Metabolism - Basic Science Core

Metabolism/Phyisology Test

Gross Anatomy of the Small Intestine (3 Parts)

1) the duodenum

2) the jejunum

3) the ileum

duodenum

• The duodenum constitutes the first 10-12 inches. It begins at the pyloric valve, arcs around the head of the pancreas and passes to the left, and ends at a sharp bend called the duodenojejunal flexure

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• The duodenum receives the stomach contents, pancreatic juice and bile.

Duodenojejunal Flexure Junction

Arcs around the head of the pancreas and passes to the left, and ends at a sharp bend called the duodenojejunal flexure

jejunum

• The jejunum is about 8 feet long and extends from the duodenum to the ileum.

ileum

The ileum is about 12 feet in length and joins the large

intestine at the ileocecal valve.

Ileocecal valve

The end of the small intestine feeding into the ascending colon (start of the large intestine)

Surface of the Small Intestine

In order for absorption of nutrients, electrolytes, and water in the small intestine to occur,

• There needs to be a maximal surface area - this is accomplished through:

  • Plicae circulares

  • Villi and microvilli

Plicae Circulares

• Large, permanent transverse folds of the mucosa and submucosa that project into the lumen of the small intestine.

• Help the body absorb nutrients

villi

Small, finger-like projections made of multiple cells protruding from the mucosa. Range from 0.5 mm to 1.5 mm long

Microvilli

Extremely tiny, microscopic folds of the plasma membrane on the apical surface of individual epithelial cells.

• Form a dense "brush border"

Carbohydrates (How we absorb them in the human body)

Carbohydrates are widely distributed the human body they have important structural and metabolic roles

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The most important carbohydrate; most dietary carbohydrate is absorbed into the bloodstream as glucose formed by hydrolysis of dietary starch and disaccharides, and other sugars are converted to glucose in the liver (more on this in just a bit)

Glucose

• Glucose is the major metabolic fuel of humans and a universal fuel of the fetus

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Glucose is the precursor for synthesis of all the other carbohydrates in the body, including:

• glycogen for storage,

• ribose and deoxyribose in nucleic acids,

• galactose for synthesis of lactose in milk, in glycolipids, and in combination with protein to form glycoproteins

Major Dietary Carbohydrates Types (3)

• Monosaccharides

• Disaccharides

• Polysaccharides

Monosaccharides (3 Dietary Carbohydrates)

• Glucose

• Fructose

• Galactose

Disaccharides (3 Dietary Carbohydrates)

• Sucrose (Table Sugar)

• Lactose (Milk Sugar) → a galactose and Glucose

• Maltose (Sugar from Malt grain)

Polysaccharides (3 Dietary Carbohydrates)

• Glycogen (We eat from animals)

• Starch (We eat from plants)

• “Fiber” (cellulose, others) → Humans cannot digest this

Digestion of Carbohydrates

• To absorb carbohydrates it is essential to break them down into there smallest components

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• Amylase → Means to digest Carbohydrates

Two Digestive Enzymes we go over:

1) Salivary amylase and pancreatic amylase:

• Degrades polysaccharides into disaccharides.

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2) Disaccharidases:

• Degrades disaccharides into monosaccharides

• Located in the small intestine

Disaccharidases

Disaccharides are degraded in the small intestine by a group of brush border enzymes called disaccharidases

• Named after the disaccharide they breakdown

Absorption of Glucose and galactose

Glucose and galactose are absorbed (via secondary active transport) through a Na+-dependent cotransporter known as SGLT1.

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A high luminal concentration of Na+ facilitates absorption of these 2 sugars against their gradients.

