Fat Fate and Formation - Medical Biochemistry II PDF

Medical Biochemistry II Fate of fats during fed state or as needed LC sat FA are synthesized from Palmitate Fatty acid elongation systems are in the smooth ER and mitochondria Elongation to stearoyl-CoA in ER is identical to formation of palmitate except: Different enzymes coA is the acyl carrier (n...

Medical Biochemistry II Fate of fats during fed state or as needed LC sat FA are synthesized from Palmitate Fatty acid elongation systems are in the smooth ER and mitochondria Elongation to stearoyl-CoA in ER is identical to formation of palmitate except: Different enzymes coA is the acyl carrier (not ACP) LC sat FA are synthesized from Palmitate Palmitate and stearate are precursors of two most common monounsat. FA: palmitoleate, 16:1(Δ9) and oleate, 18:1(Δ9) Cis double bond is introduced by fattyl acyl-CoA desaturase and NADPH LC sat FA are desaturated The substrates (FA and NADPH) undergo simultaneous oxidizations Electron flow includes cytochrome (b5) and flavoprotein (cytochrome b5 reductase) both are in smooth ER We now have C16, C18, C22, C24 (especially in the brain) FA that need to be converted to TAGs Next step: glycerol addition Remember TAGs are made in the liver released in VLDL, converted by lipases at the surface of adipose tissues into FA (taken up by adipose tissue) Adipose tissue must reconvert FA into TAGs following uptake Note: Glycogen stores in liver and muscles can last about 12 hours Fat stores of an average healthy man can last about 12 weeks Synthesis of TAGS In liver and adipose tissue, TAGs are produced by a pathway containing a phosphatidic acid intermediate Dephosphorylation = diacylglycerol Add another Fatty acyl-CoA = TAG Glycerol 3-P in liver is produced from the phosphorylation of glycerol by glycerol kinase or from the reduction of dihdroxyacetone phosphate derived from glycolysis Glycerol kinase is not in adipose tissue Triacylglycerol packaging Synthesis of VLDL VLDL packages TAG, phospholipids, cholesterol and proteins (apoB-100) Proteins synthesized on rough ER Fig. 18, 19 Summary of VLDL from liver VLDL secreted into blood VLDL will get apoCII and ApoE from HDL Figs. 20, 21 Fate of VLDL triglycerols LPL lipase cleaves TAGs to FA + glycerol (like chylomicron) ApoCII (from HDL) activates LPL [Muscle LPL low Km, grabs FA] IDL & LDL products (Ch. 34) LPL Isozyme in adipose tissue is most active after a meal Fig. 22 Storage of TGs in Adipose Tissue After a meal stores of adipose tissue increase Adipose cells synthesize LPL when the insulin/glucagon ratio is elevated → FAs enter adipose cells forming fatty acyl CoA to form TAG Glycerol travels through the blood to the liver In adipose cells, glycerol 3phosphate is derived from glucose stimulated by insulin Insulin also stimulates conversion of glucose to FAs, although liver is the major site FA’s from diet or synthesized are precursors Glycerophospholipids – cell membrane components, bile, blood lipoproteins, and lung surfactant. Also source of arachidonic acid (precursor of eicosanoids) Sphingolipids – cell membrane components, myelin sheath (important in signal transduction in CNS), and glycolipids Metabolism of glycerophospholipids, sphingolipids Components of cell membranes, blood lipoproteins, bile and lung surfactants (see also Ch. 5) glycerol backbone, serine (sphingosine) Fig. 25 Synthesis of glycerophospholipids Glycerophospholipids Similar to TAG: Glycerol-3-phosphate + 2 FA →phosphatidic acid Then two paths to addition of head group; both use CTP Synthesis of glycerophospholipids: first mechanism In first mechanism, phosphatidic acid is cleaved by a phosphatase to form diacylglycerol (DAG) DAG then reacts with an activated head group 3 methyl groups added SAM is S-adenosylmethionine ( a methyl group donor) Synthesis of glycerophospholipids: first mechanism Various types of interconversions occur among these phospholipids Synthesis of glycerophospholipids: 2nd mechanism Cardiolipin is a component of the inner mitochondrial membrane. PIP2 is found in cell membranes can for Ip3 and DAG Ether Glycerolipids: plasmalogen The ether glycerolipids are synthesized from the glycolytic intermediate dihydroxyacetone phosphate (DHAP). A fatty acyl CoA reacts with C 1 of DHAP, forming an ester Fatty acyl is exchanged for a fatty alcohol; the ether linkage is formed Then the keto group of C 2 of the DHAP moiety is reduced and esterified to a FA and addition of the head group proceeds Ether Glycerolipids Formation of a double bond between Cs 1 and 2 of the alkyl group produces a plasmalogen Ethanolamine plasmalogen is found in myelin and choline plasmalogen in heart muscle Platelet-activating factor (PAF) is similar to choline plasmalogen PAF is released from phagocytic blood cells in response to various stimuli: causes platelet aggregation, edema, and hypotension and it is involved in the allergic response Example: Sphingolipids Important in inter-cell communication AB blood groups Receptors for viruses Ceramide is central molecule Serine basis 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 Ceramide reacts with phosphatidylcholine to form sphingomyelin (a component of the myelin sheath) & with UDP-sugars to form cerebrosides Fig. 32