cholesterol and complex lipids

Question 1

· Describe the sources of and fates of cholesterol.

Answer 1

sources: dietary (300-600g per day, half is absorbed and half is excreted in stool) and de novo synthesis (1g per day). Fates: cell membranes, precursor for steroid horomones, bile acids and vit D

Question 2

location of cholesterol synthesis

Answer 2

Occurs in cytosol of liver mainly, but also adrenal cortex, the ovaries and the testes also synthesize cholesterol to make steroid hormones

Question 3

what is the source of energy for cholesterol synthesis

Answer 3

NADPH

Question 4

· Describe in general the steps in the de novo synthesis of cholesterol

Answer 4

Acetyl CoA > HMG CoA > mevalonate (HMG CoA reductase) > geranyl pyrophosphate > farnesyl pyrophosphate > squalene > cholesterol

Question 5

list 3 pathways that contribute to intracellular cholesterol content in hepatocytes

Answer 5

Synthesis, uptake of lipoprotein cholesterol from LDL, and enterohepatic circulation of bile acids.

Question 6

· Identify the key regulated step in cholesterol synthesis and describe how this step is regulated

Answer 6

HMG CoA reductase is rate limiting step and key regulated step. Regulated by transcriptional regulation, translational regulation, degradation of the enzymes and phosphorylation

Question 7

describe transcriptional regulation of HMG CoA reductase

Answer 7

When cholesterol is present in excess, the HMG-CoA reductase gene is transcribed 20X less via actions of transcription factor sterol regulatory element binding protein. Insulin increases expression of the enzyme and glucagon decreases

Question 8

describe translational regulation of HMG CoA reductase

Answer 8

When cholesterol is present in excess, the translation rate of the mRNA encoding HMG-CoA reductase is 5X less than in the absence of cholesterol. mRNA half life decreases with excess cholesterol

Question 9

describe degradative regulation of HMG CoA reductase

Answer 9

In excess cholesterol the half life of the enzyme HMG-CoA reductase decreases from 11 to 2 hours (targeted to proteasome)

Question 10

describe phosphorylation regulation of HMG CoA reductase

Answer 10

AMP kinase phophorylates HMG-CoA reductase which inactivates the enzyme. Protein phosphatase removes the phosphate and this activates the enzyme.

Question 11

MOA of statins

Answer 11

Structurally similar to mevalonate and as a result act as competitive inhibitors of HMG CoA reductase. The compound lovastatin is a natural product of fungi.

Question 12

· Describe the key features of the structures of glycerophospholipids, sphyngomyelin and glycerosphingolipids and the general aspects of their synthesis.

Answer 12

glycerophospholipids: glycerol backbone, 2 fatty acids and a phosphate attached to an alcohol. Sphingomyelin: ceramide (sphingosine) backbone, a single fatty acid and a phosphate attached to choline. Glycerosphingolipids: sphingosine backbone, single fatty acid and a sugar moiety.

Question 13

· Describe how the different glycerophospholipids are synthesized.

Answer 13

Backbone comes from phosphatidic acid. Then polar head group is added (formed de novo or come from diet), they are activated by CDP and attached to backbone. Another pathway involves base exchange where head groups are exchanged onto previously synthesized phospholipids

Question 14

list glycerophospholipids

Answer 14

phosphatidyl serine, phosphatidylcholine, phosphatidylinositol

Question 15

· List the important functions of phosphatidylcholine

Answer 15

Main component of lung surfactant and present in bile. Serves as reservoir of choline.

Question 16

· List the important functions of phosphatidylinositol

Answer 16

important in signal transduction, membrane protein anchoring and as reservoir for arachadonic acid

Question 17

· List the important functions of sphyngomyelin.

Answer 17

major structural lipid in nervous tissue,

Question 18

examples of glycolipids

Answer 18

aka glycosphingolipids- cerebrosie, globoside and ganglioside

Question 19

Describe in general the synthesis of arachidonic acid and prostaglandins

Answer 19

linoleic acid > arachidonic acid > prostaglandins (COX) OR leukotrienes (5-lipoxygenase)