Lipids Metabolism
VLA 2019
2. 4. 2019
Metabolism stages
Figure 24.3
•
Complete oxidation – energy
expenditure zisk
 Fatty acids: 9 kcal/g
 Sugars: 4 kcal/g
 Proteins: 4 kcal/g
Hepatic fructose metabolism: A
highly lipogenic pathway. Fructose is
readily absorbed from the diet and rapidly
metabolized principally in the liver.
Fructose can provide carbon atoms for
both the glycerol and the acyl portions of
triglyceride. Fructose is thus a highly
efficient inducer of de novo lipogenesis.
High concentrations of fructose can serve
as a relatively unregulated source of
acetyl CoA. In contrast to glucose, dietary
fructose does NOT stimulate insulin or
leptin (which are both important
regulators of energy intake and body
adiposity). Stimulated triglyceride
synthesis is likely to lead to hepatic
accumulation of triglyceride, which has
been shown to reduce hepatic insulin
sensitivity, as well as increased formation
of VLDL particles due to higher substrate
availability, increased apoB stability, and
higher MTP (microsomal triglyceride
transfer protein , the critical factor in
VLDL assembly.
Lipids as a energy reserve
 Most of body energy is formed by
oxidation of sugars and lipids.
 Sugars: quick source of energy
 Lipids: energy reserve
 Energy reserve of lipids is much higher
compared to glycogen reserve
Lipids metabolism
 Most of lipids metabolism products is transported
fo lymph as chylomicrones.
 Lipids in chylomicrones are hydrolysed by
plasmatic enzymes and absorbed by cells.
 For energy formation only neutral lipids are
oxidized
 Lipids catabolism includes two distinct pathways:
 Glycerol pathway
 Pathway of fatty acids
Subcutaneous adipocyte tissue (SCAT) and visceral
adipocyte tissue (VAT)
 When compared to SCAT, VAT is more vascular, cellular
and innervated. It contains a greater number of immune
cells and large adipocytes when compared to that of
SCAT. There are also more androgen and glucocorticoid
receptors in VAT than in SCAT. Adipocytes in VAT are not
only more metabolically active but also are more
sensitive to lipolysis than adipocytes in SCAT. VAT also
generates higher amounts of free fatty acids, has an
enhanced uptake of glucose and a higher sensitivity to
adrenergic stimulation, while SCAT is more involved in
absorbing circulating free fatty acids and triglycerides
(TGs).
 Overall, VAT accumulation increases the risk of metabolic
disorders, such as T2D, hypertension, hyperlipidemia
and atherosclerosis
Prog Cardiovasc Dis. 2018 May - Jun;61(1):3-9
Due to fructose-induced inflammation (increased
infiltration of adipose tissue by macrophages) there
is also an increase in 11B-hydroxysteroid
dehydrogenase-1. This leads to an increase in
intracellular cortisol in subcutaneous adipocyte
tissue (essentially making them insulin resistant)
causing less fatty acids to enter the subcutaneous
adipocyte while more are expelled for storage into
visceral depots and in and around organs, such as
the liver, skeletal muscle, heart, and pancreas,
further disrupting metabolic processes and
impairing organ function.
Prog Cardiovasc Dis. 2018 May - Jun;61(1):3-9
TOFI
 Thus, overconsumption of added sugars promotes “thin on the
outside, fat on the inside” (TOFI).
 The term TOFI is used to describe lean individuals with an
increased fat deposition within their abdomen (visceral
adiposity).
 Subjects with TOFI have a body mass index < 25 kg/m2 with
an increase in risk factors associated with the metabolic
syndrome. This phenotype is a subtype of “metabolically-obese
but normal-weight”.
 The prevalence of TOFI is uncertain but it is estimated that
14% of men and 12% of women have TOFI.
 TOFI can be diagnosed by MRI or CT scan which can help in
differentiating fat (bright white) and other tissues (dark).
Prog Cardiovasc Dis. 2018 May - Jun;61(1):3-9
Lipolysis
Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley-Liss, Inc., New York, 1997.
ISBN 0-471-15451-2
Acetyl CoA
 Under aerobic conditions the end product of glycolysis is pyruvic acid.
The next step is the formation of acetyl coenzyme A(acetyl CoA) - this
step is technically not a part of the citric acid cycle, but is shown on
the diagram on the top left.
 Acetyl CoA, whether from glycolysis or the fatty acid spiral, is the
initiator of the citric acid cycle. In carbohydrate metabolism, acetyl
CoA is the link between glycolysis and the citric acid cycle.
