Lipids biochemistry and metabolism

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Lipids: Biochemistry and Metabolism

1. Classification of Lipids

Lipids are a chemically diverse group of hydrophobic or amphipathic molecules. The major classes are:

Lipid structures — fatty acids, triglycerides, phospholipids, and sterols

Class	Structure	Examples
Fatty acids	Long hydrocarbon chain + carboxyl group	Palmitic (C16:0), Stearic (C18:0), Oleic (C18:1)
Triglycerides (triacylglycerols)	Glycerol + 3 fatty acids	Storage fat
Phospholipids	Glycerol + 2 FA + phosphate + polar head	Phosphatidylcholine (lecithin), phosphatidylserine
Sphingolipids	Sphingosine backbone	Sphingomyelin, cerebrosides
Sterols	Steroid nucleus	Cholesterol, steroid hormones, bile acids, vitamin D

Saturated fatty acids have no double bonds (e.g., palmitic acid).
Unsaturated fatty acids have one or more double bonds (e.g., oleic acid has one; linoleic acid has two — an essential fatty acid).

2. Dietary Lipid Digestion & Absorption

Dietary fat is predominantly triglycerides. Key steps:

Lingual/gastric lipase begins hydrolysis in the stomach.
Pancreatic lipase (with colipase) cleaves triglycerides to 2-monoglycerides + free fatty acids in the small intestine.
Bile salts emulsify lipids, forming micelles that allow uptake by enterocytes.
Inside enterocytes, monoglycerides and fatty acids are resynthesized into triglycerides → packaged into chylomicrons with apolipoprotein B-48.
Chylomicrons enter the lymphatics (lacteals) → thoracic duct → venous blood at the jugular-subclavian junction.

Guyton and Hall Textbook of Medical Physiology, p. 842

3. Lipid Transport: Lipoproteins

Lipids are insoluble in plasma and are transported as lipoproteins — spherical particles with a hydrophobic core (triglycerides, cholesterol esters) surrounded by an amphipathic shell (phospholipids, free cholesterol, apolipoproteins).

Chylomicron structure — phospholipid/apolipoprotein shell surrounding TG/cholesterol core

Lipoprotein Classes

Lipoprotein	Origin	Main Cargo	Key Apolipoprotein	Function
Chylomicron	Intestine	Dietary TG (highest)	Apo B-48, Apo C-II, Apo E	Deliver exogenous TG to periphery
VLDL	Liver	Endogenous TG (high)	Apo B-100	Deliver hepatic TG to periphery
IDL	From VLDL	TG + cholesterol	Apo B-100, Apo E	Intermediate; cleared by liver or → LDL
LDL	From IDL	Cholesterol (highest)	Apo B-100	Deliver cholesterol to tissues
HDL	Liver + intestine	Cholesterol (high protein)	Apo A-I	Reverse cholesterol transport

Guyton and Hall Textbook of Medical Physiology, p. 843
Lippincott's Biochemistry, p. 673

Key Enzymes in Lipoprotein Metabolism

Lipoprotein lipase (LPL): On capillary endothelium; activated by Apo C-II; hydrolyzes TG in chylomicrons and VLDL → releases fatty acids for storage or energy.
Hepatic lipase: Converts IDL → LDL.
LCAT (Lecithin-Cholesterol Acyltransferase): Activated by Apo A-I; esterifies free cholesterol in HDL (core of HDL grows).
CETP (Cholesterol Ester Transfer Protein): Transfers cholesterol esters from HDL to VLDL/LDL.

Reverse Cholesterol Transport (RCT)

HDL is assembled from lipid-poor Apo A-I secreted by the liver and intestine. Peripheral cells export cholesterol via the ABCA1 transporter → loaded onto HDL → LCAT esterifies it → HDL delivers cholesterol esters to the liver via SR-B1 receptor for elimination as bile acids.

Cholesterol synthesis and lipoprotein metabolism concept map

4. Fatty Acid Oxidation (β-Oxidation)

β-Oxidation is the primary pathway for catabolizing fatty acids, occurring in the mitochondrial matrix.

Step 1 — Activation: Fatty acid + CoA → Fatty acyl-CoA (uses ATP; occurs in cytoplasm/outer mitochondrial membrane).

