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Lecture Overview

  • Lecture Number: 29

  • Topic: Lipoproteins and Fat Metabolism

  • Required Reading: Lehninger, 8th edition, Chapters 17 and 21

  • Course and Semester: MCB 354, Fall 2025

Learning Objectives

  • Explain where and how dietary fats are digested in the gut and transported in the bloodstream to tissues. Identify the causes and consequences of lipid malabsorption.

  • Describe substrates for lingual and gastric lipases. Discuss the degradation of dietary lipids by pancreatic lipase/colipase, cholesterol esterase, phospholipase A2, and lysophospholipase.

  • Describe the source, structure, and role of bile salts in the digestion of lipids.

  • Explain the difference between pancreatic lipase, lipoprotein lipase, and hormone-sensitive lipase, including their roles in fat transport and utilization.

  • Identify major types of lipoprotein particles and outline their specific roles in fat transport in the blood.

  • Explain the roles of VLDL, LDL, and HDL in cholesterol transport between tissues.

  • Understand the ABCA1 transporter’s role in mediating cholesterol efflux from cells and its contributions to familial HDL deficiency and Tangier disease.

  • Describe underlying causes of Familial hypercholesterolemia.

Fats: Digestion, Mobilization, and Transport

  • Sources of Fatty Acids for Cellular Use:

    1. Fats stored in cells as lipid droplets

    2. Fats synthesized in one organ and exported to another

    3. Dietary fat:

      • Contributes 40% or more to daily energy intake in industrial societies like the U.S.

      • Dietary guidelines suggest that no more than 30% of energy should come from fat.

Advantages and Disadvantages of Triacylglycerol-based Stores

  • Advantages:

    • High energy content (highly reduced).

    • Compact storage in an anhydrous state (as lipid droplets), resulting in no osmotic effect on cells.

  • Disadvantages:

    • Insoluble in water, necessitating special handling for transport between various tissues.

Fat Digestion in the Fed State

  • Scenario: Following a high-fat meal, understanding the digestion, transportation, storage, and utilization of fats during fed and fasting states.

Dietary Lipids Digestion Overview

  • Digestive Process:

    • Mouth: Ingestion and minimal initial processing.

    • Stomach: Lingual and gastric lipases begin lipid digestion, primarily targeting short and medium-chain fatty acids from triacylglycerols (TAGs).

      • Lingual and Gastric Lipases:

      • Acid-stable enzymes; work effectively for short/medium-chain fatty acids.

      • More active in infants consuming milk than in adults.

    • Small Intestine: Major site of lipid digestion; bile salts emulsify fats enhancing the effectiveness of pancreatic enzymes.

      • Pancreatic lipase, colipase, cholesterol esterase, phospholipase A2, and lysophospholipase participate in significant degradation of dietary lipids.

Role of Bile Salts

  • Synthesized in the liver from cholesterol, stored in the gallbladder, and released into the small intestine.

  • Functions as biological detergents, forming emulsions with lipids through a coupling of their detergent properties and mechanical mixing via peristalsis.

Hydrolysis of Dietary Fats

  • In the small intestine, emulsified fats undergo hydrolysis via pancreatic lipase and other enzymes releasing free fatty acids.

  • Pancreatic Lipase:

    • Removes fatty acids preferentially at carbons 1 and 3 of triacylglycerols.

  • Colipase:

    • Anchors pancreatic lipase at the lipid-aqueous interphase, enhancing its activity.

  • Orlistat: An anti-obesity drug that inhibits gastric and pancreatic lipases, reducing fat absorption.

Cholesteryl Ester Hydrolysis

  • 90% of dietary cholesterol is non-esterified form.

  • Hydrolyzed by pancreatic cholesteryl ester hydrolase (cholesterol esterase) to release cholesterol and free fatty acids, greatly enhanced by bile salts.

Phospholipid Digestion

  • Phospholipase A2 removes one fatty acid from carbon 2, forming lysophospholipids. Following this, lysophospholipase acts to further degrade the structure.

  • Both enzymes' activities are enhanced by bile salts.

Hormonal Regulation of Lipid Digestion

  • Cholecystokinin (CCK):

    • Produced by jejunum mucosal cells in presence of lipids; slows gastric motility, contracts gallbladder (releasing bile), and stimulates pancreatic lipase release.

  • Secretin:

    • Triggers bicarbonate release from pancreas and liver in response to low pH of chyme.

Absorption of Lipids in the Intestinal Mucosa

  • Lipid-soluble compounds form mixed micelles with bile salts, facilitating absorption by enterocytes (intestinal mucosal cells).

