Lipid mobilization and catabolism

Triglyceride is an

ester formed from glycerol and 3 fatty acids

What is the main consitutent of natural fats and oils

triglycerides

triglycerides are broken down into

fatty acids

Fatty acid metabolism generates

ATP

How is triglycerides generally broken down

TLG → hormone sensitive lipase (Active) → glycerol and fatty acids

this takes place in adipose tissue

glycerol is broken down from TGL in the adipose tissue and enters the blood stream, what happens after that

glycerol from blood stream enters liver where it undergoes gluconeogenesis to form glucose

Fatty acids enter the blood stream after being released from adipose tissue, what happens after that

fatty acids form fatty acid albumin → liver → fatty acids → beta-oxidation → acetyl coA

acetyl coA can enter ketogenesis or Citric acid cycle

In conditions with decreased insulin, increased epinephrine and cortisol what is happening in adipose tissue

hormone sensitive lipase activation (phosphate)

TGL degradation → glycerol and fatty acids

Increased glucagon and cortisol causes what processes to happen during lipid mobilization

glycerol (from TGL) to undergo gluconeogenesis to from glucose

Postabsorptive state in TGL mobilization in adipocytes

• decreased blood glucose → many hormones mobilize

• decreased insulin (starvation)

• increased glucagon

• increased epinephrine (exercise)

• increased cortisol

insulin, epi, cortisol → adipose tissue → increased hormone sensitive lipase (HSL)

Glycerol can be handled by what organ/s

LIVER ONLY

How does glycerol travel in the blood

water soluble

dumped in blood

no transport needed

In the liver, glycerol undergoes …..

gluconeogenesis

glycerol → DHAP → glucose (gluconeogenesis)

Gluconeogenesis is regulated by

glucagon and cortisol (increases gene level) → PEP increased carboxykinase

How do FAs travel in the blood stream

carried by albumin

ultimately enters liver

What happens to FAs once they enter the liver

Beta-oxidation

FAs produce acCoA

ketone bodies + ATP

AcCoA generated in the liver travels to

STAYS IN LIVER

ketogenesis

Ketone bodies travel/used by

dumped into the blood to be used by cardiac and brain cells (starvation only)

What is the link between beta-oxidation and gluconeogenesis

Beta-oxidation directly supports gluconeogenesis by providing both ATP energy required to build glucose and the acetyl CoA needed to turn on the key starting enzyme

Major oxidation of FAs

beta-oxidation

Minor-oxidation of fatty acids

alpha-oxidation

omega- oxidation

perisomal beta-oxidation

Where does beta-oxidation occur

mitochondria

General process of beta-oxidation

two carbon fragments are successively removed from carboxyl end of fatty acetyl CoA

produces acetyl CoA, NADH and FADH2

Short chain fatty acids

SCFA

less than 6 C

Medium chain FAs

MCFAs

6-12 C

Long chain FA

LCFAs

12-18 C

Very long chain fatty acids

VLCFA

22+ C

SCFAs are generated

mostly via colonic bacteria

SCFAs are predominantly metabolized by

enterocytes and liver

MCFAs arise from

dietary TGLs

(milk and dairy)

SCFAs and MCFAs common feature

carnitine-independent uptake

intra-mitcohondrial activation of acyl-CoA thioesters

what type of FAs undergo beta-oxidation

LCFAs

LCFA oxidation occurs where and requires what to get there

mitochondria

carnitine shuttle

What is the major source of energy for prolonged low intensity exercise

LCFA oxidation (beta-oxidation)

produces a lot of ATP, NADH, FADH2

utilizes TCA and ETC

Ketones are produced

VLCFA oxidation occurs in

peroxisomes

Differences between LCFA oxidation and VLCFA oxidation products

LCFAs produce FADH2 and NADH

VLCFAs do not (no TCA no ETC)

VLCFAs produce H2O2 instead

Alpha oxidation occurs in FAs that have

a CH3 on their beta carbon

prevents beta-oxidation

Mechanism behind alpha-oxidation

1 carbon is removed from the a-position

Alpha oxidation foes not require

CoA

does not generate high energy phosphates

Alpha oxidation occurs in what tissues

brain tissues to oxidize SCFAs

phytanic acid goes through what oxidation

alpha-oxidation

dietary FA

occurs entirely withing peroxisome

NO ATP production

Omega oxidation mechainsm

oxidation occurs at omega carbon

carbon most distant from carboxyl group

What FAs undergo omega oxidation

LCFAs and MCFAs

When and where does omega oxidation occur

prolonged fasting

occurs in liver peroxisomes

minor pathway, but becomes effective when beta-oxidation is defective

omega oxidation results in

formation of dicarboxylic acids (DCAs)

