Lipid digestion and absorption

FNN200

Mouth

• lingual lipase

  • small amount of lipid is digestion

  • short and medium chain FAs

Stomach digestion

• Gastric lipase

  • lipids in stomach delay gastric emptying and therefore have a high satiety value

  • makign you feel full

Small intestine

• bile emulsification + pancreatic lipase + colipase + cholesterol esterase + phospholipase 

  • Phospholipids and cholesterol 

• The micelle breaks down and releases its fats at the BBM which allows for the fats to diffuse through the phospholipid bilayer 

Overview of digestion and absorption of lipids

• pancreatic lipase + small entestine does the emulsification of bile essential for breakdown break apart

digestion of triglycerides

• mouth and stomach

  • do the digestion of short and medium chain Fatty acids

  • lingual lipase produced by salivary glands

  • gastric lipase produced in the stomach

• Small intestine

  • bile; no lipase 

    • then they are emulsified triglycerol

  • pancreatic lipase produced in the pancreas 

• results in monoactlglycerols and fatty acids

Digestion and absorption of lipids

• intraluminal phase

  • fatty acids and monoglycerides are emulsified by bile salts to form micelles

  • these then are burst and able to diffuse across membranes

• Mucosal phase

  • fatty acids enter the epithelial cells and link to form triglycerides 

  • they are repackaged in the enterocyte into these triglycerides 

• Secretory phase 

  • triglycerides combine with proteins in the golgi to form chylomicrones 

  • these are what is able to enter the lacteal and therefore be transported away from the intestine

    • short and medium chain FAs → portal vein 

    • Long chain FAs → lacteals 

Transportation of nutrients into body cells

• fructose → facilitated diffusion to epithelial  → blood stream 

• Glucose and galactose → active transport into the epithelial→ facilitated diffusion → blood 

• Amino acids → active transport to enterocyte, diffusion to blood 

• FATS 

  • lumen

    • large lipid droplets + bile salts → micelles → FFAs + monoglycerides 

  • enterocyte 

    • triclycerides are formed → chylomicrons → exocytosis 

    • go into the lacteal 

Water soluble nutrient pathway in body cells

• small intestine → capillary → blood stream → hepatic portal vein → liver → tissue and organs 

  • GO TO LIVER BEFORE TISSUES 

Fat soluble pathway for nutrient transport in body

• small intestine → lacteal → lymph system → thoracic duct → blood stream → tissues and organs. → liver 

  • GO TO LIVER AFTER TISSUES 

Lipid transport and storage

• lipids are insoluble in the blood which is aqueous and therefore has to be transported as lipoproteins

  • Chylomicrons, VLDL, IDL, LDL, HDL 

• Transport systems 

  • Exogenous (dietary) lipid transport 

  • endogenous lipid transport 

  • reverse cholesterol transport 

Structure of lipoproteins

• phospholipid membrane, contain cholesteryl esters and triglycerol

  • core is mainly non polar lipids 

• contain integral apoproteins (Eg. APOB)

• Peripheral Apoproteins (Eg. APOC)

Ratios of dietary fat in the lipoproteins

• Chylomicron → highest TG: CHolesterol 

  • transport dietary fat out of small intestine 

• VLDL → 2nd highest TG: Cholesterol 

  • transport endogenous fats to adipose tissue/muscle 

• IDL → intermediate TG: chol ratio

  • carries cholesterol to liver and then releases TG to become LDL

• LDL → mostly cholesterol 

  • carries cholesterol to liver → main circulating form of cholesterol 

• HDL → reverse cholesterol delivery 

  • pick up cholesterol from the tissues 

Chylomicron

• mostly TG 

• least cholesterol 

• transports dietary fat out of the small intestine

VLDL

• more cholesterol

• less TG

• transports endogenous fat to adipose tissue/ muscles

IDL

• Carries cholesterol to the liver 

• releases TG to become LDL 

• Contains more less TG and more Cholesterol 

LDL

• Carries the cholesterol to the liver 

• main circulating form of cholesterol 

• HIGHEST Cholesterol and lowest TG 

HDL

• contains higher cholesterol than TG 

• picks up cholesterol from the tissues 

Post Prandial state chylomicrons

• triglycerides and cholesterol esters are packaged in a phospholipid and an apoprotein shell to forma nascent chylomicron 

  • this then leaves the enterocytes and enters the lacteal then the blood stream 

  • nacent chylomicrons contain APO a proteins

• Apo E and C are transferred from other lipoprotein to mature the chylomicrons

  • the chylomicron contains triglycerides and cholesterol

• Lipoprotein lipase attaches to endothelial lining of capillaries and the enzymes have binding sites to anchor the chylomicron to the enzyme whcih hydrolyzes triglycerides

  • this is less sense in triglycerides but rich in cholesterol

• After triglycerides are hydrolyzed from the chylomicrons, apoproteins A and C are transferred to HDL

  • the reminant binds to liver APO receptors to undergo pinocytosis 

• HDL contains apa A, E and C

Post prandial Exogenous state of glucose

• LPL - lipoprotein lipase 

• TG → FAs + Glycerol 

• adipose = major TG storage site

  • Chylomicron goes through the LPL and give storage in tissues for free fatty acids

