L23: Lipid Metabolism IV

Question 1

What are sphingolipidoses?

Answer 1

• Sphingolipids is a group of molecules that differ by head groups - Enzymes for the degradation of these head groups are very specific. - Sphingolipidoses are a group of diseases where a particular enzyme whose function is to degrade specific head groups are missing or defective causing the slow accumulation of a particular type of sphingolipid - These accumulate in lysosomes of phagocytic cells

Question 2

Name the sphingolipidoses. Name the enzyme defect, accumulated lipid and presentation.

Answer 2

1.) Tay-Sachs Disease Enzyme defect: beta-hexosaminidase A Accumulated lipid: ganglioside GM2 Presentation: mental retardation, blindness, cherry red spot on macula, death before age 3 2.) Gaucher Disease Enzyme defect: beta-glucosidase (beta-cerebrosidase) Accumulated lipid: glucocerebroside Presentation: liver and spleen enlargement, erosion of long bones 3.) Fabry Disease Enzyme defect: alpha-galactosidase Accumulated lipid: ceramide trihexoside Presentation: skin rash, kidney failure 4.) Niemann-Pick Disease Enzyme defect: sphingomyelinase Accumulated lipid: sphingomyelin Presentation: liver and spleen enlargement, mental retardation 5.) Sandhoff Disease Enzyme defect: beta-hexosaminodase A and B Accumulated lipid: GM2 ganglioside and globosides Presentation: similar to Tay-Sachs, progresses more rapidly 6.) Metachromatic Leukodystrophy Enzyme defect: arylsulfatase Accumulated lipid: sulfatide Presentation: mental retardation

Question 3

Tay-Sachs disease. What is it? What is the presentation?

Answer 3

Tay-Sachs Disease = sphingolipidosis Enzyme defect: beta-hexosaminidase A Accumulated lipid: ganglioside GM2 Presentation: mental retardation, blindness, cherry red spot on macula, death before age 3

Question 4

Gaucher disease. What is it? What is the presentation? Explain how it is diagnosed?

Answer 4

Gaucher Disease = sphingolipidosis Enzyme defect: beta-glucosidase (beta-cerebrosidase) Accumulated lipid: glucocerebroside Presentation: liver and spleen enlargement, erosion of long bones (stunted growth) Diagnosis: requires x-ray, which shows cortical thinning and flaring of long bones; WBCs show low glucocerebrosidase activity (aka beta-glucosidase) and macrophages have “crumpled tissue paper” appearance indicating accumulation of glucocerebroside

Question 5

Fabry disease. What is it? What is the presentation?

Answer 5

Fabry Disease = sphingolipidosis` Enzyme defect: alpha-galactosidase Accumulated lipid: ceramide trihexoside Presentation: skin rash, kidney failure

Question 6

Niemann-Pick disease. What is it? What is the presentation?

Answer 6

Niemann-Pick Disease = sphingolipidosis Enzyme defect: sphingomyelinase Accumulated lipid: sphingomyelin Presentation: liver and spleen enlargement, mental retardation

Question 7

Sandhoff disease. What is it? What is the presentation?

Answer 7

Sandhoff Disease = sphingolipidosis Enzyme defect: beta-hexosaminodase A and B Accumulated lipid: GM2 ganglioside and globosides Presentation: similar to Tay-Sachs, progresses more rapidly

Question 8

Metachromatic Leukodystrophy. What is it? What is the presentation?

Answer 8

Metachromatic Leukodystrophy = sphingolipidosis Enzyme defect: arylsulfatase Accumulated lipid: sulfatide Presentation: mental retardation

Question 9

Contrast sphingolipidoses and mucopolysaccharidoses.

Answer 9

• Sphingolipidoses are problems with degradation of sphingolipids resulted in accumulation of undegraded sphingolipids in lysosomes - Mucopolysaccharidoses are problems with degradation of proteoglycans, resulting in accumulation of undegraded glycosaminoglycans in lysosomes.

Question 10

Where is cholesterol synthesized, what is the rate-limiting step/enzyme, what is the precursor used, in what other pathway is this precursor seen? What enzyme is used to make this precursor? Is this the same enzyme used in the previous pathway? Explain. During what environmental conditions is the precursor made in both pathways?

