Biochemistry Ch 36 678-692
Integration of Carbohydrate and Lipid Metabolism
Regulation of Carbohydrate and Lipid Metabolism
Mechanisms that Affect Glycogen and Triacylglycerol Synthesis in Liver – liver synthesizes
glycogen + triacylglycerol after meal, raising stored glycogen from 80g  300g
-liver synthesizes triacylglycerol and packages it into VLDL  secretes into blood and stored as
adipose triacylglycerols (adipose has unlimited potential to store fat)
1. Glucokinase – after a meal, glucose converted to glycogen/triacylglycerol in liver; but it is first
converted to G6P by glucokinase, a liver enzyme with a high Km for glucose
-the low affinity for glucose of glucokinase makes it most active during FED state, when
concentration of glucose is high through hepatic portal vein
-synthesis of glucokinase is induced by insulin and repressed by glucagon; set up so that
liver can only metabolize glucose when sugar levels are high
2. Glycogen Synthase – key regulatory enzyme in conversion of G6P to glycogen; enzyme is
activated by dephosphorylation when insulin/glucose is elevated and glucagon is decreased
3. Phosphofructokinase-1 and Pyruvate Kinase – for lipogenesis, G6P is converted through
glycolysis to pyruvate, with key enzymes being PFK-1 and pyruvate kinase
-PFK-1 activated in fed state by F-2,6-BP and AMP
-PFK-2 produces the activator F-2,6-BP is dephosphorylated/active after a meal
-pyruvate kinase is activated by dephosphorylation stimulated by insulin
4. Pyruvate Dehydrogenase and Pyruvate Carboxylase – conversion of pyruvate to fatty acids
requires source of acetyl-CoA in cytosol, but pyruvate can only be converted to Ac-CoA in
mitochondria, so it enters the mitochondria and forms acetyl CoA through pyruvate
dehydrogenase (PDH) reaction
-PDH is dephosphorylated and most active when supply of substrates and ADP is high,
its products are used, and insulin is present
-pyruvate is also converted to oxaloacetate by pyruvate carboxylase, activated by Ac-CoA
-Ac-CoA cannot cross mit membrane, so it condenses with oxaloacetate to form citrate, which if
not used by TCA, crosses back to cytosol
-as fatty acids are produced under high energy, a high NADH/NAD ratio in mitochondria inhibits
isocitrate dehydrogenase, which leads to citrate accumulation in mitochondrial matrix, which is
transported out into cytosol
5. Citrate Lyase, Malic Enzyme, and G6P Dehydrogenase – in cytosol, citrate cleaved by citrate
lyase to form oxaloacetate and acetyl-CoA (used for fatty acid/cholesterol synthesis and
activated by insulin)
-oxaloacetate is recycled to pyruvate via cytosolic malate dehydrogenase and malic enzyme,
which is inducible
-malic enzyme generates NADPH for reactions of fatty acid synthase complex; NADPH is
also produced by 2 enzymes of pentose phosphate pathway
6. Acetyl-CoA carboxylase – acetyl coA converted to malonyl coA to provide 2 carbon unit for
elongation of fatty acyl chain on fatty acid synthase complex
-acetyl-CoA carboxylase catalyzes conversion from Ac-CoA  malonyl coA controlled by
3 major mechanisms that regulate enzyme activity
-activated by citrate, causing enzyme to polymerize, inhibited by long-chain
acyl-CoA; phosphatase stimulated by insulin activates enzyme by
dephosphorylation, and is activated by induction; in fed state, amount of
enzyme increases
-malonyl-CoA, the product of acetyl-CoA carboxylase reaction, provides carbons for
synthesis of palmitate on fatty acid synthase, and malonyl coA INHIBITS carnitine
palmitoyl transferase I (CPTI), the enzyme that prepares long-chain fatty acids for
transport into mitochondria
-in fed state, when acetyl-CoA carboxylase is active and malonyl CoA levels are
elevated, new fatty acids are converted to triacylglycerols for storage rather
than being transported across mitochondria for oxidation
7. Fatty Acid Synthase Complex – in well fed person, fatty acid synthase is increased – genes
induced by insulin/glucagon ratio
-G6P dehydrogenase which generates NADPH in pentose phosphate pathway and malic enzyme
producing NADPH both induced by increased insulin
-palmitate produced by synthase complex is converted to palmitoyl coA and elongated and
desaturated to form other fatty acyl-coA molecules, which are converted to triacylglycerols
which are packaged and secreted into the blood as VLDL
Mechanisms that Affect the Fate of Chylomicrons and VLDL – VLDL/chylomicrons are
hydrolyzed to fatty acids and glycerol by lipoprotein lipase (LPL), an enzyme attached to
endothelial cells and capillaries in muscle/adipose
-muscle LPL has a low Km for lipoproteins, so it is active at low concentrations; in adipose,
higher Km makes it active only after a meal
