Untitled Flashcard Set


  1. Lipid Metabolism

    1. Intro to Lipid Catabolism

πŸ”Έ Hormonal Regulation

  • Glucagon

    • Promotes phosphorylation via GPCR signaling.

    • ↑ cAMP β†’ activates PKA.

    • Activates catabolic pathways: glycogenolysis, lipolysis.

  • Insulin

  • Promotes dephosphorylation via PP1 (protein phosphatase 1).

  • Activates anabolic pathways: glycogenesis, fatty acid synthesis.

  • Signals via receptor tyrosine kinase.

πŸ”Ή Overview of Lipid Catabolism

  • Lipids = triacylglycerols (TAGs) β†’ 3 fatty acids + 1 glycerol.

  • Even-chain fatty acids β†’ acetyl-CoA.

  • Odd-chain fatty acids β†’ succinyl-CoA (via propionyl-CoA).

  • Glycerol β†’ DHAP β†’ G3P or pyruvate/glucose (depending on direction).

  • Fatty acids broken down by Ξ²-oxidation β†’ energy (ATP).

  • Energy yield: 1 g fat β‰ˆ 2Γ— energy of 1 g glucose (more reduced carbons).

  • Each round of Ξ²-oxidation yields:

    • 1 FADHβ‚‚

    • 1 NADH

    • 1 acetyl-CoA β†’ enters TCA cycle

πŸ”Ή Dietary Fats

  • Ingested fats β†’ emulsified by bile acids β†’ smaller droplets.

  • Pancreatic lipases hydrolyze ester bonds β†’ free fatty acids + glycerol.

  • Reassembled into new TAGs in intestinal cells.

  • Packaged into chylomicrons (plasma lipoproteins):

    • Single phospholipid layer + cholesterol + apolipoproteins.

    • Key apolipoprotein: ApoC-II β†’ activates lipoprotein lipase (LPL).

  • LPL hydrolyzes chylomicron TAGs β†’ FFAs + glycerol for tissue use.

Study tip:
Visualize the sequence β€” digestion β†’ emulsification β†’ lipase action β†’ repackaging β†’ chylomicron transport β†’ LPL breakdown β†’ energy use.

πŸ”Ή Stored Fats (Adipocytes)

  • Triggered by energy demand/fasting β†’ low blood glucose β†’ glucagon.

  • Glucagon β†’ ↑ cAMP β†’ activates PKA.

  • PKA phosphorylates:

    • Hormone-sensitive lipase (HSL)

    • Perilipins surrounding fat droplets

  • Perilipin phosphorylation β†’ exposes lipid droplet; releases CGI-58, which activates ATGL.

  • Lipolysis sequence:

    • ATGL: TAG β†’ DAG + 1 FFA

    • HSL: DAG β†’ MAG + 1 FFA

    • MGL: MAG β†’ glycerol + 1 FFA
      β†’ Total:       3 FFAs + 1 glycerol

    • FFAs carried in blood by albumin (can hold ~10 fatty acids).

    • Glycerol travels to liver β†’ gluconeogenesis.

    • Glycerol kinase only active in liver.

πŸ”Ή Clicker Question

  • Correct answer: Glyceraldehyde-3-phosphate (G3P)

  • Glycerol β†’ glycerol-3-phosphate (via glycerol kinase) β†’ DHAP ↔ G3P

  • Enters glycolysis or gluconeogenesis

πŸ”Ή Fatty Acid Activation & Transport

  • FFAs in tissues must be activated:

    • Fatty acyl-CoA synthetase β†’ FFA + CoA + ATP β†’ fatty acyl-CoA (in cytosol)

    • Requires ATP and is irreversible (commits FA to metabolism)

  • Ξ²-oxidation occurs in mitochondria, but fatty acyl-CoA cannot cross membrane.

