Cholesterol Synthesis:

HDL

"Good, friendly" smallest, most dense lipoprotein. Contains more protein/less fat than others. Removes cholesterol from bloodstream, delivers it to liver for excretion in bile. -Collects fat molecules (phospholipids, cholesterol, triglycerides, etc.) from the body's cells/tissues, and take it BACK to the liver. -*HDLs are sometimes referred to as "good" lipoprotein because higher concentrations correlate with low rates of atherosclerosis progression and/or regression

What is the rate limiting enzyme for cholesterol synthesis?

*HMG-CoA reductase* -converts: HMG-CoA → mevalonate

4. Low-Density Lipoprotein (LDL):

-Carry 3,000 - 6,000 fat molecules (phospholipids, cholesterol, triglycerides, etc.) around the body. -LDL particles are sometimes referred to as "bad" lipoprotein because concentrations, dose related, correlate with atherosclerosis progression.

Free fatty acid

-Free fatty acids are the primary products of dietary lipid degradation in the jejunum -Before fat can be metabolized by the muscle cells, it must first be broken down into

What are the main apolipoproteins and their function:

1. E: (mediate remnant uptake) 2. A-I (activates LCAT) 3. C-II (lipoprotein lipase cofactor) 4. B-48 (mediates chylomicron secretion 5. B-500 (binds LDL receptor

Cholesterol function:

1. Maintain cell membrane integrity 2. Synthesize: bile acid, steroids, vitamin D

Key enzymes of lipid transport:

1. Pancreatic lipase 2. Lipoprotein lipase (LPL) 3. Hepatic TG lipase (HL) 4. Hormone-senstive lipase

Lecithin-cholesterol acyltransferase (LCAT)

2/3 of plasma cholesterol is esterified by LCAT

Apolipoprotein A-I

Activates LCAT (lecithin-cholesterol acyltransferase) Found in: -Chylomicron and HDL

Apolipoproteins:

Apo-lipoproteins: PROTEINS that bind lipids to form lipoproteins (which transport lipids through lymph and circulatory system).

III- Familial dys-beta-lipoproteinemia

ApoE protein Defect -↑chylomicrons, and VLDL remnants Premature atheroslcerosis -Palmar xanthomas

Bile acids:

Bile contains bile acids, which are critical for digestion and absorption of fats and fat-soluble vitamins in the small intestine. Many waste products, including bilirubin (breakdown product of heme), are eliminated from the body by secretion into bile and elimination in feces. -Bile acids are made in the liver from cholesterol precursors

Apoliprotein B-100

Binds LDL receptor Found in: -VLDL, IDL, LDL

LCAT:

Catalyzes esterification of cholesterol

What is the function of chylomicrons?

Chylomicrons transport lipids absorbed from the intestine to: [adipose, cardiac, and skeletal muscle] -In these tissues, the triglyceride (TG) components are hydrolyzed by the activity of lipoprotein lipase (LPL) and the released free fatty acids are absorbed by the tissue. -When a large portion of the triacylglycerol core have been hydrolyzed, chylomicron remnants are formed and are taken up by the liver, hereby transferring dietary fat also to the liver.

What is an atheroma?

Degeneration of the walls of the arteries caused by accumulated fatty deposits and scar tissue, and leading to restriction of the circulation and a risk of thrombosis.

2. Lipoprotien lipase (LPL)

Degradation of TGs circulating in chylomicrons and VLDL. Location: on the surface of vascular endothelial surface

3. Hepatic TG lipase (HL)

Degradation of TGs remaining in IDL

Hormone sensitive lipase

Degradation of TGs stored in adipocytes (release fatty acids)

1. Pancreatic Lipase:

Degradatoin of dietary triglycerides (TGs) in the small intestine

Chylomicron:

Deliver dietary TGs (absorbed from intestine) to peripheral tissue. -Deliver cholesterol to the liver in the form of chylomicron remnants (which are mostly depleted of their TGs) [Secreted by intestinal epithelial cells]

LDL:

Delivers hepatic cholesterol to peripheral tissues. -[Formed by the hepatic lipase (HL) modification of IDL in the peripheral tissue] -Taken up by target cells via receptor-mediated endocytosis

VLDL:

Delivers hepatic triglycerides (TGs) to peripheral tissue. [Secreted by liver]

Chylomicron:

F(x): transport dietary lipids (triglycerides [fat] from the intestines to to liver, skeletal muscle and adipose tissue Apolipoproteins contained: -E (mediates remnant uptake) -A-I (activates LCAT) -C-II (lipoprotein lipase cofactor) -B-48 (mediates chylomicron secretion

Density of the 5 lipoproteins:

From least dense to most dense: -Chylomicrons < very low-density lipoprotein (VLDL) < intermediate-density lipoprotein (IDL) < low-density lipoprotein < high-density lipoprotein (HDL). *Larger / less dense → smaller and denser. Lipoproteins are larger and less dense when the fat to protein ratio is increased. -["less dense" = more fat than protein content]

HDL:

Good lipoprotein; removes cholesterol from bloodstream, delivers it to liver for excretion in bile. Apo-lipoprotiens contained: -E: mediates remnant uptake -A-I: activates LCAT -C-II: Lipoprotein lipase cofactor

Familial Dyslipidemias:

I- hyperchylomicronemia IIa- familial hypercholesterolemia IV- hypertriglyerdiemia

IDL:

IDL: intermediate density between VLDL and LDL. -Breakdown from VLDL (by LPL). Transports a variety of triglyceride fats and cholesterol. Like LDL, can also promote the growth of atheroma. Apo-lipoproteins contained: -E: mediates remnant uptake -B-100: Binds LDL R

3. Intermediate-density lipoprotein (IDL)

IDL: intermediate density between VLDL and LDL. They are not usually detectable in the blood when fasting. -IDL (somewhat similar to LDL), transports a variety of triglyceride fats and cholesterol and, like LDL, can also promote the growth of atheroma.

