Chapt. 33Overview lipogenesisOverview Fate of VLDL-TGOverview – membrane lipidsFatty acid synthesisB. Citrate in cytosolFatty acid synthesis needs Acetyl CoA, NADPHB. Acetyl CoA to Malonyl CoAC. Fatty acid synthase complexFatty Acid synthase – 1st stepsFatty Acid synthesis Reduction reactionsFatty Acid synthesis to palmitate (C16)New fatty acid is not reoxidized in liverTriacylglycerol synthesisSummary of VLDL from liverFed Fate of VLDL triglycerolsFasting releases FA from Adipose tissuesVII. Metabolism of glycerophospholipids, sphingolipidsA. Synthesis of glycerophospholipidsSome glycerophospholipidsPhospholipases degrade glycerophospholipidsSphingolipidsSynthesis of some sphingolipidsotherKey conceptsReview questionChapt. 33Ch. 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 sphingolipidsOverview lipogenesisFig. 1OAA, oxaloacetateTG, triacylglycerolOverview 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 -oxidationOverview Fate of VLDL-TG Fig. 2Overview: 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. 2Overview – membrane lipidsFig. 3Overview – membrane lipidsA.Glycerophospholipids – diverse head groupsB.Plasmalogen – platelet activation factor (ether link)C.Sphingolipid – serine not glycerol backboneD.Glycolipid – no PO4See also Figs. 5.19, 20Fatty acid synthesisFig. 4I. 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 enzymesFatty acid synthesis needs Acetyl CoA, NADPHFig. 7Fatty acid synthesis needs Acetyl CoA, NADPHin the cytoplasm•NADPH from Pentose phosphate pathway•NADPH from Malic enzyme•Acetyl CoA from citrate lyaseB. Acetyl CoA to Malonyl CoAFigs. 8,9B. 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] sensitiveC. Fatty acid synthase complexFig. 10C. 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 otherFatty Acid synthase – 1st stepsFig. 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 reactionsFatty 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 additionFig. 12Fatty Acid synthesis to palmitate (C16)Fig. 13Fatty 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/ releasedNew fatty acid is not reoxidized in liverFig. 14New 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, 19Summary of VLDL from liverFigs. 20, 21Summary VLDL from glucose in liver:•VLDL secreted into blood •VLDL will get apoCII and ApoE from HDLFed Fate of VLDL triglycerolsFig. 22IV. 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 tissuesFig. 23V. 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 forgluconeogenesisVII. Metabolism of glycerophospholipids, sphingolipidsFig. 25VII. Glycerophospholipids, sphingolipids:• Components of cell membranes, blood lipoproteins, bile and lung surfactants (see also Ch. 5)• glycerol backbone, serine (sphingosine)A.