Absorption of Fructose

• Fructose enters by facilitated diffusion via glucose transporter 5 (GLUT5)

• GLUT5 does not require Na+

How are monosaccharides are transported out of the enterocytes

• Transported into the capillaries by GLUT2

• Facilitated Diffusion (How this is done)

Lactose Intolerance

• A Intolerance makes you fart a lot, you can just avoid lactose or take medication

• Normally lactose is broken down into Glucose & Galactose in the small intestine

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• Lactose Intolerent people, cannot breakdown lactose and it ferments in the large intestine by bacteria

Every Carbohydrate in the body eventually turn into …

Glucose

Metabolic fates of glucose: (4)

• Stored as glycogen in the liver and skeletal muscle

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• Stored as triglyceride in adipose tissue

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• Metabolized into pyruvate or lactate via glycolysis

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• Metabolized in the pentose phosphate pathway

Glycolysis Facts

• Involves 10 enzymatic reactions

• Occurs in the CYTOSOL of cells

• Does NOT require oxygen (i.e., glycolysis is ANAEROBIC)

• Results in the formation of:

• 2 ATP molecules (a very small amount of energy)

• 2 NADH (nicotinamide adenine dinucleotide + hydrogen) molecules, which if oxygen is present, can produce 5 ATP later on in the ETC

Pyruvate (Glycolysis)

• End product pf Glycolysis is PYRUVATE

• Most of the pyruvate undergoes OXIDATIVE degradation in the mitochondria if AEROBIC conditions exist

If no Oxygen

• Conversion of pyruvate into LACTATE occurs under ANAEROBIC conditions or in those cells (RBCs, platelets) that have no mitochondria and therefore lack the ability to oxidatively degrade pyruvate altogether

For every 1 molecule of glucose … (Glycolysis)

2 molecules of pyruvate are produced

Pyruvate to Acetyl CoA

Catalyzed by pyruvate dehydrogenase in the mitochondrial membrane

Krebs (Citric Acid, TCA) Cycle

Occurs in the MITOCHONDRIA of cells

Does not USE oxygen…but will STOP in its

absence

Results in the formation of:

• 6 molecules of NADH

• 2 molecules of FADH2 (flavin adenine

dinucleotine + 2 hydrogen)

• 2 molecules of GTP

Generates CO2 as a waste product

Four VITAMINS are essential for the Krebs cycle:

• Thiamine (vitamin B1)

• Riboflavin (vitamin B2)

• Niacin (vitamin B3)

• Pantothenic acid (vitamin B5)

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If you have vitamin deficiencies of any of these the Krebs cycle may not be as efficient

Respiratory (Electron Transport) Chain

• Found in the MITOCHONDRIA of cells (specifically the inner mitochondrial membrane)

• Consists of 4 protein complexes (called I-IV)

Respiratory (Electron Transport) Chain

• ABSOLUTELY requires oxygen

• Converts NADH and FADH2 that

was created in the TCA cycle to

NAD+ and FAD by “stripping

away” hydrogen (H+) molecules

• ATP SYNTHASE is the key

enzyme associated with the ETC

that creates ATP from the H+

gradient

Ultimately:

• Each NADH to NAD+

generates 2.5 ATP from ADP

• Each FADH2 to FAD generates

1.5 ATP from ADP

• ATP SYNTHASE

• ATP SYNTHASE is the key

enzyme associated with the ETC

that creates ATP from the H+

gradient

Final Reaction Tally of Complete oxidation of Glucose

• Every molecule of Glucose

• Net Yield of ATP is 32

• NEED OXYGEN

Hexose Monophosphate Shunt (HMP; Pentose

Phosphate Pathway)

Is an alternate route for the metabolism of glucose

Has nothing to do with creating energy (ATP)…..instead the pathway generates

NADPH (nicotinamide adenine dinucleotide phosphate) and 5-carbon sugars called

PENTOSES (the most important being RIBOSE)

Occurs in the cytosol, no organelles are needed, so this pathway can happen in all

cells

The key enzyme in the pathway is glucose-6-phosphate-dehydrogenase (G6DP)

So…..what is RIBOSE used for in the Hexose Monophosphate Shunt

Basically for synthesizing the

nucleotides found in RNA and

DNA, especially in cells that are

rapidly dividing (both normal and

cancerous

So…..what is NADPH used for?

