Lipid Digestion & Lipoprotein Metabolism

Unit 4: Carb & Lipid Metabolism

Overview of Course Content

  • Topic Area: Lipid Digestion & Lipoprotein Metabolism

  • Course Code: Biochemistry 555

  • Instructor: Elizabeth Hull, PhD

  • Recommended Reading: Marks Chapters 29, 31, 32; Lippincott Chapter 18; Lipoprotein Review Video

Learning Objectives

  • Understand the structures of key lipids:

    • Triacylglycerols (TAG)

    • Fatty Acids (FA)

    • Diacylglycerols

    • Cholesterol

    • Cholesterol Esters

  • Understand roles of:

    • Cholecystokinin (CCK)

    • Secretin

    • Bicarbonate

    • Pancreatic lipases (targeting TAG, CE, phospholipids)

    • Bile acids/salts in lipid digestion.

  • List products of:

    • Cholesteryl ester hydrolase

    • Phospholipase A2

    • Lysophospholipase

  • Distinguish between:

    • Lingual lipase, gastric lipase, and pancreatic lipase

    • Detail their products and list absorbed products by enterocytes.

  • Understand the resynthesis process of TAG and CE in the enterocyte.

  • Note the role of chylomicrons in bulk transport of dietary lipids.

  • Contrast chylomicrons' function with albumin in transporting short and medium-chain free FAs and FAs during fasting.

  • Understand the role of lipoproteins in lipid transport (LPL, HTGL, transfer proteins) and lipoprotein lifecycle:

    • Distinguish cargo transported by three families of lipoproteins.

    • Identify key apolipoproteins: ApoB100, ApoB48, ApoA, ApoCII, ApoE.

    • Understand HDL's role as a reservoir for ApoCII and ApoE, and the significance of chylomicrons and VLDL being “nascent”.

Lecture Outline

  • Review of lipid structure

  • Lipid digestion, absorption, and transport

  • Lipoprotein structure and function

  • Classification, apolipoproteins, lifecycle

  • Chylomicrons

  • VLDL, IDL, LDL

  • HDL

  • Transport of Lipids without Lipoproteins

  • Albumin & Fatty Acid Transport

  • Short Chain Fatty Acids

Review of Lipid Structures

  • General Characteristics:

    • Lipids are insoluble in water and soluble in organic solvents.

    • Structural diversity with no common monosaccharide unit.

  • Classification based on polarity:

    • Membrane lipids (amphipathic):

    • Cholesterol, Diacylglycerols (incl. phospholipids), Sphingosine-based glycolipids

    • Non-polar lipids (not used in membranes):

    • Triacylglycerols (TAGs): function as energy storage.

    • Cholesterol esters (CE): transportable form of cholesterol.

Cholesterol Structure

  • Components:

    • Steroid nucleus.

    • Hydrocarbon chain.

    • Hydroxyl group (–OH) incorporated at C3 of A ring.

  • Hydrophobic nature: Mostly hydrophobic due to steroid nature.

  • Cholesterol Ester Formation:

    • Occurs when fatty acid is linked by an ester bond to the hydroxyl group, increasing hydrophobicity.

    • Majority of plasma cholesterol exists in esterified form within lipoproteins.

Digestion, Absorption, and Transport of Dietary Lipids

  • Main Lipid Component:

    • 90% of ingested fats are TAGs.

    • Composition: three FAs esterified to a glycerol backbone.

    • TAGs serve as an efficient energy storage structure.

  • Digestion Initiation:

    • Begins in mouth with lingual lipase, followed by gastric lipase.

    • Target preference for short and medium-chain FAs in TAGs (typically <12C).

  • Optimal Conditions:

    • Both lipases are relatively stable in acid with optimal pH levels of 4 – 6.

Digestive Processes in the Small Intestine

Role of Bile and Pancreatic Enzymes

  • Lipids, being water-insoluble, engage enzymes that are water-soluble which facilitate digestion:

    • Mixed micelles form, enhancing the surface area of lipid droplets, making it easier for enzymes to act.

    • Bile Salts: From gallbladder emulsify dietary lipids in conjunction with peristaltic actions.

  • Cholecystokinin (CCK) and Secretin release upon chyme movement triggers:

    • Bile release containing bile salts and bicarbonate.

    • Digestive enzymes from the pancreas for fats.

