetyl CoA

Question 6

Where in the body does most cholesterol synthesis occur?

Answer 6

liver

Question 7

What is the key regulated step in cholesterol synthesis and how is it regulated

Answer 7

Conversion of HMG CA to mevalonate by HMG CoA reductase

This enzyme is functionally the primary means for controlling intracellular cholesterol levels.

Regulated on many levels:

1. Transcriptional regulation: When cholesterol is present in excess, the HMG-CoA reductase gene is transcribed at a dramatically reduced rate. Result of the actions of the transcription factor Sterol Regulatory Element Binding Protein (SREBP) for HMG CoA.
2. Translational regulation: When cholesterol is present in excess, the translation rate of the mRNA encoding HMG-CoA reductase is much less than in the absence of cholesterol; the mRNA half life decreases with excess cholesterol.
3. Regulation of the degradation of the key enzyme: When cholesterol is present in excess in the hepatocyte, the half-life of the key enzyme HMG-CoA reductase decreases from 11 to 2 hours (targeted to proteasome)
4. Phosphorylation of the key enzyme: AMP kinase phophorylates HMG-CoA reductase, inactivating it. Protein phosphatase removes the phosphate and this activates the enzyme.

Question 8

Statins

Answer 8

Class of drugs that have structural similarities to mevalonate and as a result act as competitive inhibitors of HMG CoA reductase.

Successful medication in preventing coronary artery disease.

Question 9

Glycerophospholipids

Answer 9

Main class of phospholipids and makes up the bulk of membrane lipids. The backbone comes from phosphatidic acid which is a precursor in triglyceride biosynthesis. Then the head group is added.

Ex.: phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylcholine (PC). Each of these is named for the structure of the polar head group. The polar head groups of PC and PE are formed de novo or come from the diet, are then activated by CDP then attached to the backbone.

Another pathway for synthesis involves “base exchange” whereby the head-groups are exchanged onto previously synthesized phospholipids.

Question 10

Phosphatidylcholine

Answer 10

Glycerophospholipid

Along with PE is the most abundant phospholipid in the body

It is the main component in lung surfactant

Serves as a reservoir of choline

Present in bile

Question 11

Phosphatidylinositol

Answer 11

Important in signal transduction.

Serves as a reservoir for arachadonic acid which is used in prostaglandin synthesis.

Important in membrane protein anchoring.

Question 12

Sphyngomyelin

Answer 12

Has a sphingosine/ceramide backbone, not glycerol, and a choline headgroup

Major structural lipid in nerve tissue

The precursor to this lipid is ceramide made from a fatty acid and an amino acid (serine).

Question 13

Synthesis of arachidonic acid and prostaglandins

Answer 13

These lipids are synthesized from the dietary fat linoleic acid which is converted to arachadonic acid and then to prostaglandin by the enzyme cyclooxygenase (COX).

Arachadonic acid can also be converted to leukotrienes via the enzyme 5-lipoxygenase

Prostaglandins are important in fever generation and inflammation

Leukotrienes are also important in inflammation and inhibitors of 5-lipoxygenase are used in the treatment of asthma.

Question 14

Glycosphingolipids

Answer 14

Have sphingosine/ceramide backbone but instead of a phosphate and an alcohol headgroup, they have a sugar headgroup.

Sugars are added as the UDP form (UDP glucose or UDP galactose)

These lipids are found primarily in the brain and peripheral nerves

Ex: cerebroside, globoside and gangliosides

Disorders in the breakdown of these molecules can cause severe multisystem disorders