  • Micelles contain:

    • 2-monoacylglycerols, free fatty acids, free cholesterol, and fat-soluble vitamins (A, D, E, K).

Causes of Lipid Malabsorption

  • Leads to steatorrhea: Increased lipid in feces due to disturbances in digestion or absorption, associated conditions include cystic fibrosis and shortened bowel.

Olestra: An Artificial Fat Substitute

  • Composition: Sucrose with esterified fatty acids, which resist pancreatic lipase and pass through the intestine intact, potentially carrying essential fat-soluble vitamins out with it.

Fatty Acid Metabolism in Enterocytes

  1. Absorbed lipids are translocated to endoplasmic reticulum.

  2. Fatty acids activated by fatty acyl-CoA synthetase to form acyl-CoA.

  3. Monoacylglycerols (MAGs) converted to triacylglycerols (TAGs).

  4. Lysophospholipids re-acylated to form phospholipids.

  5. Cholesterol is re-esterified to cholesteryl esters.

  6. Short- and medium-chain fatty acids are not re-esterified.

  7. Resulting TAGs and cholesteryl esters are packaged into chylomicrons.

Lipoprotein Particles

  • Structure:

    • Exterior: Apolipoproteins and phospholipid monolayer.

    • Interior: Lipid payload (TAGs, cholesteryl esters, fat-soluble vitamins).

  • Function:

    • Apolipoproteins (e.g., apoB-48, apoC-II) provide structural support, activate enzymes, and assist in receptor recognition.

Metabolism of Chylomicrons

  • Synthesized in intestine, picking up apoE and apoC from HDL.

  • Lipoprotein lipase (LPL) in adipose tissue degrades TAGs into fatty acids and glycerol.

  • Chylomicrons deliver dietary lipids to tissues and empty chylomicron remnants bind receptors on liver cells for uptake.

Fate of Chylomicrons

  • Chylomicrons are cleared from circulation in about 9 hours.

  • Chylomicron remnants deliver dietary cholesterol and fat-soluble vitamins to the liver.

VLDL and LDL Metabolism

  • VLDL (Very Low-Density Lipoprotein):

    • Liver packages TAGs and cholesterol into VLDL for export.

    • In capillaries, LPL degrades VLDL into free fatty acids and glycerol, facilitating tissue uptake.

  • IDL (Intermediate Density Lipoprotein):

    • Result of further lipolysis of VLDL; converted into LDL, which is rich in cholesteryl esters.

LDL and Cardiovascular Disease

  • LDL receptors on liver and other cells facilitate the uptake of cholesterol via endocytosis.

  • High LDL cholesterol levels are associated with increased risks of cardiovascular diseases, hence termed “bad cholesterol”.

HDL Metabolism

  • High-Density Lipoprotein (HDL):

    • Secreted as nascent HDL from liver and intestine, picking up cholesterol near peripheral membranes.

    • Mature HDL delivers cholesterol to adrenal cells, gonads, and liver via a reverse cholesterol transport pathway, often associated with reduced cardiovascular disease risk, termed “good cholesterol”.

Tangier Disease

  • Rare autosomal recessive condition characterized by low HDL cholesterol levels, cholesterol accumulation in tissues, increased risk of arteriosclerosis, and specific symptoms such as enlarged spleen and liver, eye, and neurological abnormalities.

Cholesterol and Heart Disease Risk

  • Total Cholesterol Levels:

    • Less than 200 mg/dL: Desirable

    • 200-239 mg/dL: Borderline high

    • 240 mg/dL and above: High

  • LDL Cholesterol Levels:

    • Less than 100 mg/dL: Optimal

    • 100-129 mg/dL: Near or above optimal

    • 130-159 mg/dL: Borderline high

    • 160-189 mg/dL: High

    • 190 mg/dL and above: Very high

  • HDL Cholesterol Levels:

    • Less than 40 mg/dL: Major risk factor for heart disease

    • 40-59 mg/dL: Moderate

    • 60 mg/dL and above: Protective against heart disease.

Types of Hyperlipidemias

  • Type I Hyperlipidemia: Familial lipoprotein lipase deficiency; characterized by fasting chylomicronemia and hypertriacylglycerolemia due to enzyme deficiency.

  • Type II Hyperlipidemia: Familial hypercholesterolemia; common condition with high levels of LDL cholesterol, often due to mutations in LDLR or apoB genes.

  • Type III Hyperlipidemia: Dysbetalipoproteinemia; characterized by impaired receptor binding of remnants leading to their accumulation in plasma.