GI 8: Digestion of Fat and Proteins

Liver performs many essential metabolic functions, including?

• Carbohydrate Metabolism

• Protein Metabolism

• Lipid Metabolism

• Drug & Hormone Metabolism

liver functions

1. production and secretion of BILE

- essential for the normal digestion and absorption of dietary lipids

- 600-1200 ml/day

2. eliminate certain metabolic waste products such as Bilirubin

- Bilirubin Accumulation = Toxic (Jaundice)

Biliary System

serves to produce and deliver BILE secretions into the GI tract

includes:

- liver

- gallbladder

- duodenum

Bile

- produced and excreted by the Liver

- stored and concentrated in the Gallbladder

- released into the Duodenum in response to a meal

Bile Production & Secretion

Bile: 600-1200 ml/day

• Digestion & Absorption of Lipid from GI Tract

Bilirubin Elimination

• Accumulation = Toxic (Jaundice)

Liver histology

- basic functional units of the liver: Liver Lobules

- Groups of lobules are organized around a Central Hepatic Venule

- Sinusoids

- Other types of sinusoids termed Bile Canaliculi

Liver Lobules

- a peripherally located system of blood vessels (Portal Vein & Hepatic Artery)

- secretory Bile Duct branches

- "plates" of hepatocytes (liver cells)

Sinusoids

formed by blood vessels and ducts extending branches between and within the plates of hepatocytes

- function to distribute blood to hepatocytes

Bile Canaliculi

Other types of sinusoids

- located between adjacent rows of hepatocytes

- function as a conduit to deliver bile secreted from hepatocytes to the bile duct

Functions of Bile

1. Lipid Digestion

- Bile Acids: are responsible for Fat Emulsification (like detergent action)

- allows digestion by pancreatic Lipase

- Dietary Fat is Insoluble in the aqueous GI fluids

2. Lipid Absorption

- solubilize fat digestion products (e.g. monoglycerides & fatty acids) into Micelles

- important for the fat absorption

3. Waste Elimination

- Cholesterol and Bile Pigments (Bilirubin) as well as some drugs and heavy metals

Composition of bile

About 1 L/day of Bile fluid

• Bile Salts (conjugated bile acids)

• Phospholipids

• Cholesterol

• Bile Pigments

- Combined with an alkaline isotonic fluid secreted from Bile Duct epithelial cells

• H2O & Electrolytes

• HCO3-,

• Ca++, K+, Cl-, Na+

Bile Acids

• 50% of the organic component of bile

• emulsify lipid material in the intestine through Micelle formation

Primary (1°) Bile Acids

• synthesized in the Liver from Cholesterol

• secreted into the Duodenum

• a fraction is converted to 2° Bile Acids by ileal bacteria

Bile salts

• Amino Acid Conjugation & Ionization convert Bile Acids into more water-soluble Bile Salts

• the actual participants in micelle formation

• Bile salts are Amphipathic (Hydrophobic & Hydrophilic), which is important for forming Micelles

Phospholipids

contribute to 30-40% of organic bile

- Lecithins

- Interact with bile salt to support micelle formation

Cholesterol

contributes to 4% of bile

- can only be excreted through bile

- regulates body stores of cholesterol

Bile pigments

do not contribute to lipid emulsification or micelle formation

o Secretion of the bile pigment bilirubin

o Serves as a route for its excretion in feces

o Main cause of characteristic brown fecal coloration

Bile Components & Functions Overview

Bile Secretion

- produced continuously by Liver Hepatocytes

- after secretion, additional H2O, HCO3- and Other Electrolytes, are secreted by the Bile Duct

- regulated by Secretin

Functions of Gall Bladder

- between meals, serves as a storage site

- ready release of bile in response to a meal

− concentrates the fluid by reabsorbing H2O and electrolytes (Na+, Cl-, HCO3-) until release is stimulated

Bile Expulsion: Gall Bladder Contraction

− Stored bile is released into the duodenum when the gallbladder is stimulated to contract.

- contraction is stimulated in response to a meal

Major stimulants of gall bladder contraction during excretory phase:

• Cholinergic Vagal Stimulation (ACh)

• Cholecystokinin (CCK)

Bile Acid Recycling: The Enterohepatic Circulation

• Most (95%) Bile Acids released into the intestine are Reabsorbed mainly in the ILEUM through passive and active processes

• reabsorbed bile acids are then returned to the liver via the Portal Blood, where they are extracted from the blood by hepatocytes.

