Biochemistry of Lipids and Lipoproteins

Question 1

Triglycerides

Answer 1

“storage fats” /triacylglycerols/neutral fats Composed of 3 fatty acids, each in an ester linkage with a single glycerol. Simple Triglycerol have the same kind of fatty acid in all 3 positions. Most naturally occuring Triglycerides are mixed and contain 2-3 different fatty acids.

Question 2

Cholesterol

Answer 2

Essential component of membranes Precursor for synthesis of bile acids and steroid hormones Reduces fluidity of membranes Enriched in lipid rafts (in Golgi and plasma membrane) -> areas enriched in proteins that participate in signal transduction. Covalent modification of embryonic signaling proteins

Question 3

Cholesterol cytotoxicity

Answer 3

Excess cholesterool is cytotoxic to cells: - Formation of cholesteol crystals - Triggering of apoptotic pathways - Formation of toxic oxysterols - Disruption of membrane domains that are crucial for function of enzymes and signaling molecules - Contributes to mechanisms that promote atherosclerosis

Question 4

4 steps in cholesterol synthesis

Answer 4

1. Formation of mevalonate from three acetate molecules 2. Mevalonate converts to phosphorylated 5-c isoprene 3. Six isoprenes polymerize to form the 30-C linear squalene 4. Squalene cyclizes to form the four rings that are modified to produce cholesterol

Question 5

Step 1. Formation of Mevalonate from Acetyle-CoA

Answer 5

2 Acetyl-CoAs -> Acetyoacetyl-CoA - catalyzed by acetyl-CoA acyl transferase Acetyle-CoA + Acetoacetyl-CoA -> Beta hydroxyl- Beta methylglutaryl-CoA (HMG-CoA) - catalyzed by HMG-CoA Synthase HMG-CoA + 2 NADPH -> mevalonate -catylized by HMG-CoA reductase -rate limiting step and point of regulation - HMG-CoA reductase is a target for some cardiovascular drugs.

Question 6

Step 2: Conversion of Mevalonate to Activated Isoprenes

Answer 6

• 3 PO4 transferred stepwise from ATP to mevalonate - Decarboxylation and hydrolysis creates a diphosphorylated 5-C product (isoprene) with a double bond - Isomeization to a second isoprene - The two “activated” isoprene units are delta3-isopentyl pyrophosphate and dimethylallylpyrophosphate

Question 7

Step 3: Activated Isoprene Units Condense to Form Squalene

Answer 7

• The two isoprenes join and displace one set of diphosphates -> forms geranyl pyrophosphate - Geranyl pyrophosphate joins another isopentenyl pyrophosphate -> forms 15-C farnesyl pyrophosphate - Two farnesyl pyrophosphates join to form phosphate-free squalene

Question 8

Step 4 Conversion of Squalene to 4-Ring Cholesterol

Answer 8

• Squalene monooxygenase adds one oxygen to the end of the squalene chain -> forms squalene 2,3-epoxide - Here pathways diverse in animal cells vs. plant cells - The cyclization product in animals is lanosterol, which converts to cholesterol - In plants, the epoxide cyclizes to other sterols such as ergosterol.

Question 9

In vertebrates, most cholesterol is synthezied in the ____, then what?

Answer 9

In vertebrates, most cholesterol is synthezied in the liver, and then exported. - As bile acid, biliary cholesterol or cholesteryl esters

Question 10

Where is Bile Stored, Secreted?

Answer 10

Stored in the gall bladder, and secreted into small intestin after a fatty meal.

Question 11

Bile Acid _____ fats.

Answer 11

Emulsify = surround dropltes of fat, increase the surface area for attack by lipases

Question 12

The adrenal Gland synthesizes ______ and _____

Answer 12

mineralcorticoids and glucocorticoids

Question 13

What are some gonad-synthesized steroids

Answer 13

Progesterone Androgens Estrogens

Question 14

Cholesteryl Esters are more _____ than cholesterol

Answer 14

non-polar

Question 15

Cholesteryl Esters

Answer 15

Contain a fatty acid esterified to the oxygen - Come from a fatty acyl-CoA - makes the cholesterol more hydrophobic, unable to enter membranes Transported in lipoproteins to other tissues or stored in liver.