  • Carnitine shuttle system:

    • CAT1 / CPT1 (outer membrane):

      • Replaces CoA with carnitine β†’ fatty acyl-carnitine

      • Rate-limiting enzyme, inhibited by malonyl-CoA

    • Translocase: transports fatty acyl-carnitine into matrix

    • CAT2 / CPT2 (matrix):

      • Converts fatty acyl-carnitine back to fatty acyl-CoA

  1. FA Synthesis

πŸ§ͺ Ketogenesis (Ketone Body Formation)

  • Location: Mitochondria of liver cells (hepatocytes)

  • Triggered by:

    • Excess acetyl-CoA from Ξ²-oxidation

    • Limited TCA cycle activity due to oxaloacetate diversion for gluconeogenesis

  • Key molecules:

    • HMG-CoA: Intermediate shared with cholesterol synthesis

    • Ketone bodies:

      • Acetoacetate

      • Ξ²-hydroxybutyrate (energy source)

      • Acetone (exhaled)

  • Clinical relevance: Diabetic ketoacidosis: Excess ketone bodies β†’ low blood pH, high plasma/urine ketones

🧬 Ketone Body Utilization

  • Occurs in: Extrahepatic tissues (e.g., brain, muscle)

  • Pathway:

    • Ketone bodies β†’ acetyl-CoA β†’ TCA cycle

  • Key enzymes:

    • Ξ²-hydroxybutyrate dehydrogenase

    • Succinyl-CoA transferase

  • Note: Liver lacks succinyl-CoA transferase β†’ cannot use ketones

🧠 Fatty Acid Synthesis

  • Location: Cytosol (mainly liver and adipose tissue)

  • Starting point:

    • Acetyl-CoA β†’ Malonyl-CoA

      • Enzyme: Acetyl-CoA carboxylase (ACC) β€” biotin-dependent

  • Enzyme complex: Fatty Acid Synthase (FAS) β€” multifunctional

    • Domains:

      • KS: Ξ²-ketoacyl synthase

      • MAT: Malonyl/acetyl-CoA transferase

      • DH: Dehydratase

      • ER/KR: Reductases

      • ACP: Acyl carrier protein

      • TE: Thioesterase

πŸ”„ Steps of Elongation Cycle

  • Condensation: Acetyl-CoA + Malonyl-CoA β†’ 4-carbon Ξ²-ketoacyl-ACP

  • Reduction: Ξ²-keto β†’ Ξ²-hydroxy (uses NADPH)

  • Dehydration: Ξ²-hydroxy β†’ trans-double bond

  • Reduction: Double bond β†’ saturated chain (uses NADPH)

  • Transfer: Growing chain moved to KS domain

  • Repeat: Adds 2 carbons per cycle β†’ builds palmitate (C16)

  • Final step: Thioesterase releases palmitate from ACP

⚑ Energy Cost & Regulation

πŸ”‹ Energy Requirements

  • For palmitate (C16):

    • 8 Acetyl-CoA

    • 7 ATP

    • 14 NADPH

    • Produces: Palmitate + 14 NADP⁺ + 8 CoA + 7 ADP + 7 Pi + 6 Hβ‚‚O

πŸ”§ Regulation

  • Rate-limiting enzyme: Acetyl-CoA carboxylase (ACC)

    • Activated by citrate

    • Inhibited by palmitoyl-CoA

  • Malonyl-CoA:

    • Inhibits carnitine acyltransferase I β†’ blocks Ξ²-oxidation

    • Ensures synthesis and breakdown don’t occur simultaneously

πŸ” Transport & Integration

πŸ”„ Acetyl-CoA Transport to Cytosol

  • Source: Glycolysis β†’ Pyruvate β†’ PDH β†’ Acetyl-CoA

  • Transport:

    • Acetyl-CoA + Oxaloacetate β†’ Citrate (via citrate synthase)

    • Citrate β†’ Cytosol β†’ Acetyl-CoA (via citrate lyase)

    • Oxaloacetate β†’ Malate β†’ Pyruvate (via malic enzyme) β†’ generates NADPH

πŸ”— Pathway Integration

  • Connects:

    • Glycolysis

    • TCA cycle

    • Pentose phosphate pathway (NADPH source)

    • Lipid metabolism

🧬 Cholesterol & Plasma Lipoproteins (Preview)

  • Cholesterol synthesis:

    • Begins with acetyl-CoA

    • Key enzyme: HMG-CoA reductase

    • Regulated by feedback inhibition, phosphorylation, and transcriptional control

  • Plasma lipoproteins:

    • Transport cholesterol and triglycerides

    • Types: Chylomicrons, VLDL, LDL, HDL

    • Clinical relevance: Atherosclerosis, lipid panels, statin therapy

    • Cholesterol & Plasma lipoproteins

🧬 Long Chain Fatty Acids (LCFAs)

  • Palmitate (16:0) is the primary product of fatty acid synthesis.