1) For synthesizing fatty acids

2) For indirectly eliminating

toxic oxygen “radicals” (e.g.,

HYDROGEN PEROXIDE)

For synthesizing fatty acids

or synthesizing fatty acids

& cholesterol in liver,

adipose tissue &

mammary glands and for

synthesizing steroid

hormones in certain

endocrine glands (ovaries,

testes, adrenal glands,

placenta)

• Basically, NADPH donates

  electrons (i.e., it is a REDUCING

  AGENT) in the anabolic reactions

  used to make fatty acids,

  cholesterol and steroid hormones

For indirectly eliminating

toxic oxygen “radicals” (e.g.,

HYDROGEN PEROXIDE)—

highly reactive oxygen

molecules produced by

some reactions in the body,

which can cause significant

damage to cells

So………which cells produce

lots of hydrogen peroxide?

RBCs (erythrocytes)

RBCs generating hydrogen peroxide (

ll day long………and can be

induced to make more by certain medications, infections and fava

beans…..yes, fava beans…

RBCs possess a very important

chemical called GLUTATHIONE, which

can exist in both a reduced state (GSH)

and an oxidized state (GSSG)

It is critical for glutathione to be in the

REDUCED STATE (GSH)….or if you

prefer, we want glutathione to be an

ANTI-OXIDANT

GLUTATHIONE

RBCs possess a very important

chemical called GLUTATHIONE, which

can exist in both a reduced state (GSH)

and an oxidized state (GSSG)

It is critical for glutathione to be in the

REDUCED STATE (GSH)….or if you

prefer, we want glutathione to be an

ANTI-OXIDAN

What keeps glutathione to be in the

REDUCED STATE

• NADPH

Glutathione and RBCs

Glutathione is THE major endogenous antioxidant produced by all cells, participating directly

in the neutralization of free radicals and reactive oxygen compounds, as well as maintaining

exogenous antioxidants such as vitamins C and E in their reduced (active) forms

-Here’s where it all comes together to prevent HEMOLYTIC ANEMIA

Glycogenesis

• Occurs in fed state in liver and skeletal muscle

• Helps prevent hyperglycemia because it allows

sequestration of blood glucose is the storage

form of GLYCOGEN

• Glucokinase is found in liver hepatocytes,

whereas hexokinase is found in skeletal muscle

cells

So what happens if there is still a lot of blood

glucose and the liver and skeletal muscle hang

there “No Vacancy” signs…………?

Insulin function

• Key enzyme in both tissues is GLYCOGEN

SYNTHASE which is stimulated by INSULIN

Skeletal muscle can store 350-500 grams

(provides about 1400-2000 calories) and liver

can store about 100 grams (provides about 400

calories)

• Insulin Stores glucose a glycogen (in the liver)

• If you eat too much carbs the glucose is used as triglyceride stores

Process of Glycogenesis

Fatty Acid Synthesis

• Fatty acids are synthesized from ACETYL-CoA

• Occurs mainly in adipose tissue and liver

• A very round- about set of pathways between the cytosol and mitochondria….

WHAT’S HAPPENS WHEN WE

NEED TO “MAKE” GLUCOSE?

1. GLYCOGENOLYSIS

2. GLUCONEOGENESIS

Glycogenolysis

Occurs in fasting state in liver and skeletal muscle…….BUT the pathways are slightly different between the two tissues

In the liver, glycogenolysis helps prevent hypoglycemia because it allows for the breakdown of glycogen into glucose

In the skeletal muscle, glycogenolysis provides a locally available source of glucose-6- phosphate that can then enter the glycolysis pathway

Gluconeogenesis

Synthesizes glucose from non-

carbohydrate sources, namely:

• amino acids (except leucine and

lysine)

• lactate

• glycerol (from triglycerides)

Occurs primarily in liver hepatocytes,

and to a minor extent, in epithelial cells

of the kidneys and small intestine

Gluconeogenesis occurs in 11 steps and

is NOT simply a reversal of glycolysis

THIS IS MAKING GLucose without Carbohydrates

There are two important inter-organ cycles Involving glycolysis in

muscle and gluconeogenesis in liver

1) Cori Cycle

2) Alanine Cycle

Cori Cycle

There are two important inter-organ cycles involving glycolysis in muscle and gluconeogenesis in liver.