Step 2 — Transport into mitochondria:

Short- and medium-chain FAs enter freely.
Long-chain FAs require carnitine shuttle:
- Acyl-CoA + Carnitine → Acylcarnitine (catalyzed by CPT-I on outer membrane)
- Translocase shuttles acylcarnitine across inner membrane
- CPT-II regenerates Acyl-CoA in the matrix
- Carnitine is synthesized from lysine + methionine.

Step 3 — β-Oxidation spiral (repeating 4-step cycle):

β-Oxidation pathway — 4-step spiral removing 2C units as acetyl-CoA

Step	Reaction	Cofactor
1. Oxidation	Acyl-CoA → 2,3-Enoyl-CoA	FAD → FADH₂
2. Hydration	Enoyl-CoA → 3-Hydroxyacyl-CoA	—
3. Oxidation	3-Hydroxyacyl-CoA → 3-Ketoacyl-CoA	NAD⁺ → NADH
4. Thiolysis	3-Ketoacyl-CoA + CoA → Acyl-CoA (–2C) + Acetyl-CoA	—

Each cycle shortens the chain by 2 carbons, releasing one acetyl-CoA, one FADH₂, and one NADH. Acetyl-CoA enters the TCA cycle.

Energy yield: Catabolism of 1 mol of a 6-carbon fatty acid yields 44 mol ATP vs. 38 mol ATP from glucose — fatty acids are far more energy-dense than carbohydrates.

Ganong's Review of Medical Physiology, p. 37

5. Ketone Body Formation & Metabolism

When acetyl-CoA production exceeds TCA cycle capacity (starvation, diabetes, high-fat diet), the liver diverts acetyl-CoA to ketone body synthesis:

Pathway (in liver mitochondria):

2 Acetyl-CoA → Acetoacetyl-CoA
Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA (mitochondrial HMG-CoA synthase)
HMG-CoA → Acetoacetate + Acetyl-CoA (HMG-CoA lyase)
Acetoacetate → β-Hydroxybutyrate (reversible) or Acetone (irreversible, volatile)

Ketone bodies (acetoacetate, β-hydroxybutyrate, acetone) are exported to peripheral tissues (brain, heart, muscle), where they are converted back to acetyl-CoA → TCA cycle.

Ketoacidosis occurs when ketone body production exceeds peripheral utilization — pH falls, characteristic acetone breath develops. Triggered by: DKA, starvation, alcoholism.

Guyton and Hall Textbook of Medical Physiology, p. 846

6. Fatty Acid Synthesis (De Novo Lipogenesis)

Fatty acid synthesis is the reverse of β-oxidation in direction but uses a different set of enzymes, location, and cofactors.

Feature	β-Oxidation	De Novo Synthesis
Location	Mitochondria	Cytoplasm
Carrier	CoA	ACP (Acyl Carrier Protein)
Reducing agent	FAD, NAD⁺ (oxidized)	NADPH (consumed)
Key enzyme	Thiolase	Fatty Acid Synthase (FAS)
Key intermediate	Acetyl-CoA	Malonyl-CoA

Key steps:

Acetyl-CoA (mitochondrial) → exported to cytoplasm as citrate via the citrate shuttle
Acetyl-CoA + CO₂ → Malonyl-CoA (catalyzed by Acetyl-CoA Carboxylase, ACC; requires biotin) — the committed, rate-limiting step
Fatty Acid Synthase (FAS) elongates the chain by 2 carbons per cycle using malonyl-CoA as donor
NADPH is supplied by the pentose phosphate pathway (HMP shunt)
The primary product is Palmitate (C16:0); further elongation/desaturation occurs in the ER

Regulation:

Insulin activates ACC (stimulates lipogenesis)
Glucagon/epinephrine inactivate ACC via PKA phosphorylation
AMPK phosphorylates and inactivates ACC when energy is low
Malonyl-CoA inhibits CPT-I, preventing simultaneous synthesis and oxidation

7. Cholesterol Biosynthesis

All 27 carbons of cholesterol come from acetyl-CoA. Synthesis occurs primarily in the liver, also in the intestine, adrenal cortex, and gonads. The pathway is cytoplasmic (ER).

