NST 103 MT 1 - KLATT

absorption of lipid digestion products by enterocytes

occurs mostly in the duodenum and jejunum

passive diffusion

• lipid digestion pdts dissolve in the lipids of the brush border membrane

• absorbed lipid digestion products are rapidly bound by fatty acid binding proteins and re-esterified

carrier mediated uptake

intestinal fatty transport

proteins in brush border membrane for carrier-mediated lipid transport

• CD36

• Fatty Acid Binding Protein-plasma membrane (FABPpm)

• GPR109A, GPR120

• MCT1 (SCFA)

proteins can compensate for knockout of other proteins

CD36 transport of fatty acids

abundant in duodenal and jejunal brush border membrane

• palmitoylated and glycosylated, facilitating membrane localization

directly binds fatty acids

• positively charged lysine interacts with fatty acid carboxylic acid group

• acyl chain is fed through a tunnel that facilitates passage by the phospholipid head groups

cholesterol absorption

dietary cholesterol enters the body’s cholesterol pool

absorption: NPC1L1 transports cholesterol from lumen into enterocyte

excretion: ATP Casette Binding Protein family members facilitate transintestinal cholesterol excretion (TICE)

• ABCA1a/b

• ABCG5/8 (also exports plant sterols)

• targets nuclear receptor (transcription factor) - Liver X Receptor (LXR)

NPC1L1 transport of cholesterol

NPC1L1 binds extracellular cholesterol and deposits cholesterol into the surrounding plasma membrane

high concentrations of cholesterol induce endocytosis of this microdomain

internalized cholesterol is directed towards intraclllular compartments

cholesterol efflux transporter dysfunction

β-sitosterolemia: disease caused by inactivating mutations in ABCG5/8

high levels of cholesterol and plant sterols

characterized by abnormal cholesterol/lipid deposits (xanthomas) and atherosclerosis

treatment: reducing dietary plant sterols, ezetimibe

lipid processing once inside the intestine

similar to pre-micellization, the individual lipid species are liberated from micelles in an aqueous intracellular environment

lipids get..

• bound and trafficked by intracellular storage proteins

• most lipids are to be regenerated to their storage form to be exported in lipoproteins (chylomicrons) —> lymph —> blood stream —> peripheral tissues

fatty acid binding proteins (FABPs)

intracellular transport of lipids

reduce concentration of molecules in free form, promoting transport across apical membrane via simple and facilitated diffusion

direct lipid molecules to organelle (ER for metabolism)

I-FABP/FABP2 (intestinal): binds FFA

L-FABP/FABP1 (liver): Binds LCFA, MAG, lysophosphatidylcholine, retinoids

SCP-1, SCP-2: sterols & cholesterol

chylomicrons

large TAG rich lipoprotein particles (vehicle for fat transport)

main emulsifier: phosphatidylcholine

apo B-48: proteins synthesized by enterocyte and incorporated

apoE, apo C: proteins synthesized by liver and added to chylomicrons in circulation

secreted from basolateral membrane via exocytosis

chylomicron formation

the Microsomal Transport Protein (MTP) transports lipids to the ER

ER heterodimeric protein (transfers triglycerids & cholesteryl esters to apoB) forms pre chylomicrons

pre-chylomicron transport vessel (PCTV) shuttles to golgi to facilitate final lipidation

genetic defects in MTP

results in abetalipoproteinemia

life threatening autosomal recessive condition

failure to thrive, diarrhea, fat, malabsorption

absence/low LDL-C, TG, ApoB

treated with low fat diets and supplementation

Formation and secretion of chylomicrons from enteryocytes

1. formation of mixed micelles in lumen

2. dissociation of micelles in enterocyte

3. FABP associates with lipids

4. smooth ER

   1. TAG re-esterification

   2. phospholipid reacylation

5. Rough ER

   1. Apoprotein synthesis and packaging

   2. Golgi: glycosylation & storage

6. chlyomicrons in vesicles

7. vesicles fuse with basolateral membrane - exocytosis into extracellular space (lymph)

fate of lipid constituents

TAG —> SCFA

Phosphatidylcholine —> MCFA

cholesteryl esters —> glycerol 3-phosphorylchline

Re-esterification at cystolic surface of ER

MAG -(Acetyl CoA)-→ DAG -(Acetyl CoA)-→ TAG

• MGAT and DGAT intermediates

G3P —(2xAcetyl CoA + glycerol 3P)-→ phosphatidic acid -(Acetyl CoA)-→ TAG

cholesterol -(Acyl CoA)-→ Cholesteryl Ester —> chylomicron

• facilitated by Acyl CoA: cholesterol acyl transferase (ACAT)