  • LCFAs can be:

    • Elongated β†’ e.g., palmitate β†’ stearate (18:0)

    • Desaturated β†’ e.g., stearate β†’ oleate (18:1)

  • Essential fatty acids (EFAs):

    • Linoleic acid (18:2, Ο‰-6) and Ξ±-linolenic acid (18:3, Ο‰-3) must be obtained from the diet.

    • Mammals cannot introduce double bonds beyond carbon 9.

    • EFAs are precursors to:

      • Arachidonic acid

      • EPA (eicosapentaenoic acid)

      • DHA (docosahexaenoic acid)

      • Eicosanoids: prostaglandins, thromboxanes, leukotrienes, resolvins, protectins

πŸ”’ Allosteric Control of Fatty Acid Metabolism

  • Palmitoyl-CoA: inhibits acetyl-CoA carboxylase (ACC) β†’ feedback inhibition

  • Citrate: activates ACC β†’ signals high energy and carbon availability

  • Malonyl-CoA: inhibits carnitine acyltransferase I β†’ prevents simultaneous synthesis and breakdown

  • 🧠 Hormonal regulation:

    • Glucagon/epinephrine β†’ phosphorylate and inhibit ACC

    • Insulin β†’ dephosphorylate and activate ACC

    πŸ” Regulation of Ξ²-Oxidation vs. Synthesis

Condition

Effect

High glucose / insulin

↑ Fatty acid synthesis, ↓ Ξ²-oxidation

Low glucose / glucagon

↑ Ξ²-oxidation, ↓ synthesis

Malonyl-CoA

Blocks fatty acid entry into mitochondria (via CPT I inhibition)

PKA activation

Phosphorylates ACC β†’ ↓ synthesis

Citrate lyase & malic enzyme

↑ cytosolic acetyl-CoA and NADPH for synthesis


🧬 Hormonal Control Summary

πŸ”Ή Glucagon

  • Activates protein kinases

  • Effects:

    • ↓ ACC activity

    • ↑ Hormone-sensitive lipase

    • ↓ Pyruvate dehydrogenase

    • ↑ Fat mobilization

    • ↑ Gluconeogenesis

πŸ”Ή Insulin

  • Activates phosphoprotein phosphatases

  • Effects:

    • ↑ ACC activity

    • ↓ Hormone-sensitive lipase

    • ↑ Pyruvate dehydrogenase

    • ↑ Fatty acid synthesis

    • ↑ Glycolysis

    • ↓ Gluconeogenesis

πŸ₯‘ Diet Effects on Lipid Metabolism

πŸ”Ή Low-Carbohydrate Diet

  • ↑ Glucagon, ↓ insulin

  • ↑ Fatty acid release from adipocytes

  • ↓ ACC and FAS activity

  • ↑ Ξ²-oxidation β†’ ↑ acetyl-CoA

  • ↓ citrate synthesis (due to oxaloacetate use in gluconeogenesis)

  • ↑ Ketone body production β†’ risk of ketoacidosis

πŸ”Ή High-Carbohydrate Diet

  • ↑ Insulin

  • ↑ Glucose uptake (GLUT4)

  • ↑ Citrate β†’ activates ACC

  • ↑ Malonyl-CoA β†’ inhibits CPT I

  • ↑ Fatty acid synthesis

  • ↑ NADPH (via malic enzyme and pentose phosphate pathway)

  1. Cholesterol Synthesis and Plasma Lipoproteins

Structure of Cholesterol – Know This

  • Fused 4-ring structure (A, B, C, D rings)

  • Planar molecule

  • OH on Carbon 3

  • Hydrocarbon side chain on Carbon 17

  • These positions are important because cholesterol derivatives modify C3 and C17

🧬 Cholesterol Biosynthesis – 4 Stages

  • Only Stage 1 needs detailed steps, enzymes, reactants, and products for the exam.
    Stages 2–4 β†’ know big picture & key takeaways only.

Stage 1: Acetate β†’ Mevalonate (Know Steps!)

