Biochem: FINAL (Ch. 25-26) - Cholesterol and Lipoprotein Metabolism

All info from slideshow titled "Cholesterol Metabolism" based on Harper's Illustrated Biochemistry

What (2) forms does cholesterol exist in in all cells, cell membranes and blood?

free cholesterol and cholesteryl esters

When is cholesterol synthesized? Where (2)? Where is it stored?

Synthesized in the liver and small intestines following a high fat/ sugar meal and is stored in liver predominantly.

What (2) forms is cholesterol excreted as?

free cholesterol and bile acids

What (5) things does cholesterol make/ make up?

cell membrane and lipoprotein synthesis, Precursor for steroid hormones, vitamin D, and bile acid synthesis

What (2) major roles can cholesterol play in disease states?

constituent of gall stones and development of atherosclerosis (heart disease; strokes; hypertension) due to accumulation in macrophages (WBC)

Free question say YES

YES

Approximately how much cholesterol is produced daily?

1g/day

How many major stages are there of cholesterol synthesis?

5

What is the purpose of the precursor steps in Cholesterol Synthesis?

to transport acetyl CoAs out of the mitochondria and into the cytosol

What does HMG CoA synthase do (substrate, product, reason) ? What does HMG CoA reductase do (substrates 2, product, reason)?

HMG CoA synthase converts 3 acetyl CoAs into HMG CoA which allows it to shuttle out of the mitochondria and in the cytosol, HMG CoA reductase takes HMG CoA plus 2 NADPH and converts it into mevalonate which will be used to create cholesterol

What is HMG CoA reductase inhibited by? (3)

mevalonate and NADP+ which are products of this enzyme and statins which are medications used for the treatment of high blood cholesterol

What is the regulating enzyme/ step of Cholesterol Synthesis?

HMG-CoA reductase/ converting HMG-CoA into mevalonate

What does squalene synthesize in cholesterol synthesis? What cofactor(s) does it use?

lanosterol ; FAD and NADPH

What is the precursor to cholesterol?

desmosterol

Where in the body is cholesterol excreted? In what form (2)?

in the feces in the form of primary bile acids and free cholesterol

What is the role of primary bile acids in cholesterol excretion?

They can be metabolized by bacteria to form secondary bile acids

How is free cholesterol metabolized for excretion after it is released by the liver into the digestive tract?

It can be broken down by colon bacteria to form coprastanol and coprostanone and released as feces

Where are primary bile acids synthesized?

liver

What makes up bile? (2)

primary bile acids and free cholesterol

How are the majority of primary bile acids used?

80% are reabsorbed as a part of micelles in the small intestine and returned to the liver

What does the enzyme 7 alpha-hydroxylate do? What cofactors/ reagents are needed (2)?

It converts cholesterol into 7 alpha-hydrocycholesterol using NADPH and O2

What is the regulating enzyme in the synthesis of Primary Bile Acids?

7 alpha-hydroxylate

What are bile acid sequestrants? (What do they bind to and what does this cause?)

medications that bind to primary bile acids in the small intestines to prevent reabsorption causing the liver to increase synthesis of bile acids and remove more cholesterol from blood, thus helping to lower blood cholesterol

What are primary bile acids conjugated with before being stored in the gall bladder/ what do primary bile acids need to be combined with to become bile salts?

glycine or taurine and Na+

What form is bile in when it is stored in the gallbladder?

Bile salts

What is 7alpha-hydroxycholesterol eventually converted into in Bile Synthesis? What are these molecules?

cholic acid or chenodeocycholic acid which are bile acids

What does cholic acid produce?

deoxycholic acid

What is chenodeocycholic acid converted to? What is this process called?

lithocholic acid; 7 alpha-dehydroxylation

What can lipoproteins contain?

cholesteryl esters, free cholesterol, phospholipids, triacyglycerols, and protein

What are the (4) major classes of lipoproteins in the human body?

Chylomicrons, Very low density lipoprotein (VLDL), Low density lipoprotein (LDL), High density lipoprotein (HDL)

What are chylomicrons made up of?

80% triacylglycerols

What are Very low density lipoprotein (VLDL) made up of?

50% triacylglycerols

What are Low density lipoprotein (LDL) made up of?

50% cholesterol

What are High density lipoprotein (HDL) made up of? (3) (No apos)

50% protein, 50% phospholipids, 30% cholesterol esters

What are the (3) classes of Apoprotiens in general

structural proteins, regulatory proteins, mediation proteins

What are Apo As and Apo Bs classified as? What do they do?

Structural proteins, they serve to stabilized and maintain the molecular structure of the molecule

What are Apo Cs classified as? What do they do?

Regulatory proteins; Positive regulators for enzymes involved in lipoprotein metabolism

What are Apo Es classified as? What do they do?

Serve as binding ligands for lipoproteins with cell membrane receptors

Where does synthesis of chylomicrons occur? When?

In the small intestine following a meal based on how much dietary fat is consumed

What is another name for app B-48?

nascent chylomicron

What is the process by which chylomicrons enter the blood stream?