  • Lipid Degradation:

    • TAGs are too large to be directly absorbed, requiring enzymatic degradation by pancreatic lipase, colipase, cholesteryl ester hydrolase, and phospholipase A2.

Chylomicron Transport

  • Chylomicrons formed post-digestion, carry fatty acids to tissues. They are synthesized in enterocytes with the following components:

    • TAGs and Cholesterol Esters are resynthesized into hydrophobic cargo.

    • Apolipoprotein B48 acts as a nucleating factor.

  • Exocytosed into the lymphatic system then into circulation through the left subclavian vein.

  • Lipoprotein Lipase (LPL) acts on TAGs in circulating chylomicrons to release FAs for tissue uptake.

Lipoprotein Structure and Function

  • Key Components:

    • Core: Hydrophobic TAG and CE as cargo.

    • Monolayer: Amphipathic membrane lipids making lipoproteins soluble.

    • Proteins: Facilitate lipid transfer and delivery.

  • Three Classes of Lipoproteins:

    1. Chylomicrons: Transport dietary lipids.

    2. VLDL, IDL, LDL: Transport endogenous TAGs/cholesterol.

    3. HDL: Reverse transport of cholesterol from tissues to the liver.

  • Classification by Density:

    • Lipoproteins vary in density based on lipid and protein ratio, arranged from less dense (chylomicrons) to more dense (HDL).

Apolipoproteins

Structural Apolipoproteins

  • Identifying Features:

    • Inserted during synthesis, recognized by receptors on cells that allow for endocytosis.

  • Major Apolipoproteins:

    • ApoB48: Marks chylomicrons, derived from editing ApoB100 mRNA.

    • ApoB100: Present in VLDL, IDL, LDL, derived from complete ApoB100 mRNA.

    • ApoA: Present in HDL, important for reverse cholesterol transport.

Peripheral Apolipoproteins

  • Characteristics:

    • Acquired during circulation, transforming a lipoprotein from “nascent” to fully functional “mature” status.

  • Function:

    • ApoC-II: Activates lipoprotein lipase, aiding in TAG reduction.

    • ApoE: Facilitates endocytosis of remnant lipoproteins in the liver.

Lifecycles of Lipoprotein Particles

  1. Exocytosed from cells with structural apolipoproteins.

  2. Picked up co-activating peripheral apolipoproteins.

  3. Exchange of lipids during circulation.

  4. Lose some co-activating proteins to HDL.

  5. Endocytosed by liver or kidney through receptor-ligand interactions.

Key Concepts of Lipid Metabolism

  • Activated Form of Fatty Acid: Fatty acyl-CoA is required for metabolic entry.

  • Regulatory Note: Lipid metabolism lacks regulation compared to carbohydrate metabolism.

  • Enzyme Naming Patterns:

    • Enzymes typically combine substrates with their actions (e.g., ACAT, PCAT, CETP).

  • Lipids from Digestion: TAGs are prime dietary lipids processed before absorption.

Knowledge Checks and Answers

  1. Correct Answer: D - Patients with cystic fibrosis struggle due to pancreatic secretion issues limiting digestion.

  2. Correct Answer: B - TAGs carried by chylomicrons undergo degradation by LPL.

  3. Correct Answer: D - Secretin raises pH, enabling lipid digestion.

  4. Correct Answer: C - Short and medium-chain FAs enter portal blood post-absorption.

  5. Correct Answer: B - Chylomicrons mostly consist of triglycerides.

  6. Correct Answer: D - Type III hyperlipidemia reveals elevated triglycerides.

  7. Correct Answer: D - HDL is critical for converting nascent to mature chylomicrons.

  8. Correct Answer: B - Order is HDL > LDL > VLDL > Chylomicrons.

  9. Correct Answer: C - MTP deficiency would lead to chylomicron elevation post-meal.

  10. Correct Answer: A - Milky plasma indicates high chylomicron presence.

  11. Correct Answer: C - A deficiency in ApoC-II would cause lipid metabolism issues.

  12. Correct Answer: B - A low-carb diet benefits patients with elevated VLDL.

  13. Correct Answer: B - ApoC-II activates LPL.

  14. Correct Answer: D - Consequence of ApoCII mutation results in elevated triglyceride levels.

  15. Correct Answer: C - Symptoms similar to LPL deficiency cases occur in ApoCII mutation.