BioChem Lecture 4

Cholesterol

27 Carbon lipid; HYDROPHOBIC

T/F can cholesterol diffuse into cell membrane

T

T/F Cholesterol is not required for animal life

F

Cholesterol can be synthesized by

all nucleated cells (primarily hepatocytes) and obtained through dietary intake

Cholesterol functions

include maintaining membrane fluidity and serving as a precursor for steroid hormones.

Cholesterol Structure

Where are all 27 carbons of cholesterol derived from?

Aceytal Co-A; many enzymes and precursors are necessary

The cholesterol synthesis requires energy from

ATP and reducing power from NADPH during cellular metabolism.

Squalene

serves as an intermediate in the biosynthesis of cholesterol

Squalene Structure

Aceytal-CoA structure

What is the mechanism of action of statins?

They competitively inhibit HMG-CoA reductase, reducing mevalonate formation and cholesterol synthesis.

Lovastatin

A naturally occurring statin used to lower cholesterol by inhibiting HMG-CoA reductase, therefore reducing cholesterol synthesis.

Chylomicron

A lipoprotein particle that transports dietary lipids from the intestines to other locations in the body, primarily delivering triglycerides to tissues.

break down triglyceride into free fatty acids  which are absorbed by intestinal cells, and repackaged as triglycerides and sent out ‘in bulk’ in the chylomicrons.

Lipases

Very low density lipoprotein (VLDL)

Endogenous fat transport

Low-density lipoprotein (BAD)

Lipoprotein that carries cholesterol from the liver to cells, often associated with cardiovascular disease.

Cholesterol is Transported in the Bloodstream by

lipoproteins such as VLDL, LDL, and HDL

High-density lipoprotein (GOOD)

Lipoprotein that helps transport cholesterol from the cells back to the liver (REVERSE), reducing the risk of cardiovascular disease.

Bile Acids:

Break down large macroscopic fat droplets into small triglyceride vesicles.

Initial Fat Delivery After a Meal

1. Chylomicrons deliver FFAs to adipocytes and peripheral tissues.

2. Chylomicron remnants cleaned up by liver.

What happens to excess free fatty acids (FFAs) during fasting?

The liver takes up excess FFAs released by adipocytes, preventing their accumulation in the blood, which can become toxic and cause lipotoxicity.

Liver Functions with fats

1) Rebalance Cholesterol

2) control the membrane fluidity of all cells

Cholesterol and FAs storage passage

initially sent out as VLDL, pass through a short-lived IDL form and deliver cholesterol to various tissues as LDL.

LDL/IDL receptor on the liver:

removes the LDL/IDL particle itself from circulation

HDL receptor:

receives cholesterol that HDL collected from tissues.

VLDL synthesized?

Liver

IDL & LDL synthesized?

formed in bloodstream from VLDL which was from the liver

HDL synthesized?

initially by both the liver and intestine, then matures in circulation

Lipoprotein Transport Disruption:

Familial Hypercholesterolemia

Cholesterol-Derived Important Biomolecules:

Bile Salts

Bile salts are in nature

amphipathic: hydrophobic on one side, hydrophilic on the other, like phospholipids

Bile Salts main functions

are to emulsify fats (a.k.a surfactants) and aid in the absorption of fat-soluble vitamins.

Bile Salts are turned into back into bile acids

by gut bacteria recirculated and passively reabsorbed by liver
(enterohepatic recirculation).

All about bile salts

1. Synthesized as “bile acids” from cholesterol in liver.

2. Conjugated with glycine or taurine to form a salt.

3. Stored in gallbladder until needed for digestion.

4. Released into intestine via bile duct.

VLDL pathway main driver

Excess liver fuel/fat (high carbs, insulin resistance)

HDL pathway main driver

Lipid sensors & gene regulators (PPAR-α/ω, LXR)

VLDL pathway purpose

Ship fuel and cholesterol out to tissues

HDL pathway purpose

Retrieve excess cholesterol

VLDL pathway atherogenic effect

Pro-atherogenic

HDL pathway atherogenic effect

Anti-atherogenic

VLDL pathway medical intervention

Statins, diet, weight loss

HDL pathway medical intervention

Fibrates, exercise, smoking cessation

gallstones

Cholesterol accumulation from impaired bile salt synthesis
or excess fat in diet

Cortisol

Promotes glucose and glycogen synthesis, enhances fat/protein degradation, inhibit inflammatory response.

Aldosterone

Increases Na+ reabsorption
in kidneys and
excretion of K+ and H+.

Progesterone

Establishment
and maintenance
of pregnancy

Testosterone

Male traits and
secondary sexual characteristics

Estradiol

Female traits and
secondary sexual characteristics

Steroid hormone receptors can act as

Transcription Factors

How can estrogen (a steroid hormone) regulate gene transcription?

Estrogen diffuses into the cell → binds its intracellular receptor → causes conformational change and receptor dimerization → receptor dimer binds an estrogen response element (ERE) on DNA → regulates transcription.

what is is Overexpressed in Breast cancer?

Estrogen receptor alpha (ERα)

How can estrogen signaling be therapeutically inhibited?

Aromatase inhibitors such as exemestane reduce estrogen synthesis, while SERMs such as tamoxifen bind estrogen receptors and inhibit estrogen signaling in breast tissue.

Aromatase inhibitors

such as exemestane reduce estrogen synthesis

SERMs

SERMs such as tamoxifen bind estrogen receptors and inhibit estrogen signaling in breast tissue.

Vitamin D is Synthesized

from Cholesterol and Requires Light (λ)—> Photolysis

Photolysis

is the decomposition or change of a chemical substance by light, often involving the breaking of chemical bonds.

True/False Vitamin D is a steroid

False; it acts similarly: through a receptor that acts as a transcription factor.

Vit D Deficiency

Rickets- bone and cartilage weakness

Warfarin

a strong anticoagulant,
has a structure similar to vitamin K.

Vitamin C function

Antioxidant

Vitamin C deficiency

Scurvy (swollen/bleeding gums and subdermal hemorrhaging)

Vitamin D function

Regulation of calcium and phosphate metabolism

Vitamin D deficiency in children

Rickets (skeletal deformities and impaired growth)

Vitamin D deficiency in adults

Osteomalacia (soft, bending bones)

Vitamin E function

Antioxidant; deficiency can cause muscle and nerve lesions (rare)

Vitamin K function

Blood coagulation

Vitamin K deficiency

Subdermal hemorrhaging