Adipocytes: Lipogenesis and
Lipolysis
Adipocyte lipid metabolism
• Lipogenesis: storage of excess energy as fat (TG
synthesis)
– Fatty acid sources
• Fatty acids derived from lipoproteins (CM, VLDL) by
lipoprotein lipase (LPL)
• Fatty acid derived from glucose via de novo lipogenesis
(key enzymes: acetyl CoA carboxylase (ACC) and fatty acid
synthase (FAS))
– TG synthesis: glycerol-3-phosphate + FFAs
• Lipolysis: hydrolysis of triacylglycerol to release
fatty acids for use of energy by other tissues
De novo lipogenesis: from glucose to FFA
• Glucose---acetyl CoAs through TCA cycle
• AcetylCoAs are the primary substrates for synthesis
of long-chain saturated fatty acids by ACC and FAS
Regulation of ACC and FAS
• Sterol response element binding protein 1C
(SREBP1C)
– Dominant in liver
• Carbohydrate response element binding
protein (ChREBP)
– Dominant in fat
• Both upregulated by glucose and insulin
TG synthesis
• FA activation: Fatty acids are converted to
acyl-CoA derivatives by the action of acylCoA synthetase
ATP
AMP + PPi
R.COOH+CoASH
R.Co.SCoA
TG synthesis
• Sequential acylation of glycerol-3-phosphate by
long chain acyl-CoA thioesters
– 1. Lysophosphatidic acid (LPA) by glycerol-3-phosphate
acyltransferase (GPAT) at sn-1 position
– 2. Phosphatic acid (PA): acylation of LPA by acyl-CoA
1acylglycerol-3-phosphate acyltransferase (AGPAT) at
sn-2 position
– 3. Diacylglycerol (DAG): hydrolyzed by PA phosphatase
(PAP)
– 4. TG: final esterification by DAG acyltransferase
(DGAT)
TG synthesis
Lipolysis
• A process by which FAs are hydrolyzed from
the glycerol backbone of TG
• Yield 3xFAs + 1 glycerol
Enzymes in Lipolysis (Review paper by
Zechner, Cell Metab. 15: 279, 2012)
• Adipose triglyceride lipase (ATGL): catalyze the
initial step of lipolysis
– Belong to the family of patatin domain-containing proteins,
which was originally discovered in lipid hydrolase of the
potato and other plants.
– ATGL expression is increased by PPAR agonists,
glucocorticoids and fasting
– Decreased by insulin and food intake
– The abundance of ATGL mRNA does not always correlate
with cellular lipase activity
• Beta adrenergic activation (isoproterenol) and TNFα reduce ATGL
mRNA levels but stimulate lipase activity.
– ATGL can be phosphorylated at serine 406/430 residues by
AMPK but not by PKA (which normally phosphorylates HSL)
Enzymes in Lipolysis
• Adipose triglyceride lipase (ATGL): catalyze the
initial step of lipolysis
– ATGL requires a coactivator protein comparative gene
identification-58 (CGI-58), for full hydrolase activity
• In hormonally non-stimulated state, perillipin-1 interacts with CGI-58
and prevents its binding to and induction of ATGL.
• Upon adrenergic stimulation, protein kinase A (PKA) phosphorylates
perillipin-1 and causes the release of CGI-58, which then binds to and
stimulates ATGL
– ATGL is inhibited by a peptide inhibitor G0G1 switch protein
2 (G0S2)
Enzymes in Lipolysis
• Hormone sensitive lipase (HSL): the main
diacylglycerol (DAG) lipase; first identified lipase
– It was noted in the early 1960s that a lipolytic activity
present in adipose tissue was induced by hormone
stimulation: both HSL and MGL were identified.
– Standard textbooks stated that HSL was rate-limiting step
for the catabolism of fat. However, this view was challenged
when studies showed that HSL-deficient mice displayed no
signs of TG accumulation; instead they accumulate DAG,
suggesting that other lipases may exist and HSL is more
important as a DAG hydrolase
– It is now accepted that ATGL is responsible for the initial
step of lipolysis, while HSL is rate limiting for DAG
Enzymes in Lipolysis
• Hormone sensitive lipase (HSL):
– HSL expression profile mirrors that of ATGL: induced by fasting and
suppressed by feeding and insulin
– HSL enzyme activity is strongly induced by beta-adrenergic stimulation,
while insulin has a strong inhibitory effect
– Beta-adrenergic stimulation regulates ATGL via recruitment of the coactivator CGI58, HSL itself is a major target for PKA phosphorylation (HSL
has at least 5 serine phosphorylation sites).
– Beta-adrenergic signal PKA also phosphorylates perillipin-1, which HSL
interacts with and thereby gains access to lipid droplets.
– Insulin signaling results in phosphorylation and activation of various
phosphodiesterases (PDE) isoforms by PKB/Akt. PDEs hydrolyzes cAMP--AMP, which in turn inhibits PKA.
Enzymes in Lipolysis
• Monoglycerol lipase (MGL): the final step in lipolysis
– A rate-limiting enzyme for breakdown of MG
– Localize to cell membranes, cytoplasma and lipid droplets
– Lack of MGL impairs lipolysis
Figure 1. Lipolysis in Adipose and Oxidative Tissues during FastingIn adipose tissues, beta-adrenergic stimulation of lipolysis leads
to the consecutive hydrolysis of TG and the formation of FAs and glycerol. The process requires three enzymes: ATGL cleaves th...
Rudolf Zechner, Robert Zimmermann, Thomas O. Eichmann, Sepp D. Kohlwein, Guenter Haemmerle, Achim Lass, Frank Madeo
FAT SIGNALS - Lipases and Lipolysis in Lipid Metabolism and Signaling
null, Volume 15, Issue 3, 2012, 279–291
http://dx.doi.org/10.1016/j.cmet.2011.12.018
Across mitochondria membrane
Carnitine palmitoyltransferase-I
(CPT-I)
• CPT-I plays an important role in the
regulation of fatty acid oxidation
– Malonyl-CoA, which is a key
intermediate in fatty acid synthesis, is
an allosteric inhibitor of CPT-I
– This ensures that fatty acid oxidation is
decreased when synthesis is taking
place
β-oxidation
• Second carbon atom from the
carboxyl end that is “attacked” in the
process
• The molecules of long-chain fatty
acyl-CoA are shortened by the stepwise removal of two-carbon
fragments to form acetyl-CoA, which
is then oxidized by the Krebs cycle
Mitochondria β-oxidation
• Each turn of the βoxidation splits off a
molecule of acetylCoA by 4 enzymes
catalysing:
– Oxidation (to form
a double bond)
– Hydration
– Oxidation (to form
a ketone from a
secondary alcohol)
– Transfer of the
acetyl group to coA
β-oxidation: ATP yield per palmitate molecule
Reaction
/Processes
No. of
molecules
produced
Synthesis of palmitoyl-CoA
thioester from palmitate
Molecules ATP per
molecule produced
ATP yield
-2
-2
FADH2 oxidation via
electron transfer chain
7
1.5
10.5
NADH oxidation via
electron transfer chain
7
2.5
17.5
Acetyl-CoA oxidation via
Krebs cycle
8
10
80
Total
106
ATP yield per glucose through completion oxidation
FA>>Glucose