Lipid metabolism in the liver - endogenous 

• Chylomicron remnant disassembled → cholesterol, proteins 

• Major lipid producing organ → produces TGs and incorporates them into VLDL 

• Cholesterol (synthesized in the liver + from chylomicron remnant are used to make bile) or repackaged into VLDL 

VLDL endogenous transport between meals 

• VLDL is produced by hepatocytes. Major protein is APO B 

• APO C and A are transferred to the nascent VLDL to form mature VLDL 

• Triglycerides are hydrolyzed in mature VLDL by lipoprotein lipase attached to the endothelial lining of the capillaries 

  • the lipoprotein becomes enriched in choesterol 

  • glycerol is relased through hydrolysis

• VLDL shrinks to become IDL and LDL (APO E is then given to HDL)

• LDL can bind to to LDL receptors on the liver and extrrahepatic tissues 

  • 70% of LDL binds to liver 

• LDL is the primary carrier of cholesterol in the blood 

Reverse to cholesterol transport 

• HDL is synthesized by intestine and liver

  • intestine HDL has APOA but lacks E and C

  • these are produced later and transfered onto the intestinal HDL 

  • the nascent HDL is discoidal in shape 

• ABCA1 is used to bind cholesterol and phospholipids to HDL

• LCAT - Lecithin cholesterol acyl-transferase converts the nascent into spherical particles with cholesterol cores 

  • these are the HDL that are used to go back to liver for repackaging to clear our the cholesterol 

  • Takes it from our cells back into the liver to be packaged and cleared from the blood

Sources of circulating lipids 

• LPL: uptake of FA from bloodstream into tissues

  • activity regulated by insulin

• Hormone sensitive Lipase (HSL) 

  • releases FA from adipose tissues into bloodstream 

    • activity is inbibited by insulin, and activated by glucagon 

LPL - Lipoprotein lipase

• uptake of FA from the bloodstream into the tissues

  • regulated by insulin 

HSL - Hormone sensitive lipase

• Release of FAs from adipose tissues into the bloodstream

  • activity is inhibited by insulin

    • wants to bring in energy and store it because the cell has enough

• and activated by glucagon

  • gluconeolysis and gluconeogenesis 

  • uses energy from stores

Fatty acid B oxidation

• TG are a rick source of energy because they have high energy bonds 

• 95% of chemical energy is from FAs 

  • cannot be used for glucose making

• 5% of chemical energy is from glycerol

  • can be used for glucose (gluconeogenesis)

Fatty acid catabolism

• starting location is the cytosol

• Long chain FAs 

  • Step 1: Activation of FA by Coenzyme A to make fatty acyl CoA

    • USES 2 ATP 

  • Step 2: Fatty Acyl CoA transported into mitochondrial matrix for oxidation 

• Key take aways 

  • long chain FAs require transport systems to enter the mitochondria

  • membrane transporter is a carninine

  • short-chain FAs can pass directly into the mitochondrial matrix

Key take aways of fatty acid B oxidation

• long chain FAs require a transport system using carnitine transporter

• membrane transporter is carnitine

• short-chain FAs can pass directly through the mitochondiral matrix

Sequence of reactions in fatty B oxidation

• 4 reactions occur 

• each removing 2 carbons from the carboxyl end → forms 1 acetyl CoA 

  • each cycle produces 1 FADH2 and 1 NADH

  • the remaining FA (with 2 fewer carbons) re-enters the cycle of reactions

• the chain will continu to get shorter and just keep going around 

The cycle of fatty acid B oxidation for palmitic acid

• contains 16 carbons

• each sequence will remove 2 carbons and eventually there will be 8 acetyl CoA 

  • 7FADH2 and 7 NADH (because there are 7 cycles) 

  • it makes 8 of the acetyl because there will also be one made at the end with the final carbons even though it will only do 7 cycles 

What is the first step of fatty acid catabolism for long chain FAs

• activation of the Fatty acid by coenzyme a to make Fatty acyl CoA 

• this process uses 2 ATP

Second step in fatty acid B oxidation

• faty acyl CoA is transported into the mitochondrial matrix for oxidation 

Anabolic reaction: Fatty acid synthesis

• occurs in the cytosol of the ER

• Step 1: transport of acetyl-CoA to the cytosol

  • the acetyl CoA joins with oxaloacetate to form citrate

  • citrate leaves into the cytosol

  • then the acetyl CoA and oxaloacetate break apart

• Depending on the energy need in the cell, it will be stored as fatty acids

  • Step 2: Acetyl-CoA Carboxylase (ACC)

    • THIS IS THE FIRST RATE LIMITING STEP

  • Step 3: Fatty acid synthase (FAS) Enzyme complex acts to form Palmitate

1st rate limiting enzyme for fatty acid synthesis

• Acetyl-CoA carboxylase (ACC)

what is formed in fatty acid synthesis 

• Palmitate 

  • From FAS after ACC 

• this is used for energy later for triglyceride

Regulation of Acetyl-CoA carboxylase (ACC) and Fatty acid synthase (FAS)