• small fraction (5%) of bile acids lost in Feces is replaced through hepatic synthesis of new bile acids

Bile acid recirculation

TOTAL bile acid pool in the human is only 2.5 gms

• However, between 15-30 gms/day of bile acids typically enters the Duodenum

• discrepancy is compensated for by the fact that most of the bile acid pool is reabsorbed through Enterohepatic Re-Circulation (2-2.5 gms) through the biliary system between 5-15 x/day

- only small amounts normally need to be newly synthesized by hepatocytes (New B. A.-) to replace amounts lost in the Feces (0.75-1.5 gm/day)

- importance of the enterohepatic recirculation of bile acids is underscored by the fact that the liver can maximally synthesize only 3-5 gms/day of new bile acids

Impairment of bile acid recirculation

Complications are related to:

• excess H2O & electrolyte loss (Osmotic Diarrhea)

• bile salt excretion and/or impaired fat digestion (Steatorrhea)

Clinical Manifestations of Impairment of bile acid recirculation

related to the severity of impaired bile acid recirculation:

1. Mild to Moderate impairment of ileal reabsorption

- e.g. Infection/Inflammation

- causes excess bile acids to reach the colon

- inhibits colon absorption of electrolytes & H2O due to the osmotic effect of unabsorbed bile acids

2. Severe Loss

- e.g. Ileal Resection

- outpaces new bile acid synthesis

- results in impaired digestion and absorption of long chain triglycerides.

- result in H2O & Electrolyte Loss AND the Undigested Fat Loss in stool (Steatorrhea)

If synthesis of new bile acids by the liver keeps pace with fecal loss...?

fat digestion remains normal

- clinical manifestations are primarily H2O & Electrolyte Loss, but NO Fat Loss in stool (Osmotic Diarrhea)

Steatorrhea can be improved by?

substituting medium-chain triglycerides for long-chain triglycerides in the diet

- small triglycerides do not require micelle formation for absorption

Gall bladder function

primarily functions in Bile Storage & Concentration after it is secreted from the hepatocyte and transported through the bile ducts

Gall bladder Filling

• Bile is produced continuously by hepatocytes and flows into the gallbladder (via bile ducts)

• Between meals, bile diversion into the gall bladder is also facilitated by the high tone of the Sphincter of Oddi, preventing immediate passage into the duodenum

Gall Bladder Capacity

volume capacity of the human gallbladder is limited to 20-60 ml

• total volume of bile secreted from hepatocytes before the gallbladder empties may be many times this amount

• Bile that is initially secreted from hepatocytes (Liver) greatly increases in volume due to the addition of electrolytes (mainly HCO3-) and H2O from bile duct cells

Gall Bladder Bile Concentration

discrepancy between gallbladder capacity and total bile secretion is accounted for by the gallbladder's ability to Concentrate bile 20-fold

- concentrates bile by actively reabsorbing Na+, Cl-, & HCO3-

- H2O follows passively down the osmotic gradient created by electrolyte movement

major effects of bile concentration by the gallbladder are

1. a large decrease in fluid Volume (H2O loss)

2. a large increase in the concentration of organic constituents

- Bile Salts, Cholesterol, Bilirubin

- Effects on [Electrolyte] vary

physiological importance of B.A. concentration

1. Micelle formation only occurs when Bile Acids reach a certain concentration, called the Critical Micellar Concentration

• Only at these High [B.A.] concentrations will bile salts aggregate to form micelles.

• This is why clinically, Gallbladder Removal sometimes results in Impaired Dietary Fat Digestion

2. high bile acid concentration is important to solubilize the high concentrations of cholesterol & phospholipids in the gallbladder to Prevent Gallstones

Regulation of gall bladder secretion

Stimulatory Signals

• Bile expulsion is typically initiated within 30 minutes after eating a meal

• Bile is primarily expelled from the gallbladder into the duodenum in response to the presence of Fat Digestion Products (Duodenal Lipids) in the GI tract

Regulatory Agents

• Cholecystokinin (CCK)

• Neural Stimulation (Vagus)

Digestion of proteins

Protein is ingested as large polypeptides and peptides that must be hydrolyzed to

absorbable

- proteolytic enzymes return a water molecule to the protein molecule to split them into amino acids

forms: Amino acids, dipeptides, & tripeptides

Protein Digestion: Stomach

enzyme: Pepsin

substrate: Only initiates

- Collagen and proteins

product: Proteose, peptones and polypeptides

Protein Digestion: Upper Small Intestine

enzyme: Pancreatic enzymes:

• trypsin,

• chymotrypsin,

• carboxypeptidase

• proelastase

substrate: Act on Protease, peptones and polypeptides

product: polypeptides and amino acids

Protein Digestion: Brush Border Enterocytes

enzyme: Peptidases

substrate: polypeptides and amino acids

product: amino acids

GI tract of an individual consuming a typical American diet must process how much protein?

between 90-170 gm protein per day

- well in excess of minimal needs (0.5-0.7 gm/kg body wt./day or 35-50 gm/day for a 70 kg non-lactating adult)

Protein digestion substrate

1. Most comes from Dietary Protein

• typically constitutes 10-20% of daily adult Caloric Intake

2. in addition, GI tract must digest an additional 10-30 gm protein from:

- Gastrointestinal Secretions (Pancreatic, Biliary & Intestinal)

- Exfoliated Intestinal Cells generated from the constant and rapid mucosal cell turnover of the GI tract

In humans, essentially ALL protein is digested and absorbed by?

intestinal mucosa (typically before it has traversed jejunum)

Fecal protein

mainly from bacteria and exfoliated epithelial cells from the distal tract

Source of Protein

Dietary Protein:

• Minimum = 35-50 gm/day

• Avg. American = 70-110 gm/day

GI Secreted Protein: (10-30 gm), Enzymes & Mucin

• Gastric

• Pancreatic

• Biliary

• Intestinal

Exfoliated Epithelium: (10-30 gm)

•Constant & Rapid Mucosa Turnover

Protein Ingestion

ingested as large Polypeptides & Peptides

that must be hydrolyzed to absorbable:

• Amino Acids, Dipeptides & Tripeptides

• by Proteolytic Enzyme action

Phases of Protein digestion

distinguished into 3 types based on the Site of Digestion:

1. Luminal (cavital) Digestion

2. Membrane (contact) Digestion

3. Cytoplasmic digestion

Luminal Digestion

1. Dietary Protein digestion begins in the stomach

- through the actions of Gastric Acid and Pepsin

- Gastric actions account for 15% of protein digestion, but is NOT considered physiologically essential

2. Luminal Digestion occurs mainly through actions of Pancreatic Peptidases secreted into the small intestine:

• End-products are predominantly:

- absorbable Free Amino Acids & small Di- & Tri-Peptides

- which are transported across the brush border

Membrane Digestion

Small amounts of Larger Peptides (4-8 amino acids) remain after luminal digestion

- Non-Absorbable

- must be further digested via Membrane Digestion

Brush Border Peptidases

- located at apical membrane of enterocytes

- serve to further digest Larger Peptides into Free Amino Acids & Di-/Tri-Peptides

Cytoplasmic digestion

- Very minor amounts of unabsorbable larger peptides remain after membrane digestion

- Products are rapidly absorbed across membrane into enterocyte for Cytoplasmic Digestion:

• Intracellular Cytoplasmic Peptidases complete the protein digestion process by further hydrolyzing absorbed Di-/Tri-Peptides into Amino Acids

end products: mostly Free Amino Acids (75%)

- leave the cell and the enter Blood across the basolateral membrane

Enzymes for Luminal digestion

Proteolytic enzymes produced by Pancreatic Acinar Cells (Enzymatic Component)

1. Endopeptidases

2. Exopeptidases

Endopeptidases

hydrolyze only Interior peptide bonds

- end-products of endopeptidase digestion are Mostly Small Peptides

include:

• Gastric Pepsin

- aromatic amino acids

• Pancreatic proteases:

1. Trypsin(s)

- Basic Amino Acids

2. Chymotrypsin

- aromatic Amino Acids

3. Elastase(s)

- neutral Amino Acids

exopeptidases

remove one amino acid at a time from Exterior C-terminals

- End-products: Mainly Amino Acids and some incompletely digested peptides

include:

• Carboxypeptidase A

- Aromatic & Neutral Amino Acids

• Carboxypeptidase B

- Basic Amino Acids

Luminal digestion: Pancreatic proteases

• initially secreted (Pancreatic Precursors) as inactive peptidases

• must be enzymatically cleaved to form active peptidases within the small Intestinal Lumen

• activation cascade is initiated by the brush border enzyme ENTEROKINASE (also called Enteropeptidase-)

→ cleaves a hexapeptide from the pancreatic precursor Trypsinogen, forming proteolytically active Trypsin

Trypsin

Autocatalytic

• once a small amount of trypsin becomes activated it cleaves its own precursor,

which accelerates its own activation

Trypsin then cleaves all other pancreatic protease precursors

• Chymotrypsinogen, Proelastase, Procarboxypeptidase A & B

• to their active form

- Chymotrypsin, Elastase, Carboxypeptidase A & B

end products of pancreatic protease digestion

mostly Free Amino Acids and Di- & Tri-Peptides

• absorbed across the brush border

• Pancreatic protease Inactivation occurs through Autodigestion or Cross Digestion

Big picture of Enzymatic digestion

A. Luminal (Cavital) Digestion is performed by digestive enzymes secreted into the GI Lumen

- mainly by pancreas but also stomach & salivary glands

B. Membrane (Contact) Digestion is performed by digestive enzymes bound to apical Microvilli that comprise the "brush border" of small intestine enterocytes

C. Cytoplasmic digestion is performed by digestive enzymes located within the Cytoplasm of small intestine enterocytes

- Mainly relevant to protein digestion

result is the formation of smaller molecules that can be absorbed by small intestine

- Monosaccharides, Fatty Acids, & Amino Acids