Lipolysis, B-Oxidation, and Lipogenesis

lipolysis

catabolic process which TGs in lipid droplets are broken down into FFAs and glycerol

Products are released into circulation for nrg production

B-oxidation

FFA broken down to generate acetyl-CoA, NADH, FADH2 → TCA/ETC

Why is it called B-oxidation?

B-carbon (3rd) of fatty acyl chain is oxidized @ each cycle

When does lipid catabolism happen?

during fasting and/or exercise

some tissues have HIGH levels of B-oxidation

true

Why does lipid catabolism happen?

bod adapts to low glucose by inc use of stored fat for nrg through lipolysis, B-oxidation, and ketone metabolism

where does lipolysis happen?

white adipose tissue (cystolic lipid droplets)

Systemic energy mobilization via lipolysis occurs almost exclusively from…

white adipose tissue

Liver and muscles can also store small amounts of TGs

true

B-oxidation occurs in..

most tissues: liver, heart, skeletal muscle, kidney and BAT (mitochondrial matrix)

In which tissues does B-oxidation NOT occur?

In the brain and RBCs (needs mitochondria)

Adipose Triglyceride Lipase (ATGL)

initiates breakdown (hydrolysis) of TG to diacylglycerol (DAG) + FFA (mainly sn-2 position)

Hormone-Sensitive Lipase (HSL)

Hydrolyzes DAG to monoacylglycerol (MAG) + FFA

Mooglyceride Lipase (MGL)

converts MAG to glycerol + FFA

Lipolysis enzymes

ATGL, HSL, MGL

Compartmentalization helps to,..

regulate lypolysis

Regulation of lipolysis: Embedded in the phospholipid monolayer that surrounds lipid droplets is are..

perilipin proteins (PLIN, PLIN1 in adipocytes)

Regulation of lipolysis: In the fed (insulin-dominant) state, perilipin forms..

a tight coating over the lipid droplet surface, which blocks access of lipase enzymes to the TG core

Regulation of lipolysis: When catecholamines (adrenaline) and noradrenalin activate B-adrenergic receptors…

inc cAMP → activtes protein kinase A (PKA) → PKA phosphorylates perilipin

Regulation of lipolysis: Rearrangement of the surface coat…

loosens its grip on the droplet surface, exposing part of lipid core and creating docking sites for lipases (activation)

Regulation of lipolysis: phosphorylated perilipin releases CGI-58

Free CHI-58 bings to ATGL, activating it (activator)

Rate limiting enzyme in intracellular lipolysis

HSL

Regulation of lipolysis: Adrenalin, Noradrenalin (and glucagon)

activate lipolysis → lipolytic hormones → receptor activation → inc adenylyl cyclase activity → cAMP → activation of PKA → phorphorylates HSL → inc HSL activity

Regulation of lipolysis: Insulin

inhibits lipolysis → anti-lipolytic hormone → Activates PDE → degrades cAMP → low cAMP disrupts cascade

Regulation of lipolysis: allosteric modulations

FAs and MGL exert product inhibition on HSL activity

Adipocytes lack _____…

glycerol kinase, so glycerol releasde during lipolysis cannot be re-esterified locally; glycerol exported to liver for further metabolism

Glycerol is water-soluble and diffuses easily across cell membranes, allowing rapid transport thru circulation

true

Fate of glycerol in the liver

glycerol kinase converts glycerol into G3P, which is used for novo TG synthesis of GNG

Fate of glycerol in adipocytes

G3P dehydrogenase converts DHAP to G3P

In adipocytes, glycerol not being able to be re-esterified locally is…

safeguard mechanism that prevents adipocyte from constantly rbeaking down and resynthesizing the same triglycerides

FFAs are amphipathic so they can diffuse, but in physiological concentrations this process is facilitated by..

specialized transport proteins

FFA efflux across adipocyte membrane [LONG CHAIN FAs]