• In the CORI CYCLE, glucose is metabolized to pyruvate and then to lactate in muscle, the lactate is released into the blood and carried to the liver, where it is reconverted to pyruvate and used for gluconeogenesis, and the resulting glucose is released and travels back to muscle

Alanine Cycle

The ALANINE CYCLE is similar to the Cori cycle, except that muscle pyruvate is converted to the amino acid alanine rather than lactate by transamination. In the liver, alanine is transaminated back to regenerate pyruvate, and the excess amino groups are disposed of as UREA

Types of Lipids (3)

• 1) Triglycerides (triacylglycerols)

• 2) Phospholipids

• 3) Cholesterol

Triglycerides

Fats → saturated (animal) and unsaturated (oils)

• also known as triacylglycerols

• are mainly used by cells for energy

Phospholipids

Phospholipids are mainly used by cells for building cell (plasma) membranes.

Cholesterol

Cholesterol is also used by cells for building cell (plasma)

membranes and is also the building block for steroid hormones

(e.g. – testosterone, estrogen, progesterone, cortisol and

aldosterone). When cholesterol travels in the blood, it does so

mainly as LDL-C (low density lipoproteins) & HDL-C (high density

lipoprotein)  more on this later………

Two Types of Cholesterol

• 1) LDL-C (low density lipoproteins)

• 2) HDL-C (high density lipoprotein

Overview – Digestion & Absorption of Lipids

emulsification

• pancreatic lipase

• colipase

• micelles

• chylomicrons

• lacteals

emulsification

Requires bile → make a fat molecule into droplets, this allows the surface area to increase

Transport of Chylomicrons

Once the

chylomicrons enter

the lymphatic

circulation, they are

transported upward

through the thoracic

duct and emptied

into the venous

circulation at the

juncture of the

jugular and

subclavian veins.

Lipemia

usually occurs within an hour after eating a fatty meal.

Chylomicrons have a short half-life (< 60 min), so the plasma usually

becomes clear within a few hours.

Fate of Chylomicrons

Chylomicrons are removed from the blood as they pass through the capillaries of

adipose tissue and the liver. Both contain large quantities of lipoprotein lipase.

This enzyme is especially active in the capillary endothelium, where it hydrolyzes

the TGs of chylomicrons into fatty acids & glycerol, which diffuse into adipocytes

(storage) & hepatocytes (re-packaged into lipoproteins & exported to blood). It is

also possible for other tissues to use the contents of chylomicrons.

Types of Lipoproteins (5)

Allows Fat to transport in the blood

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• There are generally 5 classes of lipoproteins:

  • Chylomicrons

  • Very low density lipoproteins (VLDL)

  • Intermediate density lipoproteins (IDL)

  • Low density lipoproteins (LDL)

  • High density lipoproteins (HDL)

• Very low density lipoproteins (VLDL)

high TGs / moderate cholesterol & phospholipids

• Intermediate density lipoproteins (IDL)

moderate TGs, cholesterol & phospholipids

• Low density lipoproteins (LDL)

low TGs / high cholesterol & phospholipids

• Bad Cholesterol

• High density lipoproteins (HDL)

low TGs, cholesterol & phospholipids

(good Cholesteerol)

Clinically which Lipids are ussally tested

1) Clinically, LDL-C & HDL-C levels are the only lipoproteins routinely monitored and used to screen for atherosclerosis, MI & stroke risk, heart disease, etc.

