LIPOTOXICITY & Liver

BDEL RAHMAN A. MOKHTAR

 Type of Lipids

 Saturated fat
 Animal oil like meat, milk, butter
 Vegetable oil like coconut and palm kernel oil
 Polyunsaturated fat
 Plant source like safflower, corn, cottonseed, sunflower oil and
soybean oil
 Monounsaturated fat
 Plant and animal product like olive oil, canola oil, avocado and
peanut oil
 Lipids Functions
 Excellent energy reserves
 Structure of cell membranes
 Organ padding
 Body thermal insulation
 Essential fatty acids (EFA)
 Hormone synthesis
 Fat soluble vitamin absorption
Normal lipid Metabolism
Transport of Lipids
Nonpolar lipids need
to be escorted through
the bloodstream via
lipoprotein complexes.

Chylomicrons carry dietary

lipids to tissues
VLDLs carry lipids synthesized
in liver to tissues
LDLs carry cholesterol to tissues
HDLs carry cholesterol to liver
from tissues
 Absorption of Dietary Fats

Dietary lipids must be emulsified and

packaged for transport in the bloodstream

taurocholic
Bile salts are made acid
from cholesterol in
the liver; stored in
gall bladder
 Absorption of
Dietary Fats

Step 1:
emulsification by
bile salts and
hydrolysis by
lipases
 Absorption of
Dietary Fats

Step 2: packaging
for transport
 Absorption of
Dietary Fats

Step 2: packaging
for transport
 Absorption of
Dietary Fats

Step 3: hydrolysis
and entry into
target tissues
 Lipid Storage
 Adipocytes have a unique capacity to store large
amounts of excess FFAs in cytosolic lipid droplets.
however, cells of non-adipose tissues have a limited
capacity for storage of lipids.

 When this capacity is exceeded ?????????????

 FA ( Energy ) Storage

Triglycerides account for ~83% of our stored

energy

Mobilized slower than carbs and only

aerobically

Principal fuel for many organs (e.g., heart,

liver)

More energy per gram than carbs (9 kcal vs. 4)

 Mobilization of Fat Stores
Hormone (glucagon
or epinephrine)
binds to fat cell
receptor, activating
protein kinase A
Phosphorylation
activates lipase and
perilipin, triggering
release of fatty acids
Fate of Triglyceride Products
Fate of Triglyceride Products
Back to the Matrix!
 Lipid Storage

 Adipocytes have a unique capacity to store large

amounts of excess FFAs in cytosolic lipid droplets.
however, cells of non-adipose tissues have a limited
capacity for storage of lipids.

 When this capacity is exceeded ?????????????

The fatty acids will accumulate
in non-adipose tissues resulting in

Lipotoxicity.
Enlargement
of visceral adipose tissue is
especially important because
it secretes FFA into the portal
circulation, i.e., directly to the
liver.
FATTY ACID METABOLISM IN THE LIVER
 Liver plays a prominent role in maintaining a
balanced nutrient supply in blood throughout
the ever changing nutritional and metabolic
conditions.

 Therefore, hepatocytes can shift from intensive

fatty acid synthesis (in fed state) to rapid fatty
acid breakdown (in starvation).
 FFA
Fatty acids, the most efficiently and economically storable
fuel molecules are synthesized from the excess of carbohydrates and amino
acids during the absorptive phase

However, they are not released into the blood plasma as non-esterified or free
fatty acids (NEFA or FFA) but incorporated into complex lipids such as
triglycerides, phosphoglycerolipids or cholesterylesters in the ER membrane
lipoprotein particles finally leave the cell through exocytosis

FFAs normally derive from triglyceride breakdown in the adipocytes, and hence their
abundance occurs in starvation when store mobilization is stimulated by hormones
(e.g., glucagon, adrenalin and glucocorticoids)
In fed state, monosaccharides & amino acids are taken up from the
portal blood and converted to fatty acyl- CoAs through acetyl-CoA
intermediate; Newly synthesized fatty acids are inserted into complex
(saponifiable) lipids, which in turn are packed in very low density
lipoprotein (VLDL) particles and so secreted from the hepatocytes.
In starvation, free fatty acids (FFAs) derive from triglyceride mobilization in the adipose tissue.
After a protein-mediated uptake across the plasma membrane, they are activated to acyl-CoA, and
catabolized in the mitochondria through β-oxidation and citrate cycle.