Phospholipid metabolism in enterocytes

fate of bile acids

bile acids released from their lipid load at the UWL of proximal small intestine

reabsorption:

• passive transport in proximal small intestine

• active transport in terminal ileum

  • apical sodium dependent bile acid transporter ASBT

Essential Nutrient

A component of food deemed essential for life and physiological functions

• inadequate intake can lead to dysfunction, impaired growth, and organismal demise.

Metabolism

The chemical conversions that occur within cells, associated with changes in energy

Nutrition

how organisms acquire adequate nutrient intakes to facilitate physiological function, encompassing aspects like feeding behavior, food composition, digestion, and absorption.

Humoral Theory

• theory popularized by Hippocrates and Galen

• suggests that the human body is a chemical system made of four humors (blood, phlegm, yellow bile, black bile), and disease results from their imbalance.

Chylous

The substance produced in the stomach after digestion, which is converted in the liver to chymous.

Chymous

Chylous is converted into chymous in the liber

• made up of 4 humors and circulates in the body

Essential nutrients

required for life

• energy

• fatty acids

• amino acids

• minerals

Non-essential-compounds

• some influence physiology & health

• some may be inert, toxins

Why do we need energy?

• various endergonic reactions

• muscle contraction

• glandular secretions

• generation of electrochemical gradients

  • Na/K ATPase pump

• synthesis/growth

Macromoleculars

• lipids, proteins, nucleic acids, carbohydrates

• cannot be synthesized - food provides the raw materials

Micronutrients

Accessory factors (vitamins and minerals) required in smaller amounts for metabolic reactions and homeostasis.

• cofactors, substrates, signaling molecules

Why care about GI Tract Anatomy and Function?

• digestive anatomy and physiology changes across life-stages and in disease

• understand the norm to assess functional degree of change

• medical assessment, diagnosis, and intervention of diseases

digestive physiology as a model for other biomedical fields

• ecology & immunotolerance: digestive tract is extracellular

• cell proliferation: digestive tract rapidly turns over, maintaining high proliferative capacity

• neurobiology: vagus nerves allows coordination between brain and gut

Parts of the Gastrointestinal (GI) Tract

• oral cavity

• esophagus

• stomach

• small intestine

• large intestine

• anus

Functions of the GI system

• digestion: reduce size & repackage to facilitate absorption

• absorption: movement from GI tract to blood/lymph

• secretion: movement into GI tract lumen

• motility: perstalsis

• storage & elimination: stomach, anus

• barrier: between external and internal environment

Common layers of the GI tract

1. mucosa

2. submucosa

3. muscularis

4. adevntitia (esophagus) or serosa (stomach, intesntine)

common tissue types of the GI tract

• epithelia: hormone + enzyme secretion

• connective: supportive structure for tissues, facilitate storage, transport, and signaling

• vascular: absorption & transport

• lymphatic: transports lipids, interstitial fluid + facilitates immune function

• muscle: smooth & striated to process + move food along GI tract

• nerve: neural and glial cells grouped into plexuses to coordinate various gut functions

oral cavity functions

• chewing

• initiate digestion (salivary glands)

• swallowing

goal: food bolus

saliva functions

• water moistens food

• glycoproteins (mucin) lubricate and prevent abrasion

• salivary amylase inititates digestion of starch

• antimicrobial agents reduce risk of infection

• acts as pH butter

inadequate saliva production results in..

dry mouth (xerostomia)

• causes discomfort, can impact swallowing capacity

• causes: medications, autoimmune diseases, radiation exposure, nerve damage

Peristalsis

The rhythmic contraction of smooth muscle cells in the GI tract that facilitates the movement of food through the digestive system.

