DIETARY FAT : - 90% is normally triglycerides. - Cholesterol, Cholesteryl esters, Phospholipids, and Unesterified fatty acids.

Average Normal Indian Diet: 20-30 gm/day Western Diet: 2 or 3 times of this

 Challenges
Lipids are not water soluble Triglycerides too large to be absorbed

Digestive solution
Triglycerides mix with bile and pancreatic secretions

Emulsification and digestion

IN STOMACH
Lingual lipase:
- Active at low ph (pH 2.5 5) - Short chain TGS. - In milk, butter and ghee. Gastric lipase:

- Up to 30% of TGS

IN SMALL INTESTINE
1.Emulisification: Dispersion of lipids into small droplets - Bile salts ( detergent action ) Function to transport cholesterol in the digestive system - Peristalsis ( mechanical mixing ) - phospholipids

2. Digestion: Pancreatic juice: - Pancreatic lipase - Cholesterol estarase - Phospholipase A2 - Colipase

Lipolytic enzymes

TG particle colipase lipase

Hydrolysis of lipids
Triglycerides (TG)

TG + H2O Diglyceride +

Diglyceride + H2O

fatty acid (FA)

Monoglyceride (MG) + FA

O O R

O R

O OR

O 2 H2O HO O OH O O + 2
lipase

+ 2 H+

 Cholesterol esters

esterase

&

phospholipids* (PL) phospholipases FA + lyso PL

FA + cholesterol (chol)

O O O O PO OR R O R
O

In all cases, products are more polar than reactants

* biliary & dietary

Physiologically important lipases

Lipase Lingual / acid stable lipase Pancreatic lipase + co-lipase Site of action Mouth , stomach Preferred substrate Product(s) TAGS with med chain FAS TAGS with long chain FAS FFA+DAG

Small intestine

FFA+2MAG

Intestinal lipase with Small intestine bile acids

Phospholipase A2 + bile acids Lipoprotien lipase insulin (+) Hormone sensitive lipase Small intestine

TAGS with med chain 2FFA+glycerol FAS

PLs with unsat. FA on position 2 Unsat FFA lysolecithin

Capillary walls

TAGs in chylomicron FFA+glycerol or VLDL TAG stored in adipose cells FFA+glycerol

Adipose cell

3. Absorption: Bile:

Produced in liver, stored in gallbladder Alkaline solution composed of: Bile salts Cholesterol Lecithin Bilirubin
secretin (target: liver) CCK (target: liver & gall bladder) Absorbed bile salts

Bile secretion stimulated by

Bile salts: synthesis, secretion

Synthesized in the liver.

cholesterol Bile acid

Bile acyl-CoA + amino acid ( glycine / taurine )

Bile salt

Biliary Lipid Secretion

Blood Hepatocyte Bile

Sinusoidal Membrane

ABCG5/G8 Cholesterol

ABCB4 Phospholipid

ABCB11
Canalicular Membrane

Bile Salt

Biliary Lipids
Lipid Class Daily Secretion (g)

Bile salts

24

Phospholipids

11

Cholesterol

Structure of Biliary and Intestinal Micelles

Cholesterol

Bile Salt Phospholipid

Biliary Lipid Transport

Liver
Duodenum Biliary Transport and Storage

Jejunum

Ileum

Colon

Fat Digestion
Liver
Duodenum Biliary Transport and Storage

Jejunum

Ileum

Colon

Fat Digestion
I II I II I II Dietary Cholesterol ester Fatty acids + choleste rol

Triglycerides

Phospholipids

Fatty Acids + Monoglycerides

Fatty Acids + Lysophospholipid I I I

I I I

I I I

I I I

I I I

Fat Absorption
Liver
Biliary Transport and Storage

Duodenum

Jejunum

Ileum

Colon

Absorption from lumen

Movement of lipid digestion products (FA, MG, etc) across mucosal plasma membrane by simple diffusion of monomers Absorption well-mixed unstirred layer also occurs luminal via fatty acid contents microvillus brush border transfer protein cytosol membrane (FATP) Microvilli FATP provide very diffusion large absorbing fatty of micelles acids surface, but through convolutions & lysophosunstirred pholipids glycocalyx layer produce unstirred layer chol

monoglycerides

Adapted from Fig. 34 -14 (B & L)