Long term starvation can deprive citrate cycle of intermediates and make it unable to keep pace
with acetyl-CoA production .

Shortage of citrate cycle intermediates leads to accumulation of acetyl- CoA, and then enhances
the synthesis of ketone bodies.

These ketone bodies are secreted from the hepatocytes into the blood plasma and serve as
alternative fuels to most aerobic tissues including the brain
Fatty acid toxicity in the liver.
 Limited increase in the fatty acids supply

When fatty acid

input overcomes
the capacity
of β-oxidation,
accumulating acyl-
CoA is drained by
triglyceride
synthesis, which
leads to steatosis in
the liver
Accumulation of
fatty acids or fatty
acyl-CoAs, however,
may be more
harmful to
hepatocytes than
deposition
of triglycerides.

Balanced (over) supply of saturated and unsaturated fatty acids allows the
hepatocyte to enhance triglyceride synthesis and deposition. Storage of
excess fatty acids prevents superfluous fatty acid oxidation and thereby
protects against oxidative stress;
 Overwhelming abundance of saturated fatty acids

Interruption of triglyceride
synthesis, apparently
because of the formation of
a pool of oversaturated
intermediates, seems to be a
key event in SFA-induced
lipotoxicity.

Retained capacity to
synthesize and
accumulate triglycerides in
the presence of unsaturated
FA, in fact, turned out to be
protective

Disproportionate abundance of saturated fatty acids might not be compensated for

by fatty acid desaturation (dashed lines). Hindrance of protective fat synthesis
favors fatty acid oxidation and leads to excessive ROS generation; The emerging
oxidative stress and the increased saturation of membrane lipids trigger
the endoplasmic reticulum (ER) stress response, which contributes to insulin
resistance and further enhances cell death (dotted lines).
Pathophysiological processes in the gut-adipose-liver axis
that potentially contribute to the Surpilus FFA

1: increased intake of fat-enriched diet (Western diet) and/or elevated release of

bacteria-derived factors such as LPS due to altered gut microbiota composition in
obesity led to increased production of pro-inflammatory cytokines in the gut.
2: such pro-inflammatory cytokines as well as diet-derived
FFA and LPS are partly drained into the portal circulation.
3: obesity-/diet-induced impairment of the gut barrier function led to (elevated) translocation of bacterial particles and
endotoxins into mesenteric white adipose tissue (WAT).
In mesenteric WAT, translocated factors stimulate adipocytes and resident immune cells to release pro-inflammatory
cytokines.
Subsequently, these cytokines may be released into the portal circulation and/or favor the development of hypertrophic
adipocytes that secrete higher levels of FFA and/or pro-inflammatory cytokines
 By the end of the
THERAPEUTIC PROSPECTS
day several Steps
Lipotoxicity may be ameliorated or overcomed in the
prevented if lipid can be way ,
redirected to adipose tissues (e.g.
through stimulation of peroxisome
proliferatoractivated
receptor (PPAR)g pathways) or
secreted in the form of
lipoproteins.

Alternatively, within the lipid-

overloaded cell, channeling of
FFAs to triglyceride stores or to
increased b oxidation (e.g. through
stimulation of PPARa pathways)
may protect against lipotoxicity.
Agents such as salicylates,
ceramide synthesis inhibitors and
scavengers of reactive oxygen
species (ROS) may block specific
signaling pathways and fatty acid
metabolic pathways that
are critical for lipotoxicity.
 In Conclusion
While previously this pathophysiological condition ( NAFLD) was mainly
attributed to triglyceride accumulation in hepatocytes,

recent data show that the development of oxidative stress, lipid peroxidation,
cell death, inflammation and fibrosis are mostly due to accumulation of fatty
acids,and the altered composition of membrane phospholipids.

In fact, triglyceride accumulation might play a protective role, and the higher
toxicity of saturated or trans fatty acids seems to be the consequence of a
blockade in triglyceride synthesis

 Increased membrane saturation can profoundly disturb cellular homeostasis by

impairing the function of membrane receptors, channels and transporters

 FFA , also induces endoplasmic reticulum stress via novel sensing mechanisms
of the organelle’s stress receptors.
 This in turn largely contribute to the development of insulin resistance and
apoptosis.