• contraction controlled by input from mechanical, chemical, and electrical stimuli

functions of the stomach

• goal: form chyme (food + secretions)

• accept bolus from esophageal sphincter

• mechanoreceptors sense food presence

• mix by peristalsis + mucus

• digest: acid, pepsinogen, gastric lipase

• empty: antral peristalisis induced by gastrin, blocked by CCK

• store food

• kill bacteria

• some metabolism of ethanol

Types of gastric Juices

• HCl + intrinsic factor (parietal cells)

• pepsinogen + gastric lipase (chief cells)

• mucus (goblet cells)

• water, electrolytes, bicarbonate

pepsinogen

inactive precursor to pepsin (protease with low pH)

• activated by HCl

phases of gastric secretions

• cephalic: prior to food entering stomach

• gastric: foods presence in stomach

• intestinal: food moves into duodenum

production of stomach acid

• Parietal cells secrete H+ and Cl- separately

• H2O dissociates into H+ and OH- in the cell

• H+ exported via H+/K+ ATPase pump

• Cl- diffuses into stomach lumen OR exchanged with HCO3 (formed when OH- condense with CO2 from metabolism)

How is HCl production and secretion regulated

G cells secrete gastrin hormone that is released in response to stomach stretching & peptides/AAs

• gastrin = positive regulator

• facilitates H+/K+ ATPase

synthesis of histamine

• histadine is converted to histamine via histidine carboxylase, which is vitamin B6 depedent

• histadine is an essential AA

• pyridoxal phosphate is an essential vitamin, acts as coenzyme to facilitate decarboxylation

What does gastrin do?

regulates histidine decarboxylase synthesis in the ECL cell

how is HCl production inhibited?

somatostatin: negative regulator

• produced by D-cells of stomach, duodenum, pancrease

positive regulation of stomach acidification

• vagal nerve: acetylcholine

• ECL cells: histamine

• G-cells: gastrin

negative regulation of stomach acidification

• D-cells: somatostatin

gastroesophageal reflux disease (GERD)

relaxed lower esophageal sphincter leads to inflamed esophagus

1. HCl: antacids

2. H+: proton pump inhibitor

3. H2: H2 blocker

gastric cells & functions: chief cells

pepsinogen: proenzyme

gastric lipase: enzyme

gastric cells & functions: goblet cells

mucous mucin: lubricant & buffer

gastric cells & functions: parietal cells

HCl: protein denaturing

intrinsic factor: absorb B12

gastric cells & functions: D-Cells

somatostain: positive regulator hormone

gastric cells & functions: ECL cells

histamine: positive regulator hormone

serotonin: hormone

gastric cells & functions: G-cells

gastrin: hormone

process of gastric emptying

• food leaves pylorus

• circular muscle wall around pylrous (pyloric sphincter) is thick, stays contracted (fluids can pass)

• pyloric contraction controlled by nervous and hormonal signals

• emptying takes around 2-4 hours

factors that influence rate of gastric emptying

• nervous reflexes sensitive to distension of duodenum and the composition, osmolaity, and acidity of duodenal chyme

• hormonal

  • stomach stretching

  • peptides/AA that stimulate gastrin

  • intestine-derive CCK (fat

  • secretin (acid)

  • GLP-1 & GIP (nutrients)

functions of small intestine

• main site of nutrient digestion and absorption

• package lipids in a form that can be asborbed

• absorb macronutrient components, vitamins, minerals

• reabsorb bile

• barrier

small intestine structure

mucosa (absorptive / secretory layer)

submucosa (vascular connective tissue)

muscularis (peristalsis)

serosa (protective)

nutrients are absorbed into what two circulatory systems

Blood: absorption of water-soluble constituents (carbohydrates, AA)

lymphatics: absorption of lipid soluble constituents (fats)

types of cells in intestinal mucosa

• undifferentiated stem cells

• enterocytes (absorptive epithelial cells)

• goblet cells (mucin)

• endocrine cells

• paneth cells (lysozyme, antimicrobial peptides)

• caveolated cells (chemoreceptors)

what is absorbed in the duodenum & jejunum?

carbs

lipids

AA

calcium, iron

what is absorbed in the illeum?

bile salts

vitamin B12

H2O

electrolytes

small intestine parts

upper: duodenum, jejunum

lower: illeum

Enterohepatic Circulation

The recycling process of bile salts between the intestine and the liver, essential for lipid absorption.