Absorption: role of micelles

Unstirred layer
200-500 m thick Prevents peristaltic

mixing from moving luminal contents close to cell surface Crossed by micelle diffusion because of very low solubility of lipid molecules & very large distance, absorption would be very slow without micelles
Mixed micelles act as:
carriers of lipid monomers (FA, MG, chol, vit. A, D, E, K) reservoirs: as monomers absorbed, they are rapidly replaced by dissociation

from micelles

Cholesterol Absorption
Intestinal Lumen

Lymph

Enterocyte

Cholesterol NPC1L1
ACAT

Cholesteryl Ester

ABCG5/ G8

Triglyceride Absorption

Lymph

Enterocyte

Intestinal Lumen

2 Fatty Acid + Monoglyceride

DGAT

Triglyceride

Phospholipid Absorption
Intestinal Lumen

Lymph

Enterocyte

Fatty Acid

+
Lysophospholipid

Phospholipid

Chylomicron Formation
Intestinal Lumen

Lymph

Enterocyte

Phospholipid Triglyceride

With apoB48

Cholesteryl Ester

Enterohepatic circulation (bile salt recycling)

bile salts cholesterol

Bile salts absorbed

toward end of ileum Absorption by Na+ driven cotransport Na+bile salt symport Carried in portal blood bound to albumin Added to bile again by liver & secreted again Typically make 3-4 roundtrips during average meal Sherwood, Fig.16-17

Formation and secretion of (A) chylomicron in intestinal and (B) VLDL in Hepatic cell.

Packaging for transport

chylomicrons
Particles for

Lehninger et al., 3rd ed., Fig. 17-2

apolipoproteins

transport of lipids PL to liver & adipocytes Size: 0.11 m Average composition: TG (84%) chol (2%) cholE (4%) PL (8%) apolipoproteins (2%)

chol

PL

cholE, TG

Fate of dietary lipids:

TGs: FFA + glycerol FFA:

muscle (energy production) adipocytes( re esterified to TGs) Glycerol : Glycerol from TGs in liver forms glycerol 3 phosphate ( glycolysis, gluconeogenesis) Chylomicron remnants: Endocytosed into liver and are hydrolysed to their component parts and recycled by the body. - If this process is decreased due to impaired binding to the receptor on liver, they accumulate in the plasma leading to type III hyperlipoproteinemia

- FFA from TGs

Stomach gastric mobility Small intesti ne cholecytokinin + Gut Endocrine cells (enlarged)

Hormonal control

Dietary lipids

+
bicarbonate Pancreatic lipase bile

Secretin (in blood)

+
pancreas + Gall bladder

Degradation of dietary lipids

Abnormalities of maldigestion/malabsorption
The main causes of malabsorption ( STEATORRHEA ) under 3 catagories:

1. Disorders of intraluminal digestion:

a) Altered gastric function b) Pancreatic insufficiency Post gastrectomy syndrome Chronic pancreatitis Cystic fibrosis Pancreatic cancer
Disease/resection of terminal ileum Small bowel bacterial over growth.

c) Bile acid deficiency

2.Disorders of transport into mucosal cells:

a) Generalised disorders due to reduction in absorptive surface area.
b) Specific disorders

Celiac disease Tropical sprue

Hypolactasia Vit B12 in pernicious anemia Zn in acrodermatitis enteropathica

3. Disorders of transport out of the mucosal cell:

a) Blockage of the lymphatics b) Inherited disorders Abdominal lymphoma Primary lymphangiectasia A--lipoprotienemia

Clinical presentation of the patient suffering from malabsorption /mal digestion classically includes the following features: - Evidence of general ill health - Isolated nutritional deficiencies - Abdominal symptoms - Watery diarrhea and possibly steatorrhea

Tests for assessing fat absorption and malabsorption: 1.Fat globules ( fecal microscopy ) 2. Mixed chain triglyceride breath test 3. Measurement of fecal fat Tests for pancreatic function: Pancreaolauryl test , fecal elastase.

oil drop

Summary of lipid digestion & absorption

Enterocyte

lipasecolipase
emulsion droplet
TG MG FA

MG 4ATPs/TG TG FA apolipoproteins (>10C) phospholipids

lipasecolipase mixed micelle

18

BILE SALTS
chylomicron chylomicron

FA (<12C)

BILE SALTS

FA

BILE SALTS

albumin