Lecture 14 (3-5): Fat Metabolism Flashcards
Fat cell genes
- some genes in fat tissue have been shown to express their own circadian rhythm
- body processes foods differently during day and night (so it turns out, it may matter when you eat - we still don’t know)
- fat genes punch the clock to carry out key metabolic functions
- “circadian regulation in human white adipose tissue revealed by transcriptome and metabolic network analysis”
Oxidizing Odd-Carbon Fatty Acids (overview, reactions, important aspects)
- beta-oxidation yields propionyl-CoA
- not all FA’s have an even number of C’s
- these are metabolized normally, until the last 3-C figment (propionyl-CoA) is reached
C15 fatty acid —beta-oxidation—> propionyl CoA + acetyl CoA + 6 FADH2
Three reactions convert propionyl-CoA to succinyl-CoA: significance is that…
- succinyl-CoA is a TCA intermediate: into TCA, get ATP back + 1FADH2 and 1NADH
- (prop-CoA) breakdown product of hydrophobic amino acids Met, Val, Ile (energy out of protein breakdown)
- Note: involvement of biotin and Vitamin B12
Not all fatty acids are the same + examples of some fatty acids
- different number of double bonds, etc.
examples of fatty acids:
- Palmitic acid
- Oleic acid
- Linoleic acid
- Arachidonic acid
- Eicopentanoic acid
- Docasahexanoic acid
Beta oxidation requires what configuration?
trans
Unsaturated Fatty Acids: how they go through beta-oxidation
- consider monounsaturated fatty acids like oleic acid
- Normal beta-oxidation for three cycles
- cis-delta3 acyl-CoA cannot be utilized by acyl-CoA dehydrogenase
- Enoyl-CoA isomerase (EC 5.3.3.8): converts this to trans-delta2 acyl CoA
- Since this is now substrate for the next enzyme in the oxidation path, beta-oxidation continues unfettered from this point
general beta oxidation path (not specific)
FA(n) -> DH -> Hydratase -> DH -> Thiolase -> FA(n-2)
Enoyl-CoA Isomerase Deficiency
- Enoyl-CoA isomerase (EC 5.3.3.8)
- No reported cases in humans but effects in mice
- ECI is the link in mitochondrial beta oxidation of unsaturated and saturated fatty acids, and essential for the complete degradation and for maximal energy yield.
- Mitochondrial beta oxidation of unsaturated fatty acid is interrupted in mice at the level of their. respective 3-cis or 3-trans-enoyl-CoA intermediates
EC Numbers + Enzyme 1.1.1.1 (reactions, symptoms, medication)
- EC: Enzyme Commission or European Commission
Enzyme 1.1.1.1: Alcohol Dehydrogenase (ADH)
- Unique - has a Zn site (structural and stability role)
Ethanol –> Acetaldehyde –> Acetic acid
(CH3CH2OH —> CH3CHO —> CH3COOH)
Ethanol -> Acetaldehyde (via ADH)
Acetaldehyde -> acetic acid (via enzyme ALDH which many Asians have a deficiency of)
Acetaldehyde -> GSH- adduct (via glutathione)
both Acetic acid and GSH-adduct excreted
Acetaldehyde:
- toxic/poisonous
- causes vomiting, headache, rapid heartbeat and flushing
- interesting connection? (same/similar symptoms to a hangover)
Antabuse: acetaldehyde build up in the body - drug inhibits ALDH
Hangover: disease name + symptoms + why you feel bad
Veisalgia: typically undesirable and unpleasant physiological consequence of excessive alcohol consumptom
Symptoms:
- lethargy, diarrhea, flatulence, headache, often a sensitivity to light and noise, nausea, dysphoria and thirst
The ‘Feel bad’ Physiology:
- acetaldehyde intoxication, immune system and glucose metabolism alterations, dehydration (inhibition of antidiuresis hormone, hence, increased diuresis), metabolic acidosis, altered prostaglandin synthesis, vasodilation, sleep deprivation and malnutrition. cases in humans
Biochemistry of Hangover (+ symptoms of the associated condition)
- Hangover is not just restricted to the head, it affects multiple organs with biochemical consequence.
It’s a 1-2 punch….alcohol:
- enhances the effects of the neurotransmitter GABA, an inhibitory neurotransmitter. Enhancing an inhibitory neurotransmitter would have the effect of making things ‘sluggish’, which matches the behavior in the inebriated state
- suppresses glutamine, an excitatory neurotransmitter. Suppression of an excitatory neurotransmitter decreases its efficacy, also leading to sluggishness
- provides hope that a drug-based treatment can be established to counter ACA
Symptoms of Acute Cerebellar Ataxia (ACA):
- impaired coordination in the torso or arms and legs
- frequent stumbling
- an unsteady gait
- uncontrolled or repetitive eye movements
- trouble eating and performing the fine motor tasks
- slurred speech
- vocal changes
- headaches
Polyunsaturated Fatty Acids: how they go through beta oxidation
- slightly more complicated
Linoleic acid same as oleic. acid up to a point:
- 3 cycles of beta-oxidation
- enoyl-CoA. isomerase
- 1 more round of beta-oxidation
- trans-delta2, cis-delta4. structure is a poor substrate for the enoyl-CoA hydrates
2,4-Dienoyl-CoA reductase to the rescue!