LDL:

LDL: carry (phospholipids, cholesterol, triglycerides, etc.) around the body; bad lipoprotein, contribute to athresclerosis. Apo-lipoproteins contained: -B-100: binds LDL receptor

HDL vs. LDL lipoproteins

LDL: transports cholesterol from liver to tissues (bad) HDL: transports cholesterol from periphery to liver (to be excreted in bile)- good

____ are organic molecules including fats, oils, waxes, and steroids, which are hydrophobic

Lipids: Any of a class of organic compounds that are fatty acids or their derivatives; are insoluble in water but soluble in organic solvents. -Examples: natural oils, waxes, and steroids.

Apo-lipoprotein C-II

Lipoprotein lipase cofactor -(which degrades TGs circulating in chylomicrons and VLDLs, found on endothelial surface) Found in: -Chylomicron -VLDL -HDL

1. Chylomicrons

Lipoprotein particles that consist of: -Triglycerides (85-92%) -Phospholipids (6-12%) -Cholesterol (1-3%) -Proteins (1-2%).[1] F(x): transport dietary lipids (triglycerides [fat] from the intestines to to liver, skeletal muscle and adipose tissue

What are lipoproteins:

Lipoproteins are composed of varying proportions of: -Cholesterol, triglycerides (TGs) and phospholipids -LDL and HDL carry the most cholesterol

Lipoproteins:

Lipoproteins: [cholesterol, triglycerides, and proteins] -Enable cholesterol, triglycerides, and other lipids (fats) to move within the water-based solution of the blood-stream and move around the body -"Emulsify the lipid molecules in the body" Lipoproteins: 1. Chylomicrons 2. Very low-density lipoprotein (VLDL) 3. Intermediate-density lipoprotein (IDL) 4. Low-density lipoprotein (LDL) 5. High-density lipoprotein (HDL)

Apolipoprotein B-48:

Mediates chylomicron secretion Found in: -Chylomicron, chylomicron remnant

Apolipoprotein E:

Mediates remnant uptake Found in: -Chylomicron, chylomicron remnant, VLDL, IDL, HDL Not in: -LDL

HDL:

Mediates reverse cholesterol transport from periphery to liver -Acts as a repository for app-lipoproteins C and E (which are needed for chylomicron and VLDL metabolism. [Secreted by liver and intestine] -Alcohol ↑ synthesis

Cholesterol Ester Transfer Protein (CETP)

Mediates transfer of cholesterol esters to other lipoprotein particles

Action and function of statins:

Statins competitively and reversibly inhibit HMG-CoA reductase to decrease cholesterol synthesis.

The ______ is composed of three fatty acids esterfied to a glycerol molecule.

Triglyceride

2. Very low-density lipoprotein (VLDL)

VLDL: carry (newly synthesised) triglycerides from the liver to adipose tissue. Function of VLDL: -The body's internal transport mechanism for lipids. -Transports endogenous products, whereas chylomicrons transport exogenous (dietary) products. -VLDL is converted in the bloodstream to low-density lipoprotein (LDL).

VLDL:

VLDL: carry (newly synthesised) triglycerides from the liver to adipose tissue. -The body's internal transport mechanism for endogenous lipids. Apo-lipoproteins contained: -E (mediates remnant uptake) -C-II (Lipoprotein lipase cofactor) -B-100 (binds LDL receptor)

Chylomicron remnant:

What is contained after LPL degrades FFA from chylomicrons Apolipoproteins contained: -E (mediates remnant uptake) -B-48 (mediates chylomicron secretion)

IIa: Familial hyper cholestolemia

[AD]- *Absent or defective LDL Receptors* (can't rep-uptake LDL, so liver will make more) Increased blood level: -↑LDL, cholesterol Dx: -Herozygotes (cholesterol~ 300mg/dL -Homozygotes~ 700+ mg/dL Findings: -Accelerated atheroslcerosis* (MI before age 20) -Tendon (achilles) xanthomas -Corneal arcus (white, grey, or blue opaque ring in the corneal margin or white ring in front of the periphery of the iris.) Prognosis: -At risk for atherosclerosis and early MI (~20)

IV- Hyper-triglyceridemia

[AD]- *Hepatic overproduction of VLDL* Increased blood level: -↑VLDL, TG Dx: -Hyper-triglyceridemia Findings: -Hyper-triglyceridemia (>1000 mg/dL) can cause acute pancreatitis Prognosis: -At risk for atherosclerosis and early MI (~20)

I-Hyper-chylomicronemia

[AR]- 2 causes: 1) *Lipoprotein Lipase (LPL) Deficiency* 2) Altered apolipoprotein C-II (which is LPL cofactor) Increased blood level: -↑Chylomicrons, TG, cholesterol Findings: -Pancreatitis, hepatosplenomegaly -Eruptuve/pruritic xanthomas (but no ↑risk for atherosclerosis) Prognosis: -not at increased risk for athersclerosis :) Other: creamy layer in the supernatant

IDL:

[Formed in the degradation of VLDL (by *LPL)] -Delivers TG's and cholesterol to liver