4 Stages:

Stage 1: Acetyl-CoA → Mevalonate

HMG-CoA synthase and reductase pathway producing mevalonate from acetyl-CoA

2 Acetyl-CoA → Acetoacetyl-CoA → HMG-CoA (cytosolic HMG-CoA synthase)
HMG-CoA + 2 NADPH → Mevalonate (HMG-CoA reductase) ← rate-limiting step; target of statins

Stage 2: Mevalonate → Activated isoprene (IPP)

3 ATP phosphorylate mevalonate → decarboxylation → isopentenyl pyrophosphate (IPP, Δ³-isopentenyl-PP)

Stage 3: IPP → Squalene (C30)

6 isoprene units condense (via geranyl-PP, farnesyl-PP) → Squalene (requires NADPH)

Stage 4: Squalene → Cholesterol (C27)

Squalene cyclizes → lanosterol → multiple steps → cholesterol

Regulation of HMG-CoA Reductase

SREBP-2 (Sterol Regulatory Element-Binding Protein 2): When intracellular cholesterol is low, SREBP-2 is activated → increases HMG-CoA reductase gene transcription.
Accelerated protein degradation: High cholesterol promotes enzyme degradation.
AMPK phosphorylation: Inactivates the enzyme when energy is low.
Insulin activates; glucagon inhibits.
Statins: Competitive inhibitors of HMG-CoA reductase → reduce hepatic cholesterol → upregulate LDL receptors → lower plasma LDL.

Lippincott's Biochemistry, p. 672; Basic Medical Biochemistry 6e

8. Cholesterol Utilization & Elimination

Cholesterol cannot be fully catabolized in humans — its ring structure is intact. It is eliminated by:

Bile acid synthesis: Rate-limiting step = cholesterol-7α-hydroxylase (inhibited by bile acids — feedback)
Steroid hormone synthesis: Cholesterol → Pregnenolone (P450scc, rate-limiting) → cortisol, aldosterone, sex hormones
Vitamin D synthesis: Skin + liver + kidney
Direct secretion into bile (risk: gallstones / cholelithiasis if bile salts insufficient)

Enterohepatic circulation: >95% of bile acids are reabsorbed in the terminal ileum and returned to the liver. Bile acid sequestrants (cholestyramine) interrupt this cycle.

9. Regulation Summary: Fed vs. Fasted State

State	Dominant Pathway	Key Hormones
Fed / Insulin ↑	FA synthesis, TG storage, cholesterol synthesis	Insulin activates ACC, FAS, HMG-CoA reductase
Fasted / Glucagon ↑	β-Oxidation, ketogenesis, lipolysis	Glucagon/epinephrine activate HSL, inhibit ACC
Starvation / DM	Maximal β-oxidation + ketogenesis	Cortisol ↑, glucagon ↑ → FFA release from adipose

Hormone-sensitive lipase (HSL) in adipocytes is activated by glucagon/epinephrine via cAMP-PKA → hydrolyzes stored TG → releases FFA bound to albumin for transport to other tissues.

10. Clinical Correlations

Condition	Defect	Consequence
Familial hypercholesterolemia (FH)	Defective LDL receptor	↑ LDL-C; premature atherosclerosis
Type I hyperlipoproteinemia	LPL or Apo C-II deficiency	Massive chylomicronemia; pancreatitis
Type III hyperlipoproteinemia	Apo E2/E2 homozygosity	IDL & chylomicron remnant accumulation
Diabetic ketoacidosis	No insulin → no glucose utilization	Massive ketone body production → acidosis
MCAD deficiency	Medium-chain acyl-CoA dehydrogenase deficiency	β-Oxidation block → hypoglycemia, hypoketosis
Abetalipoproteinemia	No Apo B synthesis	Cannot form chylomicrons/VLDL → fat malabsorption
Atherosclerosis	LDL oxidation + macrophage uptake	Foam cells → plaques

Sources: Guyton and Hall Textbook of Medical Physiology (Chap. 69); Ganong's Review of Medical Physiology, 26e; Lippincott Illustrated Reviews: Biochemistry, 8e; Basic Medical Biochemistry: A Clinical Approach, 6e

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