Answer 10

• Cholesterol synthesis takes place in the liver, intestine and reproductive tissues - Rate-limiting step = HMG-CoA reductase - Precursor = HMG-CoA – seen during synthesis of ketone bodies - Precursor synthesized by cytosolic HMG-CoA synthase isoform that is active in well-fed state. Mitochondrial HMG-CoA synthase isoform synthesizes the precursor when in starving/fasting state.

Question 11

Describe the synthesis of farnesyl PP.

Answer 11

Question 12

What is the function of farnesyl PP?

Answer 12

• converted into dolichol-PP for protein glycosylation - converted into coQ for electron transport - used for prenylation (post-translational) of proteins which influence water solubility of proteins

Question 13

What is the first sterol synthesized?

Answer 13

• Lanosterol

Question 14

How is cholesterol synthesis regulated? Explain.

Answer 14

• It is regulated at the HMG-CoA reductase reaction. 1.) AMP high (starved state): phosphorylation by AMP-dependent kinase, which inactivates enzyme and cholesterol synthesis is low during times of starvation 2.) Insulin high (well-fed state): desphosphorylation by protein phosphorylase activates enzyme, which means that cholesterol synthesis is high during times of well-fed 3.) Cholesterol inhibits the enzyme by feedback inhibition, which means that when cholesterol levels are high, cholesterol synthesis is low

Question 15

How can cholesterol synthesis be inhibited in a clinical setting? Explain how this works.

Answer 15

• Use of statins - Statins inhibit the HMG-CoA reductase enzyme and prevents synthesis of mevalonic acid, a precursor molecule to farnesyl-PP, a precursor to cholesterol.

Question 16

What is the function of statins?

Answer 16

• Statins inhibit the HMG-CoA reductase enzyme and prevents synthesis of mevalonic acid, a precursor molecule to farnesyl-PP, a precursor to cholesterol.

Question 17

What are cholesterol esters? What are their functions?

Answer 17

• Cholesterol is amphipolar, which poses a storage problems as it cannot form droplets. In order to store cholesterol in a highly hydrophobic environment, one makes cholesterol esters. - This occurs by adding a FA onto the OH group of cholesterol allowing storage in center of hydrophobic lipoproteins or in cytoplasmic fat droplets

Question 18

What are bile acids? What are their functions?

Answer 18

• In order to increase water solubility of cholesterol, the molecule is modified into a bile salt. This involves oxidation of C24 into carboxyl group and hydroxylation of C7 and C12. - Two forms of bile acid: cholic acid, chenodeoxycholic acid

Question 19

Contrast the chemical properties of cholesterol, cholesterol esters and bile acids.

Answer 19

• cholesterol: amphipathic molecules that is unable to form droplets and is difficult to store in highly hydrophobic environment. It can be inserted into hydrophilic region of lipid bilayer with OH group sticking out - cholesterol ester: molecule of cholesterol with FA added to OH group, allowing molecule to form droplets and incorporate into lipoproteins, now able to be stored in hydrophobic environment such as center of lipoproteins or in cytoplasmic fat droplets - bile salts: increases water solubility of cholesterol and makes it hydrophilic by oxidizing C24 into COOH group and hydroxylating C7 and C12. This allows for secretion of cholesterol by liver through bile duct into digestive tract where they are also used for emulsifying fat from diet.

Question 20

Can cholesterol and derivatives be degraded by human enzymes? Explain.

Answer 20

• No. - These have to be excreted in form of bile acids, which is done by liver.

Question 21

How do gallstones form?

Answer 21

• Bile contains cholesterol, bile salts and phospholipids. These aid in emulsification of dietary fats. Cholesterol is prone to precipitating in gallbladder and duct works as its water solubility is low. When in high concentration, it particularly precipitates out causing formation of cholesterol stones known as gallstones, which can obstruct the gallbladder and ducts causing painful backup of bile of pancreatic enzymes.

Question 22

Describe the synthesis of cholesterol from farnesyl PP.

Answer 22