Chapt. 33 Ch. 33 Synthesis of Fatty acids, Triacylglycerols, Membrane lipids: Student Learning Outcomes : Describe basic steps for synthesis of fatty acids.

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

Fig. 1OAA, oxaloacetateTG, triacylglycerol

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 -oxidation

Overview Fate of VLDL-TG

Fig. 2

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

Overview – membrane lipids

Fig. 3

Overview – membrane lipidsA.Glycerophospholipids – diverse head groupsB.Plasmalogen – platelet activation factor (ether link)C.Sphingolipid – serine not glycerol backboneD.Glycolipid – no PO4

See also Figs. 5.19, 20

Fatty acid synthesis

Fig. 4

I. Fatty acid synthesis from excess carbohydratesA.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;

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

Fig. 7

Fatty acid synthesis needs Acetyl CoA, NADPHin the cytoplasm

• NADPH from Pentose phosphate pathway• NADPH from Malic enzyme• Acetyl CoA from citrate lyase

B. Acetyl CoA to Malonyl CoA

Figs. 8,9

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

C. Fatty acid synthase complex

Fig. 10

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 (P-SH) of one subunit near Cys SH group on other

Fatty Acid synthase – 1st steps

Fig. 11*

Fatty acid synthase – beginning1. Acetyl CoA onto ACP P-SH group2. Acetyl CoA transfers to Cys –SH of other3. This Acetyl CoA will become the (last) C

of the fatty acid (i.e. carbon 16 of palmitate)4. Malonyl CoA attaches to ACP SH5. Malonyl CoA releases CO2; 2-C unit

condenses with the Acetyl CoA, and a 4-C product is produced on ACP (C 13-16)

Fatty Acid synthesis Reduction reactions

Fatty Acid synthesis:• Reduction reactions convert -

ketoacyl 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 -oxidation• Costs 1 ATP to form Malonyl CoA• Costs 2 NADPH per addition

Fig. 12

Fatty Acid synthesis to palmitate (C16)

Fig. 13

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

New fatty acid is not reoxidized in liver

Fig. 14

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)

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

Figs. 20, 21

Summary VLDL from glucose in liver:• VLDL secreted into blood • VLDL will get apoCII and ApoE from HDL

Fed Fate of VLDL triglycerols

Fig. 22

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)

Fasting releases FA from Adipose tissues

Fig. 23

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

VII. Metabolism of glycerophospholipids, sphingolipids

Fig. 25

VII. Glycerophospholipids, sphingolipids:• Components of cell membranes, blood lipoproteins, bile and lung surfactants (see also Ch. 5)• glycerol backbone, serine (sphingosine)

A. Synthesis of glycerophospholipids

Fig. 26

A. GlycerophospholipidsSimilar to TG: Glycerol-3-phosphate + 2 FA →phosphatidic acidThen two paths to addition of head group; both use CTP

Some glycerophospholipids

Fig. 27,28

Some glycerophospholipids• Phosphatidic acid has PO4 on 3rd C of glycerol• Slightly different paths for synthesis of two groups• Both use CTP

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

Fig. 31PLP = pyridoxal PO4

Synthesis of sphingolipids:• Intercell communication• AB blood groups• Receptors for virusesCeramide is central molecule• Serine basis• Fatty acid addition, release CO2

• Reduction• Other fatty acid to NH2 group• Oxidation

Synthesis of some sphingolipids

Fig. 32

Sphingolipids are based on ceramide:• Addition of head groups to –OH (from serine)• Addition of sugars uses UDP-sugar

• Degraded in lysosome• Deficiency diseases

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, PPAR, 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 -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