First Unit3 Lecture Goodridge Flashcards
How many grams of water to store gram of fat?
1 gram of water to store 1 gram of fat
Describe amounts of total energy (Kcal) stored in body
Fat>Protein>Carbohydrates
Human Metabolism obeys First Law of Thermodynamics
deltaU = Q - W
deltaU=Kcal of chemical energy stored (mostly as fat) = change in energy stored in a physical system
Q=Kcal in food intake = energy input to the system
W=Kcal of metabolic and skeletal muscle = work done by the system
Also delta U=Triacylglycerol (adipose tissue), Glycogen (liver and muscle), Protein (all tissues)
W
Why Regulate Metabolism of Triacyglycerol and Fatty acids?
- Store energy in times of plenty
- Use stored energy during starvation
- Accommodate intake of varying ratios of triacylglycerols, carbohydrates, proteins
- Provide insulation to reduce heat loss
- Cushion body in case of falls or assault
Cholesterol Esters
Formed by esterification with Fatty Acids
More lipophilic than cholesterol
Storage form of cholesterol
How many excess calories in a year based on 2000 calorie diet to gain one pound of fat (including its water component)?
3500Kcal excess calories in a year will gain 1 pount (or 10Kcal per day excess)
In humans on an “average” American diet, what is the major source of cholesterol (where does it come from)?
Synthesis DE NOVO from in Liver and other tissues is the MAJOR SOURCE of cholesterol
Sources of Cholesterol (on average diet)
DE NOVO SYNTHESIS = 700mg/day
- Liver = 70 (makes 10% of the cholesterol)
- Intestine = 70 (makes 10% of the cholesterol)
- Other tissues = 560 (almost all tissues make cholesterol)
DIET=400mg/day
-Transported to liver and extrahepatic tissues in blood
Sources of Cholesterol
Most Dietary Cholesterol is free cholesterol; balance is cholesterol ester
Cholesterol in diet is HIGHLY VARIABLE (vegetarians have zero from their diet, because plant sterols are not useable/metabolized in same way by animals, so they get ALL their cholesterol from DE NOVO SYNTHESIS)
DE NOVO cholesterol synthesis is INHIBITED BY DIETARY CHOLESTEROL
Amount of cholesterol in blood affects cardiovascular disease
Why Regulate Metabolism of Cholesterol
- Cholesterol is NOT a significant energy source
- Cholesterol is an important component of plasma and other organellar cell membranes
- It is a precursor to bile acids
- Major Player in quantitative turnover of total body cholesterol
- It is a precursor to Hormones and Vitamins
- Not significant in quantitative turnover of total body cholesterol
- It (cholesterol/Free Cholesterol) is Secreted into Bile. This is a Major Route of Removal of cholesterol from the body! So if you have too much cholesterol there are mechanisms to bring it back to liver, and then the liver excretes it into bile, and then a significant portion of it will go out in the stool.
Cholesterol and Fat (why hamburger is worse than egg even though egg has more cholesterol)?
Answer: Hamburger has a lot more fat (saturated fat)
Fat is important in energy balance, but fat ALSO influences the metabolism of cholesterol and exacerbates effects of cholesterol on cardiovascular function.
Gastric Lipase (first part of Digestion)
The first part of digestion of Fat occurs in the stomach. Gastric Lipase (an enzyme that HYDROLYZES triacylglycerol) is secreted by glands in the stomach
Acid pH in stomach is optimal for this enzyme (stomach acid pH is about 2)
Reaction:
triacyglycerol —-> fatty acid + 1,2-diacylglycerol
10-30% of intestinal triacylglycerol hydrolysis occurs in the stomach (by the enzyme catalyzed reaction by Gastric Lipase)
Overview of Lipid Digestion
Entering is Biliary Cholesterol (2000mg/day, because 2g per day of cholesterol is secreted into the Bile) and Dietary Cholesterol (400mg/day) as well as Dietary Triacylglycerol
98% of the Triacylglycerol that you eat will end up being absorbed!
Of the 2400mg/day of Cholesterol (total value), you will absorb only about 1200mg (so 50%) and the other half will be excreted in stool! This is the major way that cholesterol will be removed from the body if you have too much!
The Cholesterol is packaged into chylomicrons and sent to the lymphatic system (the 50% of cholesterol mentioned gets absorbed in the ILEUM, which is the lower end of the Small Intestine)
Biliary Lipids
Biliary Lipids=Bile, and it is made of the following components
Class Daily Secretion (g)
Bile Salts 24g
Phospholipids 11g
Cholesterol 2g
Biliary Lipids=Bile, and these are the components of bile. Most of the 24g of Bile Salts in the Bile will be reabsorbed. Bile Salts are also important in cholesterol metabolism in addition the fat/lipid absorption.