DCAs are further metabolized through mitochondrial beta-oxidation

After a LCFA enters a cell, it is converted to _______ by _______

After a LCFA enters a cell, it is converted to CoA derivative by long-chain fatty acyl CoA synthase

Where in the cell is LCFA converted to CoA derivative

cytosol

Where in the cell is long-chain fatty acid acyl CoA synthase located

Outer mitochondrial membrane

Beta-oxidation occurs in what part of the mitochondria

mitochondrial matrix

Carnitine action

LCFA acyl CoA derivative must pass through inner mitochondrial membrane to enter mitochondrial matrix in order to undergo beta oxidation

the inner mitochondrial matrix is impermeable to acyl CoA

Carnitine is a specialized carrier that transports long-chain acyl group from cytosol to mitochondrial matrix

What is the rate-limiting step in the LCFA transport for B-oxidation

Carnitine

What are the 4 things you need to know for beta-oxidation

acyl CoA synthetase → activates LCFAs by combining them with Coenzyme A; can then enter mitochondrial membrane

Carnitine

Carnitine palmitoyl-transferase I → combines LCFA acyl-CoA with carnitine

Carnitine palmitoyl-transferase II → detaches carnitine from LCFA acyl- CoA as it enters mitochondrial matrix

Carnitine palmitoyl-transferase I

combines LCFA acyl-CoA with carnitine

Carnitine palmitoyl-transferase II

detaches carnitine from LCFA acyl- CoA as it enters mitochondrial matrix

Carnitine can be obtained by

• Diet

  • Synthesized

How / where is carninte synthesized

from amino acids lysine and methionine

liver and kidneys

Primary carnitine deficiency

caused by defects in membrane transporter that prevent uptake of carnitine by cardiac, skeletal muscles and kidneys

leads to carnitine secreation

Secondary carnitine deficiency

due to defects in FA oxidation causing accumulation of acylcarnitine that are excreted in urine

decreases carnitine availability

acquired secondary carnitine deficiency is caused by

liver disease (decreased carnitine synthesis)

valproic acid (antiseizure drug) (decreases renal absorption)

Deficiencies in CPT-I and CPT-II are caused by

defects in mitochondrial oxidation

CPT-1 deficiency

affects the liver

inability to use LCFA for fuel greatly impairs tissues ability to synthesize glucose during fast

leads to hypoglycemia, coma or death

CPT-II deficiency

normally benign (requires triggers like exercise)

exercise induces myalgia

Myoglobinuria

Muscle weakness is much more defined

normal creatinine levels

General carnitine deficiency leads to

Muscle aches

High TGs

Lipid vacuoles in muscle

Normal enzymes

cardiomyopathy (classic presentation; affects older children; onset may occur with rapidly progressive heart failure)

How do shorter chain fatty acids enter mitochondria

without aid of carnitine or CPT system

VLCFAs under go preliminary B-oxidation in

peroxisomes

Where are the primary sites for synthetase that activates VLCFAs

peroxisomes

NOT MITOCHONDRIA

After VLCFAs leave peroxisomes where do they go

short enough to enter mitochondrial matrix via carnitine shuttle

The initial dehydrogenation of VLCFAs is catalyzed by

FAD-containing acyl CoA oxidase

After VLCFAs are catalyzed by FAD-containing acyl CoA oxidase FADH2 produced is

oxidized by O2

reduced to hydrogen peroxide (H2O2)

In peroxisomes, H2O2 produced by VLCFA preliminary b-oxidation is reduced to

H2O by catalase

Zellweger syndrome

peroxisomal biogenesis disorder

too much VLCFAs accumulate

Liver mitochondria convert Ac-CoA derived from FA oxidation into

Ketone bodies

KBs are made of 3 molecules

Acetoacetate

3-hydroxybutyrate

acetone

Mitochondrial 3-hyrdoxy-3-methylglutaryl (HMG) CoA synthase

combines Ac-CoA with acetoacytyl CoA to produce HMG CoA

Rate limiting step

What is the rate limiting step in KB synthesis

HMG CoA synthase

HMG CoA is cleaved by ________ to produce __________

HMG CoA is cleaved by HMG CoA lyase to produce acetoacetate and acetyl CoA

In KB synthesis acetoacetate is produced as a byproduct. What happens to it

reduced to form 3-hydroxybutarate with NADH as electron donor

decarboxylate to form acetone → volatile, can be detected in breath

Equalibirum between acetoacetate and 3-hydroxybutarate (KB synthesis) is determined by

NAD+/NADH ratio

(low during FA oxidation ; 3-hydroxybutarate is favored

What cells cannot use KBs

Liver and RBCs