Lipid Introduction, Digestion, and Absorption

Triacylglycerides

• Energy

• Oxidation + storage

• Composed of a glycerol molecule and a fatty acid molecule (can be saturated, monounsaturated, polyunsaturated, or a combination)

• An ester bond connects the glycerol molecule with the fatty acid

Phospholipids

• Membranes: monolayers and bilayers

• Signalling molecules

• Receptors and ligands

• Contains a hydrophilic portion (polar head groups) and a hydrophobic portion

• The foundational structural basis of all cellular membranes

• Can be phosphorylated at three different sites (C-3, C-4, and/or C-5 hydroxyl groups)

Cardiolipin (Phospholipid)

• Three glycerol molecules

• Central glycerol molecule links two phosphatidic acid moieties back-to-back

• Found almost exclusively in the inner mitochondrial membrane

Sphingolipids

Helps build cell walls and send messages inside cells:

• Amino alcohol sphingoside backbone

• Fatty acid attached to the amino group (determines the type)

Sterols

• Membranes: monolayers and bilayers

• Signalling molecules

• Receptors and ligands

Saturated Fatty Acids

No double bonds

• In cooking oils, red meats, and dairy products

Monounsaturated Fatty Acids

One double bond

• In cooking oils, red meats, and shortening

Polyunsaturated Fatty Acids

Two or more double bonds:

• N-3 PUFA

• N-6 PUFA

• In cooking oils

Triacylglycerol Digestion

• Lingual and gastric lipases

• Emulsification in the stomach

• Presence of lipids in stomach delays gastric emptying: high satiety value

• Emulsification in small intestine

• Bile salts

• Pancreatic lipase activation

• The role of colipase

Lingual Lipase and Gastric Lipase

• Hydrolyze medium- and short-chain fatty acids from the sn-3 position to yield DAG

• Can contribute to the digestion of lipids in adults in diseases with pancreatic insufficiency (e.g. cystic fibrosis and alcoholic pancreatic insufficiency)

Digestion of Triacylglycerol in the Mouth

• Triacylglycerol → triacylglycerols, diacylglycerols, and fatty acids (minor digestion)

• Via lingual lipase produced in the salivary glands (cleaves some fatty acids)

Digestion of Triacylglycerol in the Stomach

• Only TAG are acted upon in the stomach

• Additional digestion of triacylglycerol, diacylglycerol, and fatty acids

• Via gastric lipase produced in the stomach (cleaves some fatty acids)

Digestion of Triacylglycerol in the Small Intestine

• Phase one (emulsification): Emulsified triacylglycerols, diacylglycerols, and fatty acid micelles (via bile; no lipase)

  • Short and medium-chain free fatty acids do not get incorporated into micelles for absorption into the intestinal cells

• Phase two (enzymatic digestion): Produces monoacylglycerols and fatty acids (via pancreatic lipase produced in the pancreas)

  • Pancreatic lipase cleaves some fatty acids

Dietary Lipids

• Include TAG, C, CE, and PL

• These lipids enter the stomach largely intact

Glycerol, MAG, lysophospholipid, C, and long-chain FA:

• Are absorbed into the enterocyte with the aid of transfer proteins

• These lipids may also move through the brush border membrane into the enterocyte by diffusion

In the enterocyte ER:

• Glycerol is converted to an alpha-GP

• Additional alpha-GP is formed from glucose by glycolysis

• Alpha-GP, FA, MAG, and DAG are reformed to TAG

• Lysophosphatides are re-esterified with FA to make PL (phospholipids)

• C is esterified to CE

Chylomicron

• Formed by the reformed lipids, along with apo-B48

• Leaves the enterocyte by exocytosis into the lymph, then empty into blood circulation

• Other apolipoproteins are transferred to the chylomicrons from other lipoprotein. complexes

Ileocecal Sphincter

Regulates the flow of material from the ilium, the last segment of the small intestine, into the cecum, the first portion of the large intestine.

Duodenum

Receives secretions from the gallbladder via the common bile duct.

