Power point about the concept of lipotoxicity and ectopic fat diposition. This may affect different parenchymatous organs

1. LIPOTOXICITY & Liver

2.  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

3.  Excellent energy reserves
 Structure of cell membranes
 Organ padding
 Body thermal insulation
 Essential fatty acids (EFA)
 Hormone synthesis
 Fat soluble vitamin absorption

5. 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

6. Dietary lipids must be emulsified and
packaged for transport in the bloodstream
Absorption of Dietary Fats
taurocholic
acid
Bile salts are made
from cholesterol in
the liver; stored in
gall bladder

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

8. Absorption of
Dietary Fats
Step 2: packaging
for transport

9. Absorption of
Dietary Fats
Step 2: packaging
for transport

10. Absorption of
Dietary Fats
Step 3: hydrolysis
and entry into
target tissues

11.  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 ?????????????

12. Triglycerides account for ~83% of our stored
energy
FA ( Energy ) Storage
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)

13. 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

14. Fate of Triglyceride Products

15. Fate of Triglyceride Products

16. Back to the Matrix!

17.  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 ?????????????

18. The fatty acids will accumulate
in non-adipose tissues resulting in
Lipotoxicity.

19. Enlargement
of visceral adipose tissue is
especially important because
it secretes FFA into the portal
circulation, i.e., directly to the
liver.

20.  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).

21. 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)
FFA

22. 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.

23. 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

24. Fatty acid toxicity in the liver.

25. Limited increase in the fatty acids supply
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;
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.

26. Overwhelming abundance of saturated fatty acids
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).
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

27. 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.

29. 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

31. THERAPEUTIC PROSPECTS
Lipotoxicity may be ameliorated or
prevented if lipid can be
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.
By the end of the
day several Steps
overcomed in the
way ,

32. 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.