LDL-C vs. HDL-C

The role of LDLs (bad cholesterol) is to transport cholesterol and other lipids from

the liver to the peripheral tissues, making them available (via receptor mediated

endocytosis) for membrane or steroid hormone synthesis. The function of HDLs

(good cholesterol) is to transport excess cholesterol from peripheral tissues to the

liver, where it is broken down and becomes part of the bile

LDL Receptor Mediated Endocytosis

After a while the body refuses to take this fat, and leaves it in the blood

• Because it leaves you in the blood eventually Atherosclerotic plaque is formed

There are 2 main sources of cholesterol in the blood:

Cholesterol De Novo Synthesis

Using acet-l COA to create cholesterol by liver

hepatocytes

• The amount this is used is genetic

• Most important emnzynme is the HMG-CoA Reductase (what is used to stop this

HMG-CoA Reductase Inhibitors

• - Statins

• Statins are the most effective drugs currently in use for

  treating elevated LDL-C – the major ones on the USA

  market include:

• Atorvastatin (Lipitor)

• Fluvastatin (Lescol)

• Lovastatin (Altoprev, Mevacor)

• Pravastatin (Pravachol)

• Simvastatin (Zocor)

• Rosuvastatin (Crestor)

• Pitavastatin (Livalo)

Lipolysis and Fatty Acid (Beta) Oxidation

• FATTY ACID (BETA) OXIDATION is the mitochondrial aerobic process of breaking down a fatty acid into acetyl-CoA units (each containing 2 carbons).

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• Acetyl-CoA is then “fed” into the Krebs cycle, where NADH, FADH2 and GTP are generated…..and then NADH and FADH2 are used by the ETC to make ATP

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• Occurs mainly in the liver, skeletal muscles and heart (Good At breaking down fat)

Lipolysis and Fatty Acid (Beta) Oxidation Diagram

Ketone Metabolism Occurs?

• The synthesis of ketones (or ketone bodies) occurs in the mitochondria of liver hepatocytes

• Made only in the liver

Ketones

• Fatty product

• They are Acidic (Can lower the ph of the blood to be dangerous)

• Can be used to make atp

• Become a problem if there is too many of them

Ketone Metabolism

• During prolonged starvation or fasting, oxaloacetate can eventually become depleted in the liver due to extensive gluconeogenesis → this impedes the entry of Acetyl-CoA into the Krebs’ cycle

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• All of this excess acetyl-CoA has no where to go, so it accumulates………

• The liver then converts the excess acetyl-CoA into ketone bodies (3 types), which can then enter peripheral tissues (e.g., brain, skeletal muscle, kidneys) and be reconverted back to acetyl-CoA to make ATP via the Krebs’ cycle and ETC

Ketone Bodies

Synthesis of amino acids

• is of paramount importance to the human body.

• Once synthesized or ingested, amino acids are used as BUILDING BLOCKS not only for proteins but also for several other critical biological molecules such as:

  • nucleic acids (both purines and pyrimidines),

  • hormones,

  • neurotransmitters,

  • anti-oxidants

  • various signaling molecules.

Digestion of Proteins & Absorption of Amino Acids

• The stomach does a good job of denaturing proteins, but it is not as effective cleaving off individual amino acids (pepsin does some of this).

• Cleaving off amino acids occurs mainly at the brush border with

  aminopeptidases and with the active pancreatic enzymes (proteases).

Absorption

of Amino Acids

Once the digestion of

proteins is complete, most

amino acids or small

peptides are transported

via the same co-transport

mechanism utilized by

glucose -- some amino acids

do not require this sodium

co-transport mechanism

but instead are transported

in the same way that

fructose is moved, i.e. by

facilitated diffusion

Can Amino Acids Be Used For Energy?

Yes!

1. Gluconeogenesis 18/20 (except leucine and lysine)

2. Ketone body formation (leucine and lysine)

3. Directly fed into Krebs cycle

Can Amino Acids Be Broken Down Into Waste?

• Yes!

Ultimately, the amine groups cleaved from the

amino acids are converted into ammonia (NH3)

or ammonium ions (NH4+), which are then

converted into urea.

urea

• Essentially all urea formed in the human body is synthesized in the liver

• After its formation, urea diffuses from liver

hepatocytes into the body fluids and is excreted

by the kidneys.

hepatic coma or hepatic encephalopathy

In serious liver disease, ammonia can often accumulate in the blood and lead to a state

azotemia or uremia

• A build-up of urea in the blood can lead to a state of azotemia or uremia, in which high levels of urea become toxic to a variety of tissues.

• This is often a symptom of renal disease or failure.