Lipoproteins I

Question 1

List the 3 ways the liver exports cholesterol.

Answer 1

1. in vLDL
2. Excreted in bile
3. Conversion to bile salts (CYP7A1 RDS enzyme)

Question 2

Where does most of cholesterol in our body come from?

Answer 2

Most of the cholesterol is synthesized WITHIN the body.

Question 3

The building block for cholesterol synthesis is _____.

Answer 3

Acetyl CoA

Question 4

Describe the rate-limiting step in cholesterol synthesis (substrate, enzyme and product).

Answer 4

RDS of cholesterol biosynthesis is the conversion of HMG CoA (6 carbons) into Mevalonic acid (6 carbons) via HMG CoA Reductase. This 2nd step requires 2 NADPH and releases CoA.

Question 5

What drug inhibits the enzyme in the RDS of cholesterol synthesis? What is its effect?

Answer 5

Statins are competitive inhibitors of HMG CoA Reductase enzyme. This lowers cholesterol and increases the # of LDL receptors in the liver to lower LDL plasma levels.
Most commonly prescribed drug in the clinic, USA

Question 6

Cholesterol synthesis requires ____ and ____. IPP is a precursor for what important molecules?

Answer 6

Reducing power via NADPH and ATP to power conversions. IPP (5-carbon) is a precursor for Dolichol (glycoprotein synthesis) and Ubiqionone (Coenzyme Q in ETC)

Question 7

What other unintended effects does the use of statins have?

Answer 7

Reduces glycoprotein synthesis (less dolichol), Ubiqionone (Coenzyme Q of ETC) and farnesylation of lipid anchored proteins such as ras and lamin (from BMS)

Question 8

What is the most prominent mechanism for regulation of cholesterol? Describe how it works at high levels of cholesterol.

Answer 8

Regulation of cholesterol via gene expression of SREBP2 embedded in the ER.

1. SREBP2 is complexed to SCAP which is a sterol sensing domain.
2. @ HIGH cholesterol levels: conformation binds to INSIG to be ubiquinated and destroyed by the proteosome.

Question 9

How does Cholesterol-regulated gene expression work at low levels of cholesterol?

Answer 9

1. @ low levels: SCAP/SREBP2 binds to COP-II to be transferred to GOLGI.
2. Golgi proteases 1 and 2 release SREBP2 from Golgi membrane which travels to nucleus to bind Sterol response element (SRE).
3. Binding of mature SREBP2 to SRE upregulates txn of HmG CoA reductase to make MORE CHOLESTEROL.

Question 10

What is the 2nd mechanism for regulation of cholesterol synthesis?

Answer 10

1. High cholesterol has INSIG attach to Sterol sensing domain of HMG CoA Reductase to be ubiquinated.
2. HMG CoA Reductase is extracted from cell membrane and degraded via Proteasome.

Question 11

What is the 3rd mechanism for regulation of cholesterol synthesis?

Answer 11

Phosphorylation and dephosphorylation.

1. AMP-kinase adds a phosphate that INACTIVES HMG CoA Reducatase.
2. HMGR Phosphatase removes this to REACTIVATE the enzyme.
   * High levels of AMP are indications of high NRG/glucose = stop cholesterol synthesis = save energy*

Question 12

What is the 4th level of regulation for cholesterol synthesis?

Answer 12

Hormonal Regulation

1. Insulin stimulates HMGR by promoting dephosphorylation.
2. Glucagon inhibits HMGR via phosphorylation.

Question 13

What do Statins do to HMGR? What are the other effects of these drugs?

Answer 13

Statins are structural analogs of substrate HMG CoA reductase enzyme that competitively inhibit cholesterol synthesis. This increases the # of LDL receptors on liver to lower plasma LDL levels.
Other effects include: decreasing de novo CE synthesis, increasing # of specific LDL receptors on hepatocyte membranes.

Question 14

How is cholesterol transported in the body?

Answer 14

Via Lipoproteins (chylomicrons, HDL and LDL).

Question 15

If the phosphorylation site of HMG CoA reductase is mutated. What would most likely be a result of this mutated enzyme?

Answer 15

The enzyme is non-responsive to ATP depletion. This feature requires phosphorylation.

Question 16

When distinguishing between lipoproteins, the LARGER ____ and ____ are mainly composed of _____. Whereas the smaller the lipoproteins, such as ____ and ____, the more _____ content there is.

Answer 16

LARGER lipoproteins = Chylomicrons > vLDL composed mainly of lipids. Smaller lipoproteins (HDL < LDL by size) have more protein content.

Question 17

Chylomicrons, which originate in the ______, have high amounts of ______ compared to the lower ____ content.

Answer 17

Chylomicrons from the small intestines have HIGH triglycerides compared to lower Cholesterol levels.

Question 18

LDL and HDL have higher amounts of ____ and ____ content than that of chylomicrons.

Answer 18

LDL and HDL have HIGHER cholesterol and protein contents, respectively (compared to chylomicrons).

Question 19

What are apolipoproteins and what are the 4 functions they have?

Answer 19

Apolipoproteins are lipid-binding proteins in plasma. These…

1. Act as structural components.
2. Maintain lipid components in solution.
3. Act as recognition sites/ligands for receptors
4. Act as activators or coenzymes in lipid metabolism

Question 20

What 2 enzymes are involved in the packaging of chylomicrons in enterocytes?

Answer 20

1. ACAT enzyme acylates (esterifies) the lipids to yield cholesterol esters that are loaded with triglycerides.
2. MTTP acts as a chaperone to take esterified fats into chylomicrons.

Question 21

Apo-B48 is to chylomicrons as ____ is to vLDLs. What is it’s function?

Answer 21

Apo-B100 binds to LDL receptor for vLDL to drop of ENDOGENOUS TAGs to peripheral tissue (I.e. endothelial cells).

Question 22

What would be the impact of mutations in MTTP?

Answer 22

Problems in assembly of chylomicrons and vLDL since MTTP is a chaperone for fat contents into the lipoproteins into Chylomicrons (TAGs from diet) and vLDL (CEs). This results in Abetalipoproteinemia (ABL).

Question 23

Define Abetalipoproteinemia. List the cause, symptoms and treatment.

Answer 23

This is a disease (of the ENDOGENOUS pathway) linked to mutations in MTTP so chylomicrons can’t absorb dietary fat (fatty feces) and vLDLs stay in the liver (fatty liver). Symptoms include steatorrhea, HYPOcholesterolemia, fatty liver and deficiency in fat-soluble vitamins (results in ataxia/ vision issues).
Treatment: low-fat diet + vitamin supplements

Question 24

Why is LDL known as the “bad cholesterol”? What significance does it hold?

Answer 24

LDL carries MOST of the cholesterol that’s in circulation, where 1/3 is taken to peripheral tissue and 2/3 of it (is taken back to the liver. HIGH levels of both LDL and Apo-B100 have been linked to Atherosclerotic CV events.

Question 25

What effect does High cholesterol levels in the blood have on HMG CoA Reducatase? How does this work?

Answer 25

HIGH cholesterol reduces HMG CoA and LDL receptor expression. Too much CE can prevent SREBP2 from entering the nucleus to transcribe LDL receptor gene.

Question 26

In what 2 ways do LDL receptors impact the levels of circulating LDL?

Answer 26

1. Decreases LDL clearance (due to less hepatic LDL R)

2. Increase LDL production (from decrease in IDL uptake by the liver)