HBIO302 - Lipolysis, B-oxidation, and Lipogenesis

Lipolysis

TGs → FFAs and glycerol

B-oxidation

FAs → acetyl CoA, NADH, FADH

When does lipid catabolism happen

during fasting an/or exercise

Why does lipid catabolism happen

the body adapts to low glucose by inc use of stored fat thru lipolysis, B-oxidation, and ketone metabolism

Where does lipolysis happen?

white adipose tissue; very minor in liver and muscles

Compartmentalization of lipids for lipolysis

lipids surrounded by phospholipid in which perilipin (PLIN) proteins are embedded

In the insulin dominant (fed) state, what happens to perilipin?

it forms a tight coating over the lipid surface, blocking access of lipases to TF core

What happens when catecholamines such as adrenaline and noradrenaline activate B-adrenergic receptors? [Lipolysis regulation]

inc cAMP → activate PKA → phosphorylates perilipin (activation)

Rate limiting enzyme in intracellular lipolysis

HSL

Hormones that ACTIVATE HSL

adrenaline, noradrenaline (and glucagon) 

How do adrenaline, noradrenaline (and glucagon) activate lipolysis?

inc adnelyl cyclase → inc cAMP → activation PKA → phosphorylates HSL → Inc HSL activity

Hormones that INHIBIT HSL

insulin

How does insulin inhibit lipolysis?

activates phosphodiesterase (PDE) → degrades cAMP → low disrupts cascade

HSL allosteric modulators

FAs and MGs

Which is true about glycerol?

It is water-soluble and diffuses easily across cell membranes

Fate of glycerol in the liver

glycerol kinase: glycerol → glycerol 3 phosphate → TG synthesis or gluconeogenesis

Fate of glycerol in adipocytes

DHAP → G3P by glycerol-3-phosphate dehydrogenase

What is the reasoning behind glycerol not being able to be re-esterified locally?

safeguard mechanism that prevents adipocytes from entering futile cycle of constantly breaking down and resynthesizing same trigylcerides

How do long chain and very long chian FAs diffuse across the adipocyte membrane

FABP4 - cytosolic chaperone that binds FFA and carries to plasma membrane

FATP1 - bidirectional transporter

How do short chain and monochain FAs diffuse across the adipocyte membrane

passive diffusion (higher solubility)

FFA-Albumin complex allows for

keeping FFAs soluble and preventing micelle formation

buffer concentration

allows rapid exchange w/tissue

What are important roles of albumin

carrier of hydrophobic molecules

maintains oncotic pressure (prevents edema)

buffer and antioxidant functions

reservoir for AA and metal ions

What happens once FFAs are inside the cell?

they are trapped by acyl-CoA synthetase as fatty acyl-CoA

Carnitine shuttle system

1. CPTI: FA-CoA + Carnitine → Acylcarnitine can now cross inner membrane of mitochondria

2. CACT: exchanges acylcarnitine for free carnitine

3. CPTII: Breaks down acylcarnitine and regenerates FA-CoA inside matrix

From what two amino acids can humans synthesize carnitine endogenously from?

lysine and metionine

Sources of carnitine include..

meat, milk, avocado

What can low carnitine levels lead to?

impaired FA oxidation and muscle weakness

Why is it called B-oxidation

the B-carbon (3rd C) of fatty acyl chain is oxidized at each cycle

Very long chain fatty acids go to the ____ before the mitochondrion in Beta oxidation, while short, medium, and long chains go directly to mitochondrion

perioxisome

At what states does B-oxidation predominate?

fasting/starvation

prolonged exercise

low-carb/ketogenic diets

B-oxidation generates acetyl-CoA for..

TCA cycle when carbs are available and ketogenesis when carbs are low

Rule for total rounds of B-oxidation

(N/2)-1 (for FA w/even # of C)

How is B-oxidation regulated?

product inhibition

High NADH/NAD+ ratio also inhibits

Acetyl CoA stimulates ______ and inhibits ______

pyruvate carboxylase (gluconeogenesis); pyruvate dehydrogenase (TCA cycle)

Malonyl-CoA and regulating B-oxidation 

inhibits CPTI (helps move FA into inner mitochondrial membrane) 

prevents simultaneous B oxidation and FA synthesis when glucose is abundant

Net Energy yield from B-oxidation

106 ATP

Why does FA catabolism require more oxygen than glucose metabolism?

fat oxidation has higher e- load → more NADH/FADH2 → more O2 needed to accept them

Which of the following is true

even though palmitate (FA) gives much more ATP overall, each O2 used produces slightly fewer ATPs because more O2 is needed to fully oxidize all reduced carbons

Do saturated or unsaturated fats yield LESS energy? Why?