First, apo B-48 is added to the chylomicron by intentional enterocytes to create the Nascent chylomicron which is then secreted into the lymphatic system via lacteals and from there it enters blood stream

What happens to the nascent chylomicrons in the blood after they are absorbed?

HDL tranfers apo Cs and app Es to the chylomicron and it becomes a mature chylomicron

What does a mature chylomicron have that a nascent chylomicron does not?

It has apo Cs and apo Es attached

What is Lipoprotein lipase (LPL) activated by?

apo Cs

Where are Lipoprotein lipases (LPL) found?

muscle and adipose tissue

What does Lipoprotein lipase (LPL) do?

removes triacylglycerol from the mature chylomicron that was in the blood and puts it into cells for storage and energy

What does the mature chylomicron become when LPL takes its’ triacylglycerol?

A chylomicron remnant in the blood

How are chylomicron remnants removed from the blood and why? What happens to them?

they are removed by liver receptors due to binding with apo Es and then are destroyed in the liver

What organ synthesizes VLDL? What triggers this to happen?

The liver following a meal based on fat synthesis due to carbs, protein and alcohol consumption

What (3) lipoproteins have apo B-100 as a part of their structure?

VLDL, IDL, LDL

Where are nascent VLDL release from into the blood?

liver

What removes triacylglycerol from mature LDL in the blood? With what signal

Lipoprotein lipase with the signal from apo C on the surface of LDL

What is another name for a VLDL remnant?

IDL

How can a VLDL remnant/ IDL be removed? (2) What is the majority pathway?

It can be removed by the liver due to apo Es binding to liver receptors, but the majority of IDL will lose apo Es back to HDL and turn into LDL in the blood which will be cleared in the liver later on

What does LDL do?

It delivers cholesterol to all tissues including the liver

How is LDL removed from the blood?

via LDL receptors on most cells

What is defective/ deficient in familiar hypercholesterolemia type IIa?

LDL receptors on cells

What 2 receptors remove LDL from blood?

LDL receptors (apo B-100) and scavenger receptors

What is the mechanism behind the development of atherosclerosis?

macrophages have scavenger receptors that can bind to excessive amounts of oxidized LDL and become foam cells and eventually form atherosclerotic plaques

What are scavenger receptors (SR) in terms of LDL metabolism?

located on macrophages in arterial walls they pick up LDL in blood to form foam cells

What factors increase LDL receptors take up/ create more LDL receptors on the cell? (3) (LDLR regulation)

low levels of cholesterol in the blood, up-regulation by statins, and low bile acid reuptake (also done by medications)

What synthesizes HDL (2)? What allows for this synthesis (1)?

small intestines and liver: apo A-I which allows free cholesterol to be converted into cholesterol esters that can be incorporated into the HDL core

What does HDL do (4)?

regulates the transfer of apoproteins Cs and Es with chylomicrons and VLDL, removes triacyglycerol from blood, Removes free cholesterol from extra hepatic cells and delivers it to the liver for disposal, transfers some cholesteryl esters to LDL also for removal

What form of lipid are apoproteins carrying/ concerned with?

triacylglycerol

What are the (3) major forms of HDL?

discoidal HDL, HDL2, and HDL3

Where is discoidal HDL synthesized and secreted from? (2)

small intestine and liver

How does discoidal HDL become HDL3?

by removing free cholesterol from extra hepatic cells and converting cholesteryl esters

What does lecithin: cholesterol acyltransferase (LCAT) do?

combines lecithin and cholesterol into a cholesteryl ester so that it can be metabolized

What cell membrane proteins does HDL activate to remove free cholesterol? What else can activate these proteins?

SR-B1 and ABCA1; Apo E

How does HDL remove free cholesterol from extra hepatic cells?

By activating membrane proteins that shuttle out cholesterol of the cell into the HDL

How does HDL3 become HDL2?

The enzyme LCAT adds one more free cholesterol and converts into cholesteryl ester

What is the final form of HDL at the end of HDL metabolism?

HDL2

What are the 3 things HDL2 can do after finally being formed?

be removed by the blood via liver receptors, transfer cholesteryl esters to liver cells by activating SR-B1, or transfer its’ cholesteryl esters’s lipid chain to LDL which takes the form of triacylglycerol

Which lipoproteins are the major carriers of triacylglycerols?

chylomicrons and VLDL

Cholesterol metabolism is control by HMG CoA ______?

Reductase

Which lipoprotein is digested to form LDL?

IDL

The highest phospholipids content is found in _____?

HDL

What is an integral apolipoprotein present in VLDL, IDL, and LDL?

Apo B 100

Cholesterol biosynthesis takes place in what parts of the cell?

Cytoplasm and smooth ER

What are the secondary bile acids?

Deoxycholic acid and lithocolic acid

Which lipoprotein has the highest cholesterol:triglycerides ratio?

HDL and LDL

Which is the main apolipoprotein present in the LDL?

Apo B-100

The HDL is taken up by the hepatocytes via

Scavenger receptor BI

True or false: The synthesis of HMG can only take place in the cytoplasm

True