The Pancreas

Releases its secretions into the pancreatic duct, which eventually joins the common bile duct

Sphincter of Oddi

Regulates the flow of pancreatic secretions into the duodenum

Enterocytes

• Covered with small projections called microvilli which project into the intestinal lumen

• The microvilli of enterocytes make up the brush border

• Each villus contains absorptive cells called enterocytes

• The circular folds are covered with finger-like projections called villi

• Each villus contains a capillary network and a lymphatic vessel (lacteal)

Exocrine Portion of the Pancreas

Acinar and duct cells

Duct Cells

Secretes aqueous NaHCO3 solution

Acinar Cells

Secrete digestive enzymes

Endocrine (Ductless) Portion of the Pancreas

• Islets of Langerhans

• Secretes hormones such as insulin and glucogon

Phospholipase

• Secreted in the pancreas

• Acts on lecithin and other phospholipids in the small intestine

Cholesterol Esterase

• Secreted in the pancreas

• Acts on cholesterol esters in the small intestine

Retinyl Ester Hydrolase

• Secreted in the pancreas

• Acts on retinyl esters in the small intestine

Monoglyceride Lipase

• Secreted in the small intestine

• Acts on monoglycerides in the small intestine

Co-lipase

• Proenzyme Activation: secreted by the pancreas as inactive procolipase and is activated in the small intestine by the enzyme trypsin

• Acts as a bridge and prevents displacement: binds to both pancreatic lipase and bile acids on the surface of emulsified fat droplets

  • Anchors pancreatic lipase in place

• Stabilizes pancreatic lipase: Holds pancreatic lipase in its active shape

Phospholipid Digestion:

• Hydrolyzed by phospholipase A₂

  • Made and secreted by the pancreas

  • Produces lysophospholipids and free FA, cleaves sn-2 FA

• Lysophospholipase

  • Produced by enterocytes and found at brush border membrane

  • further hydrolyzes lyso-PL (at sn-1) to glycerophosphoryl base (e.g., glycerophosphocholine) and free FA

Cholesterol Ester Digestion:

Hydrolyzed to free cholesterol and free FA by cholesterol esterase

Lipid Absorption

• Micelles interact at brush border membrane, and lipid contents diffuse out into enterocytes

• Absorption process

  • Transport of digested lipids from the intestinal lumen across the brush border membrane

  • Reassembly of those lipids by esterification

  • Release of lipids into the circulation

Passive Diffusion

• Short-, medium-, and long-chain FA.

• Diffuse directly across the enterocyte membrane due to their lipophilic nature, moving down their concentration gradient from the lumen into the enterocyte.

Active Transport

Fatty Acid Transport Proteins:

• Located in the enterocyte membrane, facilitate the uptake of long-chain fatty acids by actively transporting them into the enterocyte

  • CD36

CD36

• Scavenger receptor

• Plays a key role in the active uptake of long-chain fatty acids, facilitating their movement across the enterocyte membrane.

Cholesterol Absorption

• Cholesterol comes from the diet (exogenous) and from biliary secretions (endogenous)

  • Cholesterol not absorbed is excreted

• Cholesterol may incorporate into enterocyte membranes

  • Majority is esterified in preparation for transport out of the cell as a component of chylomicrons

• Cholesterol and phytosterols

  • transported into the intestinal cell by Niemann-Pick C1 Like 1 (NPC1L1)

• ATP-Binding Cassette Transporters (ABCG5/G8)

  • limits cholesterol absorption by actively transporting phytosterols and excess cholesterol out of the enterocyte back into the intestinal lumen.

  • Foods and supplements enriched with phytosterols effective at reducing blood cholesterol concentration by 10% or more.

  • Sitosterolemia - body absorbs and stores too much plant sterol from food instead of removing it.

ATP-Binding Cassette Transporters (ABCG5/G8)

Limits cholesterol absorption by actively transporting phytosterols and excess cholesterol out of the enterocyte back into the intestinal lumen.

Sitosterolemia

The body absorbs and stores too much plant sterol from food instead of removing it

Bile Acids

1. Bile is made in the liver (0.5 g/day) and stored in the gallbladder (pool size = 4.0 g)

2. When the gallbladder contracts, bile is released into the cystic duct → the cystic duct joins the common bile duct

3. Bile aids in lipid digestion by enabling large lipid globules to disperse in the watery environment of the small intestine

4. After aiding in lipid digestion, the bile constituents are reabsorbed from the ilium and returned to the liver via the hepatic portal vein (0.5 g/day excreted)

5. The liver uses these constituents to resynthesize bile, which is then stored in the gallbladder

AGPAT (1-acylglycerol-3-phosphate O-acyltransferase)

converts lysophosphatidic acid (LPA) into phosphatidic acid (PA)

ACAT (acyl-CoA:cholesterol acyltransferase)

converts free cholesterol into cholesteryl ester

MTP (microsomal triglyceride transfer protein)

helps assemble chylomicrons in the intestine

Lipids in Circulation

Chylomicron formation:

• Enter the lymphatic system

Medium–chain fatty acids may pass from the enterocyte directly into the portal blood

• Bind to albumin and are transported directly to the liver