Lipid Digestion and Absorption

Lipid Digestion and Absorption

• Dietary lipids (TAG, cholesterol, cholesterol esters, phospholipids) enter the stomach largely intact.
• In the stomach, only TAG is acted upon by lingual and gastric lipases, which hydrolyze medium/short-chain fatty acids from the sn-3 position, yielding DAG.
• In the small intestine, TAG, along with bile salts, form micelles and are acted upon by intestinal and pancreatic enzymes.
• Short- and medium-chain fatty acids are not incorporated into micelles for absorption.
• Glycerol, MAG, lysophospholipids, cholesterol, and long-chain fatty acids are absorbed into enterocytes with transfer proteins or by diffusion.
• In enterocytes, glycerol is converted to α-glycerolphosphate. Additional α-glycerolphosphate can be formed from glucose.
• α-glycerolphosphate, fatty acids, MAG, and DAG are reformed into TAG. Lysophosphatides are re-esterified with fatty acids to form phospholipids. Cholesterol is esterified to form cholesterol esters.
• Re-formed lipids, along with apoB48, form chylomicrons, which leave the enterocyte via exocytosis into the lymphatic system, then into blood circulation. Other apolipoproteins are transferred to chylomicrons from other lipoproteins.

Lipoprotein Structure

• Lipoproteins are complexes of lipids and proteins that transport lipids in the bloodstream.
• The core of a lipoprotein is primarily composed of nonpolar lipids (triacylglycerols and cholesterol esters).
• A monolayer of amphipathic phospholipids and free cholesterol surrounds the core.
• Peripheral and integral apoproteins are also present.

Exogenous Lipid Transport

• Chylomicrons transport dietary TAG to tissues (not liver—particularly adipose and muscle).
• Apolipoproteins (apoE and C-2) are transferred to the chylomicron from HDL.
• As chylomicrons lose TAG, they become chylomicron remnants, donating apoA and apoC back to HDL.
• Chylomicron remnants attach to the liver, releasing fatty acids, cholesterol, and cholesterol esters to the liver.

Adipose Lipid Metabolism

• Glucose is converted to acetyl-CoA, which can be converted to fatty acids, stored as triacylglycerols (TAG).
• Lipoprotein lipase acts on TAG in the chylomicrons, releasing fatty acids and monoglycerides to the adipocyte. The same occurs with VLDL.
• Insulin stimulates lipogenesis, promoting glucose entry into cells and inhibiting hormonesensitive lipase that hydrolyzes stored TAG.

Liver Lipid Metabolism

• Dietary nutrients enter the liver via the portal vein.
• Glucose can be converted to glycogen or undergo glycolysis.
• Amino acids are metabolized to produce pyruvate and oxaloacetate.
• Serum free fatty acids (bound to albumin) enter the fatty acid pool (TAG).
• Chylomicron remnants are taken up by liver cells via endocytosis, releasing fatty acids, monoglycerides, and cholesterol.
• The lipids are reformed into TAG and cholesterol esters (CE) and packaged with apolipoproteins into VLDL for transport.
• VLDL delivers triglycerides to muscle and adipose tissue.

Endogenous Lipid Transport

• Nascent VLDL are formed in the liver's Golgi apparatus.
• Additional apolipoproteins (apoC and E) are added from HDL.
• Lipoprotein lipase hydrolyzes TAG in VLDL, producing smaller IDL particles.
• IDL particles are further metabolized to LDL.
• LDL particles deliver cholesterol to peripheral tissues. LDL receptors in the liver and non-hepatic tissues take up LDL.

Reverse Cholesterol Transport

• Lipid-free apoA-1 is secreted by the liver and intestines.
• ApoA-1 acquires phospholipids and cholesterol from cells via ABCA1, forming nascent HDL.
• HDL acquires more lipids from peripheral cells via ABCA1 and SR-B1.
• LCAT (lecithin:cholesterol acyltransferase) esterifies cholesterol to form cholesterol esters (CE).
• CE migrate to the HDL core, forming larger HDL particles.
• Some CE are transferred to VLDL and LDL via CETP.
• HDL can be internalized in the liver via SR-B1.

LDL Uptake

• LDL particles with apoB-100 attach to LDL receptors on cell surfaces.
• The LDL-receptor complex is internalized and fuses with lysosomes.
• LDL proteins are hydrolyzed to amino acids.
• Free cholesterol is released.
• Excess cholesterol inhibits cholesterol synthesis and LDL receptor synthesis.
• Cholesterol is esterified with ACAT and stored within the cell.