EXAM 1 - LIPID digestion & absorption

Simple lipids

Fatty acids (FA)

Triacylglycerols (TAG)

Diacylglycerols (DAG)

Monoacylglycerols (MAG)

Cholesterol esters

Compound Lipids

Phospholipids → cell membranes

Lipoproteins → HDL, LDL, VLDL

Fatty Acids

Straight hydrocarbon chain terminating with a carboxylic acid group

Fatty acid nomenclature

• Delta (D) system - length, number/ position of double bonds

• Double bonds counted from carboxyl end

Exist as fats or oils depending on nature of fatty acid components

Types of fatty acids

Lipid Digestion Fundamental Problem:

Fatty acids are not stored in feeds or animal tissues as fatty acids, they are stored as triglycerides (triacylglycerol esters), phospholipids, etc.

These lipids must be digested and the parts absorbed across the enterocyte

Lipid Digestion Fundamental Solution:

Must hydrolyze to component parts before molecules can be absorbed by the enterocyte

Must be able to accommodate hydrophobic molecules in an aqueous/hydrophilic environment

Critical steps in TAG digestion

Lingual & gastric lipases

Emulsification in the stomach

Emulsification in small intestine – bile salts

Pancreatic lipase

TAG digestion in small intestine highly efficient (about 95% digested)

Break down TAG into _____ + ____ to help emulsify additioinal fat

DAG + FA

Lipase activity + mixing/motility →

fine lipid droplets

• However TAG digestion is not extensive in stomach

• Most occurs in small intestine

Lingual lipase

from gland under tounge

Gastic lipase

from cheif cells in stomach

Highly stable at low pH (active up to pH 6.5)

Pancreatic lipase

from pancreas

digests TAGs and DAGs to MAGs and FA

______ is crutial for ABSORPTION of lipids

BILE

• Produced by hepatocytes, and drains out through the many bile ducts that penetrate the liver

• Common bile duct joins with the pancreatic duct to empty into the duodenum

_________ is released with the bile, dissolved in the acids and fats found in the concentrated bile solution

Cholesterol

• When food is released by the stomach into the duodenum in the form of chyme, the gallbladder releases the concentrated bile to provide bile salts to aid in digestion

How do lipids get into the enterocyte?

Lipids have little solubility in water

“Unstirred water layer” at brush border presents a barrier even with vigorous intestinal motility and mixing of intestinal contents

Mixed Micelles

Micelles form from bile salts (acids) + lipid moieties (cholesterol, etc.)

• Engulf hydrophobic products of fat digestion

• Provide polarity to penetrate the unstirred water barrier

Increases the concentration of lipid digestion products (100-1000X)

Cross unstirred water layer to deliver contents to apical enterocyte where contents enter via specific transporters or diffusion down concentration gradient

Micelle

Entering the enterocyte

• Glycerol and short chain FA readily diffuse into enterocyte

• Micelle products cross brush border passively (no energy required)

• Following diffusion products quickly re-esterified at the endoplasmic reticulum

  • TAG, cholesterol esters reformed to sustain concentration gradient

Re-esterification

TAG digestion products (FA, MAG, DAG)…are moved to the endoplasmic reticulum (ER) to be repackaged as TAG

Re-formed lipids (TAG) leave the enterocyte (exocytosis) largely in the form of chylomicrons (monogastrics)

Chylomicrons

Chylomicrons resemble the fatty acid composition of diet

____________ delivers dietary lipids mostly to muscle and adipose (80%

Lymph system delivers dietary lipids mostly to muscle and adipose (80%)

• Remaining lipid goes to liver as chylomicron remnants

Chylomicrons and lipoproteins

Overview of lipid digestion/ absorption

T or F: Lipases involved in cleaving fatty acids from glycerol backbone (many sites of digestion, mouth, stomach, SI)

true

Lipids have to be _______

emulsified

T or F: Lipids require special mechanisms to be absorbed, mixed micelle, exported via chylomicrons (monogastric)

true

Absorbed dietary fat is either:

1. stored as energy in the form of TAG in adipose tissue (adipocytes)

2. or fatty acids are oxidized for energy via betaoxidation

In order to store fats that originated as dietary fat and are presented to recipient tissues (like muscle or adipose!) as chylomicrons….

Lipoprotein lipase is critical

Role of lipoprotein lipase (LPL)

Problem: tissues can’t take up chylomicrons or lipoproteins directly! So how do they acquire fat products?