All of these components of Bile contribute to the emulsification and ultimately the creation of micelles with the lipids, which facilitates the digestion of fat.
Info About Bile Acids
They are synthesized in Liver
Stored in Gall Bladder
Fat in Duodenum causes release of cholecystokinin to blood (this is realized from the duodenal cells)
Cholecystokinin stimulates contraction of gall bladder, forcing bile into the duodenum
Bile acids are AMPHIPATHIC
Bile acids initially emulsify di- and triacylglycerols (emulsification particles are MACROscopic)
They ultimately form mixed micelles with products of fat hydrolysis (the micelles are MICROscopic particles in solution)
Bile Acid Synthesis First Step (Rate Limiting Step/Enzyme)
Bile Acids are Synthesized in the LIVER!
Rate limiting enzyme (slowest step and first step in Bile synthesis) = 7alphahydroxylase enzyme
You start with cholesterol and 7alpha hydroxylase uses NADPH,H+ (converting it to NADP+) and O2 (molecular oxygen) in order to convert it to 7alphahydroxycholesterol
7alphahydroxylase enzyme is the REGULATORY enzyme/step in pathway (All regulation of production of bile acids is regulated here!). It is STIMULATED BY HIGH LEVELS OF CHOLESTEROL IN THE LIVER (so feed-forward activator) and INHIBITED BY BILE ACID (the product, so bile acids are feed-back inhibitiors). Several hormones regulate the pathway as well! (don’t need to know names)
Bile Acid Synthesis Continued (After 1st/Regulatory Step)
Once cholesterol is 7alphahydroxylated to 7alphahydroxy cholesterol by the rate-limiting enzyme “7alphahydroxlase,” it can the go through either of two different paths:
1) It can either be 12alphahydroxylated and activated with proponyl-CoA
OR
2) It can just be activated with proponyl-CoA
(these are several steps but we won’t talk about)
The proponyl-Coa serves to “Activate” compounds (similar to how fatty acids get activated with CoA before beta oxidation)
This gives you either Cholyl-CoA or Chenodeoxycholyl-Coa (only difference is one product is 12hydroxylated and one is not)
These molecules can be conjugated either by GLYCINE amino acid or TAURINE amino acid
This leads to a total of 4 PRIMARY BILE ACIDS/SALTS (The four products are MADE IN LIVER and are SECRETED INTO THE BILE) when this amidation/conjugation occurs (amino acid linked to the molecule) 1) Tauracholic (amino) acid 2) Glycocholic (amino) acid OR 3)Taurachenodeoxycholic (amino) acid 4) Glycochenodeoxycholic (amino) acid
Once the bile get into the intestine, it undergoes a 7alphadehydroxylation and deconjugation of all four compounds, so you end up with TWO SECONDARY BILE ACIDS (These are the two FUNCTIONAL BILE ACIDS that will help with emulsification and creation of miscelles). They are DEOXYCHOLIC ACID and LITOCHOLIC ACID. *This reaction of dehydroxylation/removal of 7allpha hydroxyl and deconjugation/removal of aminoacid is carried out by BACTERIAL ENZYMES IN YOUR GUT (NOT Human enzymes!)
Anatomy Description (Bile Acids: STORED in Gallbladder, DELIVERED to Duodenum
The ducts that connect from the liver cells are called Canaliculi (“Bile Canaliculi”). Canaliculi=Ducts.
From the liver, the bile goes to the “right and left hepatic ducts”, these merge into the “common hepatic duct”.
The Gall bladder has it’s own duct called the “cystic duct” and when the bile goes out of the gallbladder into the cystic duct it then merges with the common hepatic duct in what we call the “Common Bile Duct” (where cystic duct and common hepatic duct merge).
The pancreas also has it’s own “pancreatic duct,” which connects to and join the common bile duct. All of these secretions will go through the “SPHINCTER OF ODDI” and enter the “Duodenum” of small intestine.
This duodenum is the very top portion of small intestine that comes right after the stomach, so it will have the food/lipids that have been partially (10-30% from Triacyglycerol have become 1,2 diacylglycerol and free fatty acid by Gastric Lipase, as well as the rest remaining as triacyglycerols).
The Sphinctor of Oddi prevent all of the secretions that enter the duodenum of the small intestine from refluxing back into the common bile duct.