unsaturated fats bc some of their DBs are already partially oxidized, so fewer FADH2 molecules during B-oxidation

What happens to monounsaturated FAs in B-oxidation

normal until DB is reached at odd numbered C

no trans created, but resolved by enoyl-CoA isomerase, skipping acyl-coa DH rxn so one FADH2 lost 

polyunsaturated FAs B-oxidation

2,4 dienoyl-CoA Reductase → reduces conjugated DB system

Enoyl-CoA isomerase → rearranges to trans

extra steps consume NADPH and bypass FADH2 formation, further dec. ATP yield

Odd chain saturated fats catabolism

3-C propionyl-CoA instead of 2-C acetyl-CoA

converted to succinyl-CoA, which enters TCA cycle or serves as gluconeogenic precursor

ketogenesis

acetyl-CoA from B oxidation to ketone bodies

Where does ketogenesis occur

liver mitochondria

Where does ketolysis occur?

Not in the liver (extrahepatic tissues)

When does ketogenesis and ketolysis occur

fasting, prolonged exercise, low-carb or ketogenic diets, uncontrolled diabetes 

Why do ketogenesis and ketolyiss occur

situations when these occur cause low insulin/high glucagon (prolonged fasting, exercise, etc) → inc in lipolysis and B-oxidation and gluconeogenesis (No OAA prod to get rid of acetyl-CoA in TCA)

accumulation of Acetyl-CoA → converted into ketone bodies

ketone bodies roles

energy supply for peripheral tissues (can cross Blood-brain barrier)
Glucose sparing (reduce glucose requirement in brain during prolonged fasting)

protein sparing

NAD+ regeneration

Rate limiting enzyme of ketogenesis

HMG-CoA Synthase (acetoacetyl-CoA + acetyl-CoA → HMG-CoA)

Product of ketogenesis

acetoacetate, can decarboxylate into acetone or be reduced into B-hydroxybutyrate

Which is true about the energetic cost of ketogenesis?

it does not cost ATP, but 1 NADH is used

Ketolysis

B-hydroxybutyrate (from ketogenesis)to acetyl-CoA molecules (2 from one)

How much ATP is yielded from B-hydroxybutyrate oxidation?

21.5 ATP per molcule

Where does lipogenesis occur

liver and lactating mammary glands in the cytosol

When does lipogenesis occur

when body has an excess of carbohydrates and energy

Isocitrate DH inhibition resulst in high ATP and higher citrate concentration which allows for…

citrate to be used for fatty acid synthesis

rate limiting step of fatty acid synthesis

ACC catalysis of acetyl-CoA → Malonyl-CoA

direct allosteric regulation of ACC (short-term)

activated by citrate

inhibited by LC-Fatty acyl CoAs (promote depolymerization and inhibit enzyme activity)

Regulation of ACC by phosphorylation

inhibited by AMP-activated protein kinase

protein phosphatase dephosphorylates and activates ACC

High carb diets ___ ACC levels, while low carb diets ___ them

increase; decrease

Fatty acid synthase

series of reactions that add two C-units from malonyl-CoA with each cycle

results in palmitate 7 CYCLES

Further elongation of palmitate to stearate

occurs in SER w/same steps of FAS, but 4 scuessive steps are performed by individual enzymes

Desaturation of palmitate

Fatty Acyl-CoA desaturates in SER, requires O2 and NADH

Palmitate

saturated 16-C LCFA, end product of FAS activity

TG synthesis reactions

1. acyltransferace: 2 fatty acids to molecule of glycerol phosphate

2. removal of phosphate group by phosphatase

3. addition of 3rd FA

Fate of TG in liver

packed into VLDL and secreted in the bloodstream

Fate of TG in adipose tissue

storeed as fat droplets in cytosol

TG synthesis in adipocytes

GPAT: Glycerol 3 phosphate + Fatty acid CoA

AGPAT: adds second fatty acid 

PAP: dephosporylation to form DAG

DGAT: FA from acyl-CoA to sn-3 pos of diacylglycerol → TG 

Transcription factors that activate lipogeneic genes after carb rich meal

SREBPs, ChREBPs, LXRs

hypertrophy

increase in adipocyte size in early stage of fat accumulation

hyperplasia

inc. in adipocyte number when max capacity of fat accumlation reached

Brown adipose tissue (BAT) is simiilar to muscle tissue and expresses high levels of…

UPC-1 → Heat

White adipose tissue is divided in…

subcutaneous adipose tissue and visceral adipose tissue

Energy cost of FA synthesis

15 ATP per palmtate and 14 NADPH

Energy required for TG synthesis

6 ATP per TG, 1 NADH