Exocrine Pancreas

The part of the pancreas that secretes digestive enzymes into the pancreatic duct for digestion.

medical intervention in stomach and small intestine for weight loss

gastric sleeve: remove large portion of stomach

gastric bypass: bypass stomach, ileum, jejunum

secretions from accessory organs into small intestine

liver & galbladder: bile

pancrease: “juice” (bicarbonate ions and digestive enzymes)

liver functions

bile production: bile salts, phospholipids, cholesterol

synthesis, secretion, & storage of glucose: gluconeogenesis, lipogenesis, glycogen synthesis, ketogenesis

detoxification: urea production, alteration of drugs, excretion

protein production: albumin, globulin, clotting factors (fibrinogen, prothrombin)

blood & bile movement in liver

blood enters liver through portal triad, passes through sinusoids, exits through central vein

bile produced by hepatocytes & secreted into bile caniculi, which carry bile to hepatic duct

blood and bile never mix

liver structures

Pancrease endocrine functions

secretes hormones like insulin and glucagon into the bloodstream to regulate glucose levels.

• insulin: glucose uptake (beta cell)

• glucagon: glycogen breakdown (alpha cell)

pancreas anatomy and function

acini cells: exocrine functions, secrete enzymes into pancreatic duct

beta/alpha cells: endocrine functions, secrete hormones into blod

pancreas exocrine functions

water, salts, bicarbonate

trypsin and chymotrypsin: protein digestion

pancreatic amylase: carb breakdown

pancreatic lipase: fat breakdown

pancrease and weight gain

exocrine function of pancreas can be compromised due to medical conditions (CF, exocrine pancreas insufficiency (EPI))

results in malabsorption, malnutrition

treatment: pancreatic enzyme replacement therapy (PERT)

anatomy and function of large intestine

absorb water, electrolytes (proximal half)

microbial fermentation

formation and storage of feces (distal half)

large intestine differences from small intestine

no villi

epithelial cells do not secrete digestive enzymes (secrete alkaline mucus instead)

absorption limited to salts, water, vitamins, microbial byproducts due to tighter junctions

site of microbial metabolism: conversion of carbs to gases & short chain fatty acids

Villi

Small, finger-like projections in the small intestine that increase the surface area for absorption of nutrients.

Microvilli

Tiny hair-like structures on the surface of epithelial cells in the small intestine that further amplify the absorptive surface area.

Somatostatin

A hormone produced by D-cells in the stomach and pancreas that inhibits gastric acid secretion and regulates other hormones.

Gastrin

A hormone secreted by G-cells in the stomach that stimulates the secretion of gastric acid and aids in digestion.

CCK (Cholecystokinin)

A hormone released by the small intestine that stimulates the release of bile from the gallbladder and digestive enzymes from the pancreas.

history of carbohydrates consumption in human diets

varying carb content diets throughout history

hominids consumed diverse carb quantities: fruits, vegetation, honey

humans recently introduced carb-rich foods: grains, tubers, and legumes

• contain amyloplast organelle where starch granules are synthesized and stored

• minimally digestible without further processing

history of carbohydrate processing

cooking allowed for introduction of tubers, legumes, grains by breaking down plant cell microstructure to release starch granules, available to contact digestive enzymes + inactivate toxic components

fermentation: bacteria contain enzymes to digest carbs that are indigestible to humans

• grain and grape fermentation for beer and wine in acient babylon & egypt

• dairy fermenting to break down lactose

carbohydrates in human nutrition

not essential for human population - plasma glucose maintained through de novo synthesis in the absence of dietary carbohydrates

source of rapidly digestible energy (4 kcal/g)

types of carbohydrates in human diet

available carbs: humans produce enzymes capable of cleaving bonds so they can be absorbed

unavailable carbs: digestibility dependent on type of glycosidic bond, food microparticle sturtcure, and dose of carbohydrate

can be naturally occuring or added to foods during processing

carbs for food processing

flavor

preservative

water retention

browning

energy for microorganisms (yeast)

thickening agent

reduce glycemic responses (sugar alcohols)

chemical variation of carbohydrates

• # of carbons in monosaccharide: tetrose, pentose, hexose

• aldose (carbonyl at the end of carbon chain) vs ketose (carbonyl within)

• stereochemistry: enantiomers (D/L, differ at all chiral centers), epimers (differ at 1 chiral center)

• degree of polymerization: mono-, di-, poly-, fused by glycosidic bonds, alpha/beta

hemiacetal

aldehyde reacting with OH

hemiketal

ketone reacting with OH