Transcript ppt

Chapt. 33
Ch. 33 Synthesis of Fatty acids, Triacylglycerols,
Membrane lipids:
Student Learning Outcomes:
• Describe basic steps for synthesis of fatty acids from
dietary glucose (or amino acids) in the liver
• Explain the role of VLDL lipoprotein particles
• Explain the use of fatty acids for triglyceride
synthesis
• Explain the use of fatty acids for synthesis of
glycerophospholipids and sphingolipids
Overview lipogenesis
Overview of lipogenesis:
synthesis of triacylglycerols from glucose:
•
•
•
•
•
•
If excess calories; citrate moved from mitochondrion
Acetyl CoA, Malonyl CoA, NADPH for fatty acids
Mostly occurs in liver
In cytosol
TG packaged as VLDL
Regulated pathway
• Compare b-oxidation
Fig. 1
OAA, oxaloacetate
TG, triacylglycerol
Overview Fate of VLDL-TG
Overview: fate of VLDL-Triacylglycerols
• TG is digested by LPL (lipoprotein lipase) on surface
of capillaries (see Ch. 32)
• FA for energy generation (muscle)
• FA for storage (reform TG in adipose)
• Glycerol returns to liver
• See also Ch. 2
Fig. 2
Overview – membrane lipids
Overview – membrane lipids
A. Glycerophospholipids – diverse head groups
B. Plasmalogen – platelet activation factor (ether link)
C. Sphingolipid – serine not glycerol backbone
D. Glycolipid – no PO4
See also Figs. 5.19, 20
Fig. 3
Fatty acid synthesis
I. Fatty acid synthesis from excess carbohydrates
A. Glucose to cytosolic Acetyl CoA
• Two paths from pyruvate (gluconeogenesis, TCA)
• Reciprocal inhibition/stimulation depends on [Acetyl CoA]
• OAA + Acetyl CoA → citrate (1st step TCA)
• Citrate transported to cytosol
• Cleave to OAA + Acetyl CoA
[PDH is only in mitochondrion;
Fig. 4
Acetyl CoA can’t cross membrane]
B. Citrate in cytosol
B. Citrate in cytosol to Acetyl CoA:
• Citrate lyase cleaves → Acetyl CoA and OAA
• NADPH is required for fatty acid synthesis:
• Some is made from Pentose Phosphate pathway
• Other from recycling OAA back to pyruvate:
• Reduce (uses NADH); recall TCA reversible reaction
• Oxidative decarboxylate (makes NADPH)
Figs. 5,6
↑, inducible enzymes
Fatty acid synthesis needs Acetyl CoA, NADPH
Fatty acid synthesis needs Acetyl CoA, NADPH
in the cytoplasm
• NADPH from Pentose
phosphate pathway
• NADPH from Malic enzyme
• Acetyl CoA from citrate lyase
Fig. 7
B. Acetyl CoA to Malonyl CoA
B. Conversion of Acetyl CoA to Malonyl CoA
• One Acetyl CoA and many Malonyl CoA are needed
• Malonyl CoA is immediate donor of the 2-C units
• Acetyl CoA carboxylase requires biotin and ATP
•
•
Acetyl CoA carboxylase is rate-limiting, highly regulated
AMP levels signal fasting ([AMP]/[ATP] sensitive
Figs. 8,9
C. Fatty acid synthase complex
C. Fatty acid synthase complex:
• Sequentially adds 2-C units from 3-C malonyl CoA
• 2 reduction reactions after each addition (NADPH)
• 16-C Palmitate is typical product
• FAS is large enzyme: 2 subunits (one polypeptide
each) with 7 catalytic activities and ACP domain
• ACP – acyl carrier protein segment (Ser) is joined
to a derivative of coenzyme A:
• Oriented with phosphopantetheinyl SH group (PSH) of one subunit near Cys SH group on other
Fig. 10
Fatty Acid synthase – 1st steps
Fatty acid synthase – beginning
1. Acetyl CoA onto ACP P-SH group
2. Acetyl CoA transfers to Cys –SH of other
3. This Acetyl CoA will become the w (last) C
of the fatty acid (i.e. carbon 16 of palmitate)
4. Malonyl CoA attaches to ACP SH
5. Malonyl CoA releases CO2; 2-C unit
condenses with the Acetyl CoA, and a 4-C
product is produced on ACP (C 13-16)
Fig. 11*
Fatty Acid synthesis Reduction reactions
Fatty Acid synthesis:
• Reduction reactions convert bketoacyl group
• NADPH is reducing agent
C=O → HCOH
• HCOH → C=C
• C=C → CH2-CH2
The 4-C unit will transfer to the SH of
the Cys on other subunit
Sort of opposite to b-oxidation
Costs 1 ATP to form Malonyl CoA
Costs 2 NADPH per addition
Fig. 12
•
•
•
•
•
Fatty Acid synthesis to palmitate (C16)
Fatty acid synthesis: cycles of 2-C addition
•
•
•
•
From 1 2-C Acetyl CoA and rest 3-C malonyl CoA
End C was first added (last unit is the COOH end)
Forms on ACP, then moves to Cys SH of other subunit
Cleavage at end
• 2 NADPH/cycle
• 1 ATP/cycle
• 1 CO2 added/ released
