🧬 Cholesterol Metabolism...............

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1. ?????? Cholesterol Metabolism
Cholesterol is a vital lipid molecule used in:
Cell membranes
Steroid hormone synthesis
Bile acids
Vitamin D production
?????? Mostly synthesized in the liver, but also obtained from the diet.
?????? 1. Cholesterol Synthesis
Site: Cytoplasm of liver and intestinal cells
Starting material: Acetyl-CoA
Rate-limiting enzyme: HMG-CoA reductase
End product: Cholesterol
?????? Key Steps:
1.Acetyl-CoA → HMG-CoA
2.HMG-CoA → Mevalonate (via HMG-CoA reductase) ← ?????? Statins inhibit here
3.Mevalonate → Isoprenoid units → Squalene → Cholesterol
?????? 2. Transport of Cholesterol
Lipoprotein Function Rich In
ChylomicronsCarry dietary fats from intestineTriglycerides
VLDL Export triglycerides from liverTriglycerides
LDL Delivers cholesterol to tissues (bad)Cholesterol
HDL Reverse transport (to liver) (good)Cholesterol, proteins
✅ HDL = "Healthy", LDL = "Lousy"
?????? 3. Regulation of Cholesterol Synthesis

2. Factor Effect on HMG-CoA Reductase
High cholesterol↓ Inhibits
Insulin ↑ Stimulates
Glucagon ↓ Inhibits
Statins (drugs)↓ Inhibit enzyme directly
?????? 4. Cholesterol Catabolism
Cholesterol is not broken down for energy.
It's converted into:
oBile acids (cholic, chenodeoxycholic acid)
oBile salts – aid fat digestion
oSteroid hormones – cortisol, estrogen, testosterone
oVitamin D – from 7-dehydrocholesterol in skin via sunlight
?????? Clinical Connections
Condition Cause
HypercholesterolemiaHigh LDL; genetic or dietary
Atherosclerosis LDL deposits in vessels → plaque
Statin therapy Inhibits HMG-CoA reductase
Gallstones (Cholelithiasis)Cholesterol supersaturation in bile
?????? Mnemonic for Cholesterol Functions: "CHoLeS"
Cell membrane structure
Hormones (steroid)
Lipoprotein formation
Salts of bile (bile acids)
?????? Fatty Acid (FA) Metabolism

3. ?????? 1. Beta-Oxidation (Breakdown of Fatty Acids)
Occurs in: Mitochondria
Function: Breaks down fatty acids to generate Acetyl-CoA
Steps:
1.Activation of FA (in cytosol) → Fatty acyl-CoA
2.Transport into mitochondria via carnitine shuttle
3.β-oxidation: Removes 2-carbon units (as Acetyl-CoA) per cycle
Each round produces:
o1 NADH
o1 FADH
₂
o1 Acetyl-CoA
✅ Acetyl-CoA enters:
Krebs Cycle (if carbs available)
Ketogenesis (if carbs are scarce)
?????? 2. Fatty Acid Synthesis (Lipogenesis)
Occurs in: Cytoplasm (mainly in liver & adipose tissue)
Starts from: Acetyl-CoA (from glucose)
Key steps:
1.Acetyl-CoA → Malonyl-CoA (via acetyl-CoA carboxylase) – rate-limiting step
2.Malonyl-CoA units are added to grow FA chain (via Fatty Acid Synthase)
✅ Needs NADPH from Pentose Phosphate Pathway
?????? Ketone Body Metabolism
?????? 1. Ketogenesis (Formation of Ketone Bodies)
Occurs in: Liver mitochondria
When: Fasting, prolonged exercise, uncontrolled diabetes
Trigger: Excess Acetyl-CoA from β-oxidation and low insulin
Steps:
oAcetyl-CoA → Acetoacetate →
→ β-hydroxybutyrate (reduced form)
→ Acetone (exhaled)

4. ✅ Ketone bodies = water-soluble energy source for brain, heart, muscles
?????? 2. Ketolysis (Utilization of Ketone Bodies)
Occurs in: Extrahepatic tissues (e.g., brain, muscle)
Liver cannot use ketone bodies (lacks enzyme thiophorase)
β-hydroxybutyrate → Acetoacetate → Acetyl-CoA → Krebs Cycle
?????? Summary Chart
Process Site Key Products
β-OxidationMitochondria Acetyl-CoA, NADH, FADH
₂
FA SynthesisCytoplasm Palmitate (C16 FA), NADP
⁺
KetogenesisLiver mitochondriaKetone bodies: acetoacetate, β-hydroxybutyrate, acetone
KetolysisMuscle, brain (not liver)Acetyl-CoA → energy
?????? Mnemonic for Ketone Bodies: "AAB"
Acetoacetate
Acetone
Beta-hydroxybutyrate