• Hormonal

  • POSITIVE: Insulin

  • NEGATIVE: Glucagon

• Allosteric Regulation

  • Cytosolic citrate (Positive)

  • Long chain FA CoA (Negative)

• PUFAS

  • decrease activity

  • this can contribute to PUFAs lowering the amount of fats in the body

Major site of fatty acid anabolic synthesis

• liver, adipose, lungs, brain, kidneys, mammary glands

Post meal lipid metabolism in adipose cells

• Favours the storage as TAG uses TG from lipids and excess glucose to make the fat pools

Post prandial pathway of fats after a meal

• Fats → Chylomicron → Release TAG and leave reminant → VLDL→ Release TAG and get acted on by LPL to form IDL → Acted on by LPL to release TAG and produce LDL

• Move into the cell as FFA, DAG and MAG → Enter triglyceride pool

Lipid metabolism in the liver

• CR from portal vein → FFA, DAG, MAG (into triglyceride pool), Phospholipids and cholesterol + apoprotein → VLDL → Hepatic veins into systemic circulation

What contributes to VLDL

• Both endogenous lipids and glucose 

  • GLucose → GLU-6-P → Glycerol → Triglyceride pool into VLDL

Eicosanoids

• Eicosa = 20 carbon 

• Signaling molecules that are metabolites of 20-carbon fatty acids synthesized from omega-3 and omega-6 fatty acids 

  • 3 is alpha linolenic and 6 is alpha linoleic 

• Prostaglandins, thromboxanes, leukotrienes, neuroprotectins, lipoxins and resolvins 

• regulators of inflammatory responses and immunity 

OMEGA-6 Fats creating eicosanoids

• Linoleic acid

• becomes arachidonic acid (this is the 20:4n-6)

OMEGA-3 Fats creating eicosanoids

• Alpha-linoleic

• becomes eicosapentaenoic acid (20:5n-3

  • this can also come directly from salmon or other fatty fish

Phospholipids at the cell membrane

• phospholipase A2 (a linolenic and linoleic acid)

  • Breaks catylizes a reaction that creates arachidonic Acid (n-6) and Eicosapentaenoic acid

COX - Cyclooxygenase on ARA (n-6)

• Creates prostoglandins and thromboxanes 

  • Series 2 

• Pro arrhythmic 

• Platelet activator 

• Vaso constriction 

LOX - Lipoxygenase on ARA (n-6)

• Leukotrienes

  • series 4

  • Proinflamatory

Arachadonic derived messangers

• prostoglandins 

  • Series 2

  • Proarrhythmic 

• Thromboxines 

  • Series 2 

  • Vasoconstriction and platelet activator 

• Leukotrinines

  • Series 4 

COX - on EPA (n-3)

• Prostaglandin 

  • series 3 

  • ANTIarrhythmic 

• Thromboxane’s 

  • series 3 

    • Platelet inhibitor 

    • vasodilation 

LOX - on EPA (n-3)

• Leukotinenes 

  • series 5 

    • Anti-inflammatory 

DHA messangers

• Lipoxins

• resolvins

• neuroprotectins 

• all are anti inflammatory 

Prostaglandins

• muscle contractin 

  • ARA is pro 

  • EPA is anti arrhythmic 

Thromboxanes

• plateleet aggregation

  • ARA Promotes clotting 

  • EPA supresses clotting 

• Blood pressure 

  • ARA constricts 

  • EPA Dialates 

Leukotienes

• INflammation 

  • ARA is proinflammation 

  • EPA is anti-inflammatory 

Lipoxins, resolvins and neuroprotectins

• Anti-inflammatory 

  • Brain health, role in vision and again 

Eicosanoids competition

• Essential fatty acids compete at the desaturase enzyme → preference is given to the more unsaturated (n-3) 

Excess N-6

• decreases EPA

  • increased inflammation 

  • increased blood clotting 

  • increased muscle contraction (heart rate)

• Cause it goes against all the functions of EPA 

Excess N-3

• Decreases ARA 

  • Decreased inflammation 

  • decreased blood clot

  • decreased muscle contraction 

    • antiarrhythmic

• Against the functions of ARA cause there is less of it

Initial concerns about N6 and n3

• thought they could be too high 

• now 

  • focus on individual omega 3 status 

  • there is an index that takes the sum of EPA and DHA in red blood cell membranes 

Study on the different polyunsaturated n6 and n3 on patients with hyperlipidemia in a RCT

• Double blind, randomized, placebo controlled trial 

• measured blood lipids and glucose & quality of life at baseline and after 60 days of interventions

  • Ran high, middle and low ratios of N6:n3

• Results:

  • those who were in the high n6 had no change

  • The middle group had higher Good cholesterol (increased HDL lowered total)

  • Low group had decreased TG and total cholesterol but no change in HDL 

• Takeaways

  • adoptign a diet lower in N6:n3 ratio can impact the blood lipid perameters for individuals with hyperlipidemia 

  • excessive reduction wont lead to additonal improvement in blood lipids