Saturated and Trans Fats: how they are formed
- Naturally-occurring. PUFAs have double bonds. and are CIS (at room temp, they are liquid….ex: olive oil)
- Take vegetable. oil and saturate those double bonds with H……you artificially make them SATURATED or TRANS
- This ‘chemical hardening’ (or shape shifting’) increases plasticity of the liquid oils at room temp - i.e. makes it solid and stable
Natural vs. Industrial Trans Fats: general overview, sources of them
Naturally-occurring: Paleo or Whole Foods diets contain trans fats
- Dairy fat and meats from grass eating “ruminant” animals contain trans fat
- Grass-fed animals actually have higher levels of trans fats than grain-fed animals
- Grass-fed steak contains. about 0.5g - 1.4g of trans fat/ounce (28.3g of total fat)
Don’t avoid grass-fed animal products/cut out red meat and eat dairy free because:
- these naturally occurring trans fats may not be harmful to our health (may actually be beneficial)
Conjugated linoleum acid (CLA): GOOD
- ‘Natural trans fats’ are formed when rumen bacteria (cows, sheep, etc.) digest the grass and form trans-rumenic acid and trans-vaccenic acid. via biohydrogenation of polyunsaturated fats in the grass
- CLA, found abundantly in grass-fed meat and dairy products (less in grain-fed products) — also produced in our body from the conversion of trans-vaccenic acid (VA) from those same animal products
Vaccenic acid
a naturally occurring trans-fatty acid found:
- in fat of ruminants
- in dairy products (milk, butter, yogurt)
- predominant ‘trans fat’ fatty acid in mothers milk
Why trans fats? Where are they found?
- Trans fats give certain foods a desirable taste, shape and texture (think flaky pie crust or perfect French fries)
Where are they found?
- crackers, cookies, and frostings
- Check labels for “hydrogenated” or “partially hydrogenated” fats
- trans fat ban recently went into effect
hydrogenation of oleic acid: add H2
Major food sources of trans fat:
- cakes, cookies, crackers, pies, bread
- animal products
- margarine
- fried potatoes
Natural vs. Industrial Trans Fats: chemical/structural differences
Industrial trans fats have slightly different chemical structure than trans fats found in beef and butter
- What’s different? location of the double bond
- CLA: contains both cis and trans bonds
- most industrial trans fats have only trans bonds
Differences:
- minor in structure….major in how the body handle these
- Industrial trans fats: increase the risk of heart disease, cancer, and obesity
- CLA (and other natural trans fats) are actually thought to decrease the risk
Summary of Beta Oxidation- importance
- it’s not just about energy
- Other implications of FAs as the fuel of choice for other animals
CH3(CH2)14CO-CoA + 108 Pi + 23 O2 —> 108ATP + 16 CO2 + 130 H2O + CoA
Camel hump is a large FAT deposit
- energy source? absolutely
- also source of WATER
Ketogenesis + Ketone Bodies: introduction
- a special source of fuel and energy for certain tissues
Fate of acetyl CoA is either:
- TCA to generate NADH and, ultimately, ATP
- formation of ketone bodies*
Coenzyme A –> ATP (via NADH)
Coenzyme A –> ketone bodies
Ketogenesis and Ketone Bodies
- transfer of long chain FA across the blood brain barrier slow
- Some of the acetyl-CoA produced by fatty acid oxidation in liver mitochondria is converted to acetone, acetoacetate and beta-hydroxybutyrate (these are called “ketone bodies”)
- source of fuel for brain, heart, and muscle
- Major energy source for brain during starvation
- These essentially are transportable forms of fatty acids
- HMG-CoA: an important branch point between catabolism and anabolism
HMG-CoA reductase
part of ketogenesis (formation of ketone bodies from acetyl-CoA)
HMG-CoA –> synthesis of cholesterol (via HMG-CoA Reductase)
HMG-CoA an important branch point between catabolism and anabolism
Ketone Bodies and Glucose Metabolism (+ type 1/2 diabetes)
- Glucose is abundant in blood, and uptake by cells in muscle, liver, and adipose cells is a necessity
- In type 1 diabetes: low or no insulin secretion (Glucose can’t get into cells)
- In type 2 diabetes: insulin secreted but altered cellular insulin receptors (Glucose can’t get into cells)
- Cells, metabolically low on glucose, turn to gluconeogenesis and fat/protein catabolism
Ketone Bodies and Diabetes
- “starvation of cells in the midst of plenty”
- Glucose is abundant in blood, but uptake by cells in muscle, liver, and adipose cells is LOW
- Cells, metabolically starved, turn to gluconeogenesis and fat/protein catabolism
- In type I diabetes, the [OAA] is low (excess gluconeogenesis), so Ac-CoA from fat/protein catabolism doesn’t go to TCA, but rather to ketone body production
- Acetone can be detected on breath of type 1 diabetics
Ketone Bodies - Neural Entree (Brain Food) - Why does the brain need glucose?
- Unlike most other tissues that have additional energy sources (i.e. fatty acids), the brain does not and gets its energy from ketone bodies when insufficient glucose is available (e.g. during fasting)
- —- acetoacetate and beta-hydroxybutyrate reconverted to Ac-CoA
- If blood glucose is low for 3 days, ~30% of energy is obtained from ketone bodies (after 40 days, up to 70A%)
The brain retains some need for glucose for two reasons:
- ketone bodies can be broken down for energy only in the mitochondria, and long thin axons of brain cells too far from mitochondria
- does not burn just ketones, since they are an important substrate for lipid synthesis
Ketogenesis, Ketosis and Ketoacidosis
A ketotic state exists when a higher than normal level of ketone bodies accumulate in the system
- Usually indicative of a CHO starved state (fasting, unbalanced diet, Atkins)
Ketoacidosis exists when a large excess of ketone bodies accumulate in the system
- ketone bodies are very acidic
- overcome the buffering capacity of blood
- body’s pH is lowered to dangerously acidic levels
Untreated Type 1 diabetics and chronic alcoholics are typically ketoacidotic
- strong odor of acetone can be detected on breath
Blood [Ketone] levels
Normal: <0.6 mmol/L
Moderate: 0.6 - 1.5
High: 1.6 to 3.0