FABP4 (cytosolic chaperone that binds FFAs and carries them to plasma membrane)

FATP1 (Bidirectional transporter)

FFA efflux across adipocyte membrane [SHORT CHAIN AND MONO-CHAIN FAs]

passive diffusion

FFAs transport in the bloodstream

carrier protein for long chain and very long chain FAs

Albumin molecules can bind _____ FFAs with _____ affinity

6-8 FFAs; High

FFA-Albumin Complex

keeps FFAs soluble in plasma; prevents micelle formation; buffers their concentration; allows rapid exchange w/tissues

99% of circulating FFAs are albumin-bound

true

Main consumers of FFAs are..

liver, skeletal muscle, heart

Near the capillary endothelium what happens to FFAs?

they dissociate from albumin and unbound fraction diffuses across endothelium to interstitial space

After dissociating from albumin, what happens to FFAs?

they enter cells by facilitated diffusion mediated by CD36 (Long chain FAs)

When inside cell, what happens to FFAs?

immediately esterified to fatty acyl-CoA by acyl-CoA synthase expressed on plasma membrane, outer mitochondrial membrane, and ER

Activation of FFas cost…

2 ATP equivalents (ATP → AMP + PPi)

Conversion of FFAs to fatty acyl-Coa does what?

traps FFAs inside cell and pull equilibrium towards uptake, biasing CD36 function toward import

Carnitine Shuttle system

moves FFAs that were converted to fatty acyl-CoA  into mitochondria since fatty-acyl CoA molecules cannot cross inner mitochondrial membrane directly

Carnitine shuttle system enzymes

CPT I, CACT, CPT II

CPT I (Carnitine palmitoyltransferase I)

transfers acyl group from CoA to carnitine

acylcarnitine can now cross inner membrane

rate-limiting step of B-oxidation

CACT (Carnitine-acylcarnitine translocase)

exchanges acylcarnitine for free carnitine

antiporter; maintains supply of carnitine

CPT I (Carnitine palmitoyltransferase II)

regenerates FA-CoA inside matrix → now ready for B-oxidation; free carnitine is returned to cytosol

Humans can synthesis carnitine endogenously from these two amino acids

lysine and methionine

Synthesis of carnitine only occurs in ____ and requires ____

liver and kidneys; several cofactors (vitamins and minerals)

External sources of carnitine

meat, milk, avocado

Low carnitine levels lead to…

impaired FA oxidation and muscle weakness

B-oxidation predominates during energy demand states such as…

fasting/starvation, prolonged exercise, low-carb/ketogenic diets

B-oxidation generates acetyl-Coa for the TCA cycle when ____ and ketogenesis when___

carbs are available; carbs are low

B-Oxidation Key enzymes

ACAD, EH, 3HAD, B-ketoacyl-Coa Thiolase

B-Oxidation Key enzymes: ACAD

forms trans DB bewteen alpha and beta carbons

produces FADH2

Family enzmes specific to chain length

B-Oxidation Key enzymes: EH

hydration

adds OH group to beta carbon and H to alpha carbon

no energy production

B-Oxidation Key enzymes: 3HAD

oxidizes beta carbon

produces NADH

B-Oxidation Key enzymes: B-ketoacyl-Coa Thiolase

thiolytic cleavage

cleaves bond btw alpha and beta carbons

produces acetyl coa + fatty acyl coa (n-2)

Total rounds of B-oxidation

(N/2) - 1 rule (ex. 16/2 - 1 = 7 rounds) N = number of carbons

Regulation of B-oxidation: Product inhibition

inhibited by specific acyl-CoA intermediate it produces

Regulation of B-oxidation: Acetyl-CoA

stimulates pyruvate carboxylase (promotes gluconeogenesis)

inhibits pyruvate dehydrogenase (limits excess acetyl-CoA production)