 The initiating step of the citric acid cycle occurs when a four carbon
compound (oxaloacetic acid) condenses with acetyl CoA (2
carbons) to form citric acid (6 carbons).
 The whole purpose of a "turn" of the citric acid cycle is to produce
two carbon dioxide molecules. This general oxidation reaction is
accompanied by the loss of hydrogen and electrons at four specific
places. These oxidations are connected to the electron transport
chain where many ATP are produced.
Glycolysis
Figure 24.6
Major enzymes and substrates
involved in the regulation of
gluconeogenesis. Red arrows and
text represent the major enzymes
and pathways involved in the
regulation of gluconeogenesis.
Direct glucose release from
glycogen via the debranching
enzyme accounts for <10% of the
total glucose made via
gluconeogenesis.
AAT, alanine aminotransferase;
fruc-1,6-bisphosphatase, fructose-
1,6-bisphosphatase;
glu-6-phosphatase, glucose-6-
phosphatase;
glyceraldehyde-3-P, glyceraldehyde-
3-phosphate;
glycerol-3-P, glycerol-3-phosphate;
LDH, lactate dehydrogenase;
OAA, oxaloacetate;
PC, pyruvate carboxylase;
PDH, pyruvate dehydrogenase
phosphoenolpyruvate carboxykinase
(PEPCK)
Gluconeogenesis
Lipids Synthesis
Functions of human plasma lipoproteins
Lipoprotein class Origin Function
Chylomicrons Intestine Transport lipids from intestine to liver and
tissues
Very low density (VLDL) Liver Transport lipid from tissues to liver
Intermediate density
(IDL)
VLDL Precursor of LDL
High density (HDL 2 and
3)
Intestine Remove cholesterol from tissues
Cholesterol – the ways of excretion.
Biliary and non-biliary cholesterol.
Functions of bile acids (BA) in regulation of BA, energy, glucose and lipid metabolism via
farnesoid X receptor (FXR) and TGR5-mediated signaling pathways. BAT—brown adipose
tissue; FGF—fibroblast growth factor; GLP-1—glucagon-like peptide 1
A wide range of Takeda-G-protein-receptor-5 (TGR5) effects. A variety of
downstream effects has spawned intense interest in the therapeutic
potential of TGR5 agonists for the treatment of metabolic and
inflammatory diseases. GLP-1, glucagon-like peptide-1; NS, nervous
system; PYY, peptide tyrosine tyrosine; T2D, type 2 diabetes.
Hodge, R. J. and Nunez, D. J. (2016), Therapeutic potential
of Takeda-G-protein-receptor-5 (TGR5) agonists. Hope or
hype?. Diabetes, Obesity and Metabolism.
doi: 10.1111/dom.12636
Lipid droplets
 Storage neutral lipids, i.e. triacylglycerols (TAG) and
sterol esters (SE), are stored in the form of lipid droplets
(LDs) in almost all eukaryotic cells.
 LDs are dynamic subcellular organelles that not only
govern the storage and turnover of lipids, but also
function in membrane and lipid trafficking, protein
storage and degradation, and even in the replication of
hepatitis C virus.
 All LDs comprise a core of storage neutral lipids which
are wrapped by a monolayer of phospholipids with
proteins embedded. LDs are believed to originate from
the endoplasmic reticulum (ER), although the exact
mechanism underlying their biogenesis remains to be
determined.
Lipodystrophies
 Heterogenic group of diseases defined as localised or generalised
loss of body fat.
 If localised, usually related with fat hypertrophy in other side of
the body.
 Usually associated with sever metabolic changes including insulin
resistance, dyslipidemia and glucose intolerance.
 Different phenotypes:
 Familiar parcial lipodystrophy, type Dunnigan (FPLD): fat reduction
on the lower part of the body, hypetrophy on the upper part
 Barraquer–Simons syndrome – reverse phenotype, milder
metabolic changes
 Problems on the level of:
 adipogenesis, insulin sensitivity, TAGs storage, lipid droplets
formation, oxidative stress and fat remodellation.
Cellular targets alterated by
mutations in lipodystrophies
A: proteins taking part in
adipogenesis at the level of
nuclear DNA and in insulin
signal trasnduction pathway
B: proteins of endoplasmatic
reticulum and lipid droplets
during fat storage
Hyperlipidemia Signs
 Atheroma- plaques in blood vessels
Hyperlipidemia signs
 Xanthoma- plaques or nodules
composed of lipid-layden histiocytes
(foamy cells) in the skin, especially the
eyelids
Tendenous Xanthoma
Xanthoma deposits in tendon, commonly the Achilles
Corneal arcus
 Lipid deposit in cornea
Thank you for your attention