Bile Acids are Amphipathic
Bile Acids are AMPHIPATHIC (contain BOTH polar and nonpolar regions)
Glycocholate (Glycocholic Acid) is the example of Bile Acid that he showed in picture. Bile acids have have an “apolar side with CH3 groups attached” (hydrophobic side) AND “polar side with OH groups attached near ring area and a carboxylic acid polar group on way end” (hydrophilic side).
Bile Salts Emulsify Dietary Fats
Intestine contains “lipid droplet” from food that came from stomach and was only partially digested by Gastric Lipase (diacylglycerol, triacyglycerol, cholesterol ester).
The Bile Acids/Salts (Bile) will surround/emulsify this fat droplet (some Phospholipid will surround it too, which came from body secretion and possibly a little from diet).
“Pancreatic Lipase and Colipase” will bind to the surface of emulsified lipid to start digesting/breaking it down more.
Pancreatic Lipase will catalyze the next steps that will hydrolyze the majority of the Triacyglycerols that came from the diet.
Hydrolysis of Dietary Triacyglycerol (Step 1)
Triacylglycerol + H20 (adding water to hydrolyze) —–enzyme PANCREATIC LIPASE ——-> 1,2-Diacylglycerol + Unesterified Fatty Acid
This removes the Fatty Acid from the THREE POSITION/C3 (THREE position of the glycerol,” making 1,2-Diacylglycerol and FFA.
Note: Unesterified Fatty Acids are sometimes called Free Fatty Acid, but actually it is on albumin or something and not just free, floating around. So Unesterified Fatty Acid is more correct, but it is the same as saying Free Fatty Acid.
Hydrolysis of Dietary Triacylglycerol (Step2)
The second step uses Pancreatic Lipase to remove the second Fatty Acid by adding water (hydrolysis). This time it removed the FA from the One Position/C1 (ONE position of glycerol) in the 1,2-Diacylglycerol. This forms another FFA (unesterified FA) and a 2-Monoacylglycerol (2-MG).
1,2-Diacyglycerol + H2O —–Pancreatic Lipase—-> 2-Monacylglycerol + FFA
IMPORTANT: About 70% of Triacyglyceried are hydrolyzed to this step/product and then enter the ENTEROCYTES/MUCOSAL CELLS as “2-MG (2-Monoacylglycerol) + FFA”. So, the majority of the time (70% of the time) the hydrolysis process stops after this step. Most of the Time the fatty acids and monacylglycerols enter the cell by “Fatty Acid Transport Protein (FATP)”. This FATP is present on all cells; here we are talking about the mucosal/enterocytes/epithelial cells of small intestine.
Hydrolysis of Dietary Triacylycerol (Step 3 and 4)
Step 3 (uses ISOMERASE enzyme):
2-Monoacylglycerol ——“ISOMERASE”—– 1-Monoacylglycerol
Step 4 (uses PANCREATIC LIPASE now that it can work on the ONE position, because it could NOT WORK ON TWO POSITION before), forming Glycerol and FFA as the final products:
1-Monoacylglycer + H20 —–Pancreatic Lipase —-> Glycerol + FA
IMPORTANT:
***The Glycerol is EXCEPTION and will enter mucosal cells/enterocytes and then go to the “Portal Vein” and travel to the LIVER. This is because there is not very much glycerol kinase to make use of it in the enterocytes, but the liver has plenty, so it will be more useful in the liver.
*****The rest of molecules (1,2-Diacyglycerol, 1-Monoacylglycerol, and FA formed) will enter mucosal cells/entoryctes, get REPACKAGED INTO TRIACYLGLYCEROL onto CHYLOMICRONS, and then ENTER THE LYMPHATIC VESSELS.
**Therefore AQUEOUS hyrophilic digestion products (like glycerol) are taken up by portal system (Portal Vein) versus hydrophobic (like cholesterol, cholesterol ester, triacylglycerol) are taken up by Lymphatic System (Lymphatic Vessels)
Cholesterol Esterase
Cholesterol Esterase is an enzyme made in the PANCREASE and secreted into the gut/small intestine.
Cholesterol Esters are broken down by “Cholesterol Esterase” into Cholesterol + Fatty Acid
Cholesterol Ester —–Cholesterol Esterase–> Cholesterol + Fatty Acid
Note: Most of Cholesterol in DIET is UNESTERIFIED. If there is any small amount, it will be hydrolyzed by Cholesterol Esterase and broken into unesterified fatty acid (FFA) and unesterified cholesterol (sometimes called free cholesterol).