Question 16

Lipoprotein protein particles

Answer 16

carry lipids through the plasma, the surface is made of proteins (apolipoproteins) and a phospoholipid monolayer. Interior contains cholesterol, triglycerides, cholesteryl esters.

Question 17

Chylomicron: Identifiying apoLp & Characteristics

Answer 17

apoB-48 + other apoLp’s, Largest lipoprotein delivers cholesterol and triglycerides from gut to tissues and liver Major contributor to composition: Triglycerides (85%)

Question 18

VLDL: Identifiying apoLp & Characteristics

Answer 18

Very Low density lipoprotein apoB-100 + other apoLp’s synthesized in liver delivers triglycerides to tissues as fatty acids via lipoprotein lipases Major contributor to composition: Triglycerides (50%)

Question 19

IDL: Identifiying apoLp & Characteristics

Answer 19

Intermediate density lipoprotein: between VLDL and LDL apoB-100 short-lived lipoprotein

Question 20

LDL: Identifiying apoLp & Characteristics

Answer 20

apo-B-100 only Stays in circulation much longer than other lipproteins Major contributor to Composition: Cholesteryl Esters

Question 21

Lp(a)

Answer 21

Homologous between LDL and plasminogen

Question 22

HDL

Answer 22

High Density Lipoprotein apoA-I and apoA-II generally good for the body Major contributor to composition: Protein

Question 23

Apolipoproteins

Answer 23

The protein portion of a lipoprotein particle, without the lipid.

Helps solubilize the lipoprotein particle in the circulation.

Change conformation to adjust to changing lipid contents, composition and metabolic states of the lipoproteins

Can activate or inhibit plasma enzymes, serve as ligands for cell surface receptors

Question 24

Dietary fatty acids are absorbed in the _____ _______.

Answer 24

Dietary fatty acids are absorbed in the small intestine.

Question 25

Intestinal choleterol and plant sterol absorption is mediated by _________ _________ ______

Answer 25

Intestinal cholesterol and plant sterol absorption is mediated by Niemann-Pick C1-Like 1 protein (NPC1L1).

Question 26

Ezetimibe

Answer 26

A cholesterol absorption inhibitor that targets the NPC1L1 protein.

Question 27

ABCG5 and ABCG8

Answer 27

ATP-binding cassette (ABC) half-transporters, which reside on the apical plasma membrane of enterocytes, channel plant sterols back into the intestinal lumen, prventing their assimilation into the body.

Question 28

Sitosterolemia

Answer 28

Autosomal recessive disorder

Mutations in the genes that encode ABCG5/ABCG8

Causes:

• An abnormally high absorption of plant sterols
• Fail to excrete dietary sterols into the bile

Thus causing accumulating plant sterol in the tissue and blood

The accumulation is associate with tendon and subcutaneous xanthomas and increased risk of remature CHD.

Question 29

Lipids are transported in the blood as ________. What is it’s main apopilpprotein?

Answer 29

Lipids are transported in the blood as chylomicrons.

The major apolipoprotein is ApoB-48

Question 30

Chylomicrons

Answer 30

Synthesized from the fatty acids of dietary triglyceries and cholesterol absorbed from the small intestine by epithelial cells.

Essential for absorption of dietary fat and fat-soluble vitamins.

The buoyancy of chylomicrons reflexts their high fat content (98-99%), of which 85% is from dietary tricylcerides

In normolipidemic individuals, chylomicrons are present in plasma for 3-6 hours after a fat-containing meal has been ingested. After a fast of 10-12 hours, no chylomicrons remain.

Question 31

Apolipoproteins on chylomicrons

Answer 31

The major apolipoprotein is ApoB-48, which is synthesized only bt intestingal epithelial cells, is unique to chylomicrons

ApoB-48 is 48% the molecular weight of apoB-100

ApoC-II activates lipoprotein lipase to allow FFA releases for fuel in adipose tissue, heart, and skeletal muscle.

Other Apolipoproteins involved: (ApoA-I, ApoA-IV) - from intestinal epithelial cells; (ApoE and ApoC-I, C-II, C-III) - from HDL

Question 32

Lipoprotein lipase (LPL)

Answer 32

Required for delivery of faty acids derived from the Trigycerides of chylomicrons and VLDL to tissues. Takes place at the vascular endothelial surface.