Fig. 13
New fatty acid is not reoxidized in liver
New fatty acid is not reoxidized in liver:
• Inhibition of carnitine acyl transferase CPT1
• Longer fatty acids are made in Smooth ER by
similar reactions involving malonyl CoA (Fig. 15)
• Other enzymes desaturate the FA-CoA to form
the unsaturated derivatives
• Use O2, NADH (Figs. 16, 17)
Fig. 14
Triacylglycerol synthesis
II. Synthesis of TG, VLDL
• Liver: phosphatidic acid + FA-CoA →
Triacylglycerol (TG), made in smooth ER
•
Adipose cells do not have glycerol kinase
• VLDL packages TG, phospholipids,
cholesterol and proteins (apoB-100)
• Processed in Golgi, secreted
• More dense than chylomicrons (less TG)
Fig. 18, 19
Summary of VLDL from liver
Summary VLDL from glucose in liver:
• VLDL secreted into blood
• VLDL will get apoCII and ApoE from HDL
Figs. 20, 21
Fed Fate of VLDL triglycerols
IV. Fate of VLDL triglycerols in Fed state:
• LPL lipase cleaves to FA + glycerol (like chylomicron)
• ApoCII activates LPL
• [Muscle LPL low Km, grabs FA]
• IDL & LDL products (Ch. 34)
Fig. 22
Fasting releases FA from Adipose tissues
V. Fasting releases FA from adipose tissue
• Insulin low, glucagon high; cAMP → PKA….
• Active Hormone Sensitive Lipase-P is TG lipase
• FA travel in blood bound to serum albumin
• Muscle oxidizes FA for energy
• Liver makes ketone bodies
from Acetyl CoA
• Liver uses glycerol for
gluconeogenesis
Fig. 23
VII. Metabolism of glycerophospholipids, sphingolipids
VII. Glycerophospholipids, sphingolipids:
• Components of cell membranes, blood lipoproteins,
bile and lung surfactants (see also Ch. 5)
• glycerol backbone, serine (sphingosine)
Fig. 25
A. Synthesis of glycerophospholipids
A. Glycerophospholipids
Similar to TG: Glycerol-3-phosphate + 2 FA →phosphatidic acid
Then two paths to addition of head group; both use CTP
Fig. 26
Some glycerophospholipids
Some glycerophospholipids
• Phosphatidic acid has PO4 on 3rd C of glycerol
• Slightly different paths for synthesis of two groups
• Both use CTP
Fig. 27,28
Phospholipases degrade glycerophospholipids
B. Degradation of glycerophospholipids
• Different phospholipases attack different bonds
• Enzymes in cell membranes, lysosomes
• PL C cleaves PIP2 → DAG + IP3
• PL D → phosphatidic acid + alcohol head group
• PL A2 cleaves off FA at C2 (often arachidonic, signaling)
• PLA2 also repairs damage by free radicals to C=C)
Fig. 30
Sphingolipids
Synthesis of sphingolipids:
• Intercell communication
• AB blood groups
• Receptors for viruses
Ceramide is central molecule
• Serine basis
• Fatty acid addition, release CO2
• Reduction
• Other fatty acid to NH2 group
• Oxidation
Fig. 31
PLP = pyridoxal PO4
Synthesis of some sphingolipids
Sphingolipids are based on ceramide:
• Addition of head groups to –OH (from serine)
• Addition of sugars uses UDP-sugar
• Degraded in lysosome
• Deficiency diseases
Fig. 32
other
Adipocytes can also make hormones:
• Leptin – identified as helping ob/ob obese mice lose weight
• Binds JAK receptor/ signals through sTAT
• Adiponectin – maybe linked to insulin resistance
• AMP kinase, PPARg, enhanced fatty oxidaiton
Metabolic syndrome associated with obesity:
• Insulin resistance, obesity, altered blood lipid levels
• High risk for type 2 diabetes, cardiovascular disease
• Read description in text (Fig. 35)
Key concepts
Key concepts:
• Fatty acids synthesized mainly in liver, from glucose
•
•
•
•
Glucose to pyruvate in mitochondrion, forms Ac CoA,
OAA, which form citrate
Citrate in cytosol then to Ac CoA, malonyl CoA
Fatty acid synthesis involve series 2-C additions from
malonyl CoA to the w-C of Ac CoA onto FA synthase.
Costs 2 NADPH and 1 ATP per cycle addition
• Fatty acids packaged as TG in liver as VLDL with
proteins and other lipids; digested by LPL on
capillaries and FA enter cells (oxidized or stored)
• Glycerophospholipids similar synthesis
• Spingolipids from sphingosine (serine + FA)
Review question
Review question:
3. A patient with hyperlipoproteinemia would be most likely to
benefit from a low-carbohydrate diet if the lipoproteins that
are elevated in blood are which of the following?
A. Chylomicrons
B. VLDL
C. HDL
D. LDL
E. IDL