  • Occurs in cytosol of cells (mostly liver).

Step

Enzyme

What Happens

1Β 

Thiolase

2 Acetyl-CoA β†’ Acetoacetyl-CoA

2

HMG-CoA Synthase

+ another Acetyl-CoA β†’ HMG-CoA

3 (Rate-Limiting Step)

HMG-CoA Reductase

HMG-CoA β†’ Mevalonate (requires NADPH)

  • πŸ”Έ Rate-limiting step: HMG-CoA β†’ Mevalonate
    πŸ”Έ Exam point: Same intermediate as ketone synthesis, but location differs

  • Ketone body synthesis: mitochondria

  • Cholesterol synthesis: cytosol
    STATINS inhibit HMG-CoA Reductase

Stage 2: Mevalonate β†’ Activated Isoprenes (Know Key Ideas Only)

  • 3 ATP are required (energy-expensive)

  • 6C mevalonate β†’ 5C activated isoprenes

  • β€œActivated” due to pyrophosphate groups

Stage 3: Isoprenes β†’ Squalene (Know Carbon Math)

  • 5C + 5C = 10C (Geranyl-PP)

  • 10C + 5C = 15C (Farnesyl-PP)

  • 15C + 15C = 30C (Squalene)
    βœ” Know Geranyl = 10C, Farnesyl = 15C, Squalene = 30C

Stage 4: Cyclization β†’ Cholesterol

  • Squalene β†’ Cholesterol (β‰ˆ19 steps – NO details needed)

  • Requires NADPH

  • Adds oxygen β†’ forms epoxide, eventually produces OH on C3

  • End result: formation of 4-ring cholesterol structure

πŸ”’ Regulation of Cholesterol Synthesis

  • Know both short-term & long-term regulation

Short-Term Regulation (Enzyme Activity)

  • Regulates HMG-CoA ReductasebOther Regulators:

  • Oxysterols (oxidized cholesterol) inhibit HMG-CoA Reductase

  • Oxysterols also promote HMG-CoA Reductase degradation

Long-Term Regulation (Gene Expression)

  • Regulates amount of enzyme made

  • Proteins involved: Insig, SCAP, SREBP

Cholesterol Level

What Happens

High cholesterol

Sterols keep Insig–SCAP–SREBP in ER β†’ no transcription of enzymes

Low cholesterol

Insig is degraded; SCAP transports SREBP to Golgi β†’ SREBP fragment goes to nucleus to activate transcription of cholesterol synthesis genes

🩸 Plasma Lipoproteins – What to Know

Types & Function

Lipoprotein

Function

Key Apo Protein

Chylomicrons

Carry dietary fat (TAGs)

ApoB-48, ApoC-II

VLDL

Carry liver-synthesized TAGs & cholesterol to tissues

ApoB-100

LDL (β€œbad”)

Delivers cholesterol to tissues

ApoB-100

HDL (β€œgood”)

Reverse cholesterol transport back to liver

ApoA-I

  • Trend: Protein % increases from chylomicrons β†’ HDL

Lipid Transport

  • Two pathways:

Exogenous Pathway (Dietary)

  • Chylomicrons deliver dietary TAGs to tissues

  • ApoC-II activates lipoprotein lipase (LPL) β†’ releases fatty acids into cells

Endogenous Pathway (Made by Liver)

  • 1. Liver packages fats into VLDL

  • 2. VLDL loses TAGs β†’ becomes IDL β†’ LDL

  • 3. LDL delivers cholesterol to tissues

  • 4. HDL cleans up excess cholesterol & returns to liver (β€œreverse transport”)

LDL Uptake – Must Know

  • LDL is taken into cells via receptor-mediated endocytosis

  • Cell receptors recognize ApoB-100

  • LDL is engulfed whole and broken down inside cell

❀ Atherosclerosis (How LDL Causes Damage)

  • If LDL is not taken up by receptors:

    • 1. Remains in blood β†’ enters arterial wall

    • 2. Becomes oxidized

    • 3. Macrophages eat it β†’ become foam cells

    • 4. Foam cells accumulate β†’ plaque formation

    • 5. Blood flow narrows β†’ atherosclerosis & heart disease

HDL helps prevent this by clearing cholesterol from foam cells