• LPL targets the TAG in chylomicrons or lipoproteins in circulation to release glycerol and free fatty acids

• Adipocytes and skeletal/cardiac myocytes need energy from lipids so they express LPL

LPL action

• Results in sequential hydrolysis of TAG

  • TAG to DAG, MAG, Glycerol, FA (to allow into cell)

• Free fatty acids, DAG and MAG

  • Taken up by tissues via diffusion and fatty acid transport proteins

• Fatty acids, DAG, MAG then re-esterified and stored as TAG (what we likely started with in the diet!)

• Glycerol is taken up by diffusion but eventually recycled to the liver

• Chylomicron remnants (chylomicrons depleted of TAG) are then recycled to the liver

Mobilizing stored TAG when needed

TAG couldn’t get in the cell…so TAG can’t get out!

• So how does the cell trigger release of stored lipids?

• Hormone sensitive lipase (HSL) cleaves TAG to release

FA and glycerol ¢ FA and glycerol get exported

• FA transported to recipient cells (muscle, etc. as NEFA)

• Glycerol recycled to liver

T or F: HSL is activated by beta-agonists like Paylean and Optaflexx, causing animals to mobilize fat stores in support of lean muscle gain

TRUe

Lipid metabolism Recap

Before a target cell (like muscle) can use FA for energy, they have to get them delivered

Chylomicrons (dietary lipids) → Increase expression of lipoprotein lipase

Non esterified fatty acids in blood → From HSL cleavage of TAG in adipose stores

Which tissues prefer FA for energy?

Liver, muscle types, kidney

Activation of FA to FA Co-A

• Fatty acids must be activated to form fatty acyl-coA derivatives because ONLY activated FA can enter metabolic pathways

• Remember…beta-oxidation of FA occurs in mitochondria!

  • Acyl-coA synthetase in cytoplasm (Long chain FA activation)

• Short and medium chain FA can pass into mito matrix and are “activated” in mito to form acyl-coA derivatives that feed into beta-oxidation cycle

Carnitine role in FA oxidation

BUT long chain FA need to be carried across inner membrane!

• Carnitine (quasi vitamin!) plays critical role here

Carnitine acyltransferase I

• Loads carnitine with activated fatty acid

• Inhibited by malonyl coA (lipogenesis product)

• Rate limiting step of beta oxidation

Carnitine acyltransferase II

• Releases acyl carnitine to form acyl-coA and carnitine

Transporting Fatty Acyl-CoA across innter mito membrane

Beta Oxidation

Occurs in mitochondria

High in muscle and liver in fasted state (looking for energy!)

Beta-oxidation: sequential oxidation of the ß-carbon of FA that generates

• 1 FADH2 1 NADH and releases acetyl Co-A + activated fatty acid that is 2C shorter (cycle continues…)

Acetyl CoA enters the TCA cycle to generate additional energy

FADH2 and NADH enter ETC…to drive ATP production!

Beta Oxidation

Key to metabolism and energy homeostasis is the fate of ______________: whether they will be oxidized for energy or be stored

Key to metabolism and energy homeostasis is the fate of pyruvate and acetyl-CoA: whether they will be oxidized for energy or be stored

• Acetyl Co-A can form citrate (TCA) to eventually support ATP synthesis or go on to form malonyl Co-A (first step of FA synthesis/lipogenesis)

• Depends on the energy state of the animal!

De novo lipogenesis

dietary carbohydrate conversion (through series of enzymatic reactions) to fatty acids

• Acetyl CoA is the key

Sources of Acetyl-CoA

Lipogenesis

• Occurs in the cytosol

• Acetyl CoA carboxylase converts acetyl-CoA to malonyl CoA

• Requires biotin (B vitamin) for carboxylation reaction

• This is the rate limiting step of lipogenesis

Lipogenesisi pt. 2

• Sequential addition of 2 carbon units (acetyl CoA) results in the eventual formation of palmitate (C16:0)

• Catalyzed by Fatty Acid Synthase

  • An enzyme complex with multiple catalytic activities

  • Catalyzes synthesis of new long chain FA in the body from

    • 1) Acetyl CoA

    • 2) Malonyl CoA and

    • 3) NADPH (reducing equivalent coming from Pentose Phosphate Pathway)

Lipogenesis: Fatty acid to triacylglycerol

Palmitate is then esterified on a glycerol backbone to form triacylglycerol (TAG) for storage (3 palmitate in 1 TAG)

Glucose to Pyruvate

glycolysis

Acetyl-Co-A to fatty acid synthesis

lipogenesis

T or F: there is no pathway to convert fat to carbohydrate

TRUE

__________ of lipid necessary to generate energy

Beta oxidation

LOTS of energy in LCFA