Regulation of B-oxidation: High NADH/NAD+ ratio 

inhibits B-oxidation

Regulation of B-oxidation: Malonyl-CoA (metabolite in lipogenesis)

strongly inhibtis CPTI (rate limiting step of B-oxidaiton)

prevents simultaneous B-oxidation and FA synthesis when glucose is abundant

Hormones can indirectly regulate B-oxidation via stimulation of lipolysis

true

Energy yield from B-oxidation

106 ATP

B-oxidation produces reducing power but does not itself consume O2

true

Why does fatty acid catabolism require more oxygen than glucose catabolism?

fats are more reduced so have more e- to give away, while glucose is partially oxidized

more e- = more NADH and FADH2 to go to the ETC (more FADH2 and NADH you make, the more O2 is needed)

Unsaturated FAs yield less energy than equivalent length saturated FAs because some of their double bonds are…

already partially oxidized, meaning fewer FADH2 molecules generated during B-oxdiation

Monounsaturated fatty acids break down

undergo B-oxidation normally until DB is reached

cis DB at odd-numbered carbon disrepts formation of an intermediate needed

block is resolved by enoyl-CoA isomerase

one FADH2 yield is lost because bypasses acyl-CoA dehydrogenase rxn

Polyunsaturated FAs

contain multiple DBs;

require two auxiliary enzymes: 2,4 dienoyl-CoA reductase → reduces conjugated double bond system (requires NADPH); enoyl-CoA isomerase → rearranges remaining DB to trans configuration

extra steps consume NADPH and bypass FADH2 formation, decreasing total ATP yield

Catabolism of Odd-Chain saturated FAs

B-oxidation proceeds normally until 3-C residue remains → propionyl-CoA

Catabolism of Odd-Chain saturated FAs: propionyl-CoA is converted to

succinyl-CoA

succinyl-CoA

enters TCA cycle for oxidation to CO2 and serves as gluconeogenic precursor (partial net glucose synthesis from odd-chain FAs)

Pros of Lipid Metabolism

highest energy value per gram (9kcal/g)

yields a lot of ATP

large storage capacity

stable and compact (not stored w/water)

Cons of Lipid Metabolism

strictly aerobic → depends on O2

yield less energy/O2 used

slow → requires mobilization and transport from WAT into mitochondria of other tissues

not an option for all tissues (RBCs and brain)

Ketogenesis

conversion of excess acetyl-CoA from B-oxidation into ketone bodies

occurs in liver mitochondria only

ketolysis

utilization of ketone bodies to regenerate acetyl-CoA for the TCA cycle

occurs in extrahepatic tissues, not in liver

Ketogenesis and ketolysis can occur during

uncontrolled diabetes mellitus

fasting

prolonged exercise

low-carb or ketogenic diets

Why do ketogenesis and ketolysis occur?

low insulin, high glucagon → inc lipolysis and B-oxidaiton = inc acetyl CoA

Gluconeogenesis in liver → less OAA available for TCA cycle

Ketone bodies produces by the liver

acetoacetate, B-hydroxybutyrate, acetone

Physiological roles of ketone bodies: energy supply for peripheral tissues

Ketone bodies are water soluble, easily cross membranes + blood-brain barrier

Physiological roles of ketone bodies: glucose sparing

ketone bodies reduce brain’s glucose requirement by up to 2/3 during prolonged fasting

Physiological roles of ketone bodies: protein sparing

reduces amino acid use for gluconeogenesis

Physiological roles of ketone bodies: NAD+ regeneration

conversion of acetoacetate → B-hydroxybutyrate consumes NADH, regenerating NAD+ helping to maintain hepatic redox balance under high B-oxidation rates

Acetoacetate can..

spontaneously decarboxylate → acetone

Be reduced (using NADH) to B-hydroybutyrate

Does hepatic ketogenesis cost ATP?

No, but one NADH is used

B-hydroxybutyrate oxidation yields..

21.5 ATP per molecule

Lipogenesis

process of synthesizing FAs from non-lipid precursors