LPL is bound to capillary endothelium in heart, skeletal muscle, adipose tissue mammary gland, and other tissues.

Activated by the presence of apoC-II on Chylomicrons and VLDL.

Hydrolyzes TG -> DAG -> MAG

Results in a shrunken TG-rich particle, where cholesterol phospholipids and apolipoproteins are transferred to HDL

FAcilitates release of FA to adipose or muscle

Question 33

When glucose levels in the plasma are elevated and the release of insuling is stimulated, what happens with LPL? Fatty acids?

Answer 33

LPL is transciptionally upregulated in adipose tissue

Fatty acids derived from TG of ciculating lipoproteins are stored

Question 34

During a prolonged fast and diabetic ketoacidosis what happens to LEL activity?

Answer 34

LPL activity of adipose tissue falls - preventing storage of fatty acids

Question 35

Heparin

Answer 35

A Co-factor for LPL.

When given IV, LPL activity is displaced into plasma, permitting its measurement.

ApoC-II is an obligatory cofactor.

Question 36

Chylomicrons remnants deposit their Cholesterol in the _____

Answer 36

Chylomicrons remnants deposity their cholesterol in the liver, when depleted of their dietary TG via LPL

ApoB-48 is degraded

Chylomicrons remnants are rapidly removed from the circulation by endocytosis at the liver through a process that requires apoE as a ligand for hepatic receptors such as the LDL receptor or the LDL receptor-related protein (LRP)

Surface lipids and C proteins are transferred to HDL - The remnant lipoproteins thus formed their original completemnt of ApoB, significant ApoE, and little ApoC.

Few, if any, chylomicrons or chylomicron remnants are present in the blood after a 12-hour fast, except in patients with disorders of chylomicron metabolism

Dietary cholesterol delivered to the liver by remnants exerts feedback control of cholesterol biocynthesis in liver.

Question 37

LDL receptor-related protein

Answer 37

found in plasma lipid metabolism, LRP is important becasue it is the backup receptor responsible fo rthe uptake of apoE-enriched remnants of chylomicrons and VLDL

inherited absence of a functional apoE impedes remnant clearance by the LDL receptor and the LRP, increasing TG- and cholesterol-righ remnant lipproteins in the plasma (type III hyperlipoproteinemia)

Question 38

VLDL transport ______ _____

Answer 38

Very Low Density Lipoproteins transport endogenous lipids.

Produced in the liver when TG production is stimulated by an increased flux of free fatty acids or by increased denovo synthesis of fatty acids by the liver.

Cholesteryl esters and TG from excess FA and cholesteroll are packed into the core of VLDL and exported to peripheral tissues

Excess carbohydrate in the diet can also be made into TG in the liver and packed into VLDL

Contain apoB-100, apoC-I, ApoC-II, apoC-III, and apo-E all consittuively synthesized in the liver.

Question 39

Microsomal triglyceride transfer protein (MTP) helps transfer Triglycerides to the ____ _____

Answer 39

Microsomal triglyceride transfer protein (MTP) helps transfer TG to the VLDL core

After their synthesis in the enoplasmic reticulum, TG is transferred by microsomal triglyceride transfer protein (MTP) to the site where newly synthesized apoB-100 is available to form VLDL (or sites of apoB-48 syntesis for chylomicron formation).

Required for concentration of TG molecules within the core of VLDL

MTP is also required for TG transfer to chylomicrons in the intestine

Patients with dysfunctional MTP fail to make any of the apoB-containing lipoproteins (chylomicrons, VLDL, or LDL)

As a consequence, mutations of MTP cause the genetic disorder abetalipoproteinemia (vitamin deficiency, fat in stool, developmental delays)

Question 40

Acyl-CoA:cholesterol Acyltransferase (ACAT) esterifies free cholesterol to form ______ ______

Answer 40

Acyl-CoA:cholesterol Acyltransferase (ACAT) esterifies free cholesterol to form cholesteryl esters (CE)

ACAT-2 is found in the intestine and in the liver, where cellular free cholesterol is esterified before TG-rich lipoproteins are assembled.

• regulates the absorption of dietary cholesterol and