Mechanisms that Affect Triacylglycerol Storage in Adipose Tissue – insulin stimulates adipose
to synthesize and secrete LPL to hydrolyze chylomicrons and LPL;
-ApoCII, given to VLDL and chylomicrons by HDL, activates LPL. Fatty acids released by LPL are
stored as triacylglycerols in adipose cells
-glycerol released can be used by liver cells (contain glycerol kinase), but not adipose
-insulin causes glucose transporters in adipose to increase and allow glucose to enter adipocytes
and be oxidized to produce energy and glycerol-3-phosphate for triacylglycerol synthesis
**Regulation of Carbohydrate and Lipid Metabolism during Fasting
Mechanisms in Liver that Serve to Maintain Blood Glucose Levels – during fasting,
insulin/glucagon ratio decreases; liver glycogen is degraded to produce blood glucose because
enzymes of glycogen degradation are activated by cAMP-directed phosphorylation
-glucagon  adenylate cyclase  cAMP  protein kinase A  phosphorylates phosphorylase
kinase to phosphorylate glycogen phosporylase
-protein kinase A also inactivates glycogen synthase
-gluconeogenesis stimulated because the synthesis of PEP carboxykinase, F-1,6-BP, and G6P is
induced and because there is increased availability of precursors
-F-1,6-BPtase is also activated because levels of its inhibitor, F-2,6-BP is low
-transcription factors like CREB are involved in enzyme synthesis – it is phosphorylated and
activated by protein kinase, which is itself activated on glucagon or epinephrine stimulation
Mechanisms that Affect Lipolysis in Adipose Tissue – during fasting, blood insulin falls and
glucagon rises, and cAMP rises. Protein kinase A is activated and phosphorylates hormonesensitive lipase to activate it and cleave fatty acids from triacylglycerols
-epinephrine, ACTH, growth hormone also activate this hormone
-glyceroneogenesis and resynthesis of triglyceride in adipocyte regulates release of fatty acids
during fating. (insulin INHIBITS hormone-sensitive lipase)
Mechanisms that Affect Ketone Body Production by the Liver – as fatty acids are released from
adipose during fasting, they are oxidized, especially by muscle
-in liver, fatty acids transported to mitochondria because acetyl-coA carboxylase is inactive,
malonyl-coA levels are low, and CPTI is active
-acetyl-CoA, produced by B-oxidation, is converted to ketone bodies which are used as energy
sources in many tissues to spare use of glucose and necessity of degrading muscle protein
-high levels of acetyl-coA in liver inhibit pyruvate dehydrogenase to prevent pyruvate conversion
to acetyl coA and activate pyruvate carboxylase which produces oxaloacetate for
gluconeogenesis
-under these conditions, oxaloacetate + Ac-CoA does NOT form citrate because energy
levels in mitochondria are high (high levels of NADH and ATP to inhibit isocitrate
dehydrogenase) citrate accumulates and inhibits citrate synthase from producing more
citrate
-also, citrate synthesis is depressed because high NADH/NAD ratio diverts
oxaloacetate to malate, so malate can exit mitochondria for gluconeogenesis
Regulation of Use of Glucose and Fatty Acids by Muscle – during exercise, muscle first uses
glycogen stored in muscle cells; as exercise increases, glucose is taken up from blood and is
oxidized
-liver glycogenolysis and gluconeogenesis replenishes blood glucose supply; because insulin
levels drop, concentration of GLUT4 receptors on membrane is reduced to reduce glucose entry
from circulation into muscle
-as fatty acids become available because of lipolysis of adipose triacylglycerols, the exercising
muscle begins to oxidize fatty acids to produce NADH and acetyl-CoA to slow flow of carbon
from glucose through reaction catalyzed by pyruvate dehydrogenase
-oxidation of fatty acids provides major portion of increased demand for ATP generation and
spares blood glucose
Importance of AMP and Fructose-2,6-Bisphosphate – AMP and F-2,6-BP regulate switch
between catabolic and anabolic pathways, particularly in liver
-cell using ATP accumulates AMP more than ADP because of adenylate kinase which catalyzes
the reaction of 2 ADP  1 ATP + 1 AMP
-AMP signals that more energy is required on allosteric enzyme sites; as AMP drops, ATP rises
and anabolic pathways are activated
-F-2,6-BP regulates glycolysis and gluconeogenesis in liver. Under high blood glucose and
insulin, F-2,6-BP are high because PFK-2 is in an activate state to activate PFK-1 and inhibit
fructose-1,6-bisphosphatase to allow glycolysis to proceed
-when blood glucose is low, glucagon is released, PFK-2 is phosphorylated by cAMP-dependent
protein kinase and is inhibited to lower F-2,6-BP and inhibit glycolysis/stimulate gluconeogenesis