Download Biochemistry Ch 33 597-624 [4-20

Biochemistry Ch 33 597-624
Synthesis of Fatty Acids
-Structure of glycerophospholipid: head group + 2 fatty acid + glycerol; choline commonest head
-Structure of plasmalogen: head group + fatty acid + long chain fatty alcohol + glycerol
-Structure of sphingomyelin: sphingosine backbone + 1 fatty acid + choline (ceramide = sphingolipid
with fatty acid joined to its amino group by amide linkage)
-Structure of Glycolipid – sphingosine backbone + fatty acid + carbohydrate
Fatty Acid (FA) Synthesis – FA are synthesized whenever there are excess calories, and major source of
carbon for synthesis is dietary carbohydrate or protein (converted to Acetyl-CoA or TCA intermediates)
-FA synthesis occurs in the liver, but it can occur in adipose tissue
-when excess of carbs are consumed, glucose converted to Ac-CoA  2 carbon subunits that condense
in a series of reactions on a fatty acid synthase complex to produce  palmitate
Conversion of Glucose to Cytosolic Acetyl CoA – pathway begins with glycolysis, converting glucose to
pyruvate in cytosol
-pyruvate enters mitochondria  Ac-CoA by pyruvate dehydrogenase and oxaloacetate by pyruvate
carboxylase.
-pathway that pyruvate follows is dictated by the acetyl CoA levels: when ACoA levels are high, pyruvate
dehydrogenase is inhibited and pyruvate carboxylase is stimulated
-oxaloacetate would increase due to pyruvate carboxylase activity, and oxaloacetate condenses with
acetyl-CoA to form citrate to reduce acetyl CoA levels, leading to activation of pyruvate dehydrogenase
-this cycle allows citrate to be synthesized and transported across inner mitochondrial membrane,
where it is cleaved by citrate lyase to REFORM acetyl-Coa and oxaloacetate
**-this is needed because acetyl- CoA cannot cross mitochondrial membrane on its own, and
this mechanism allows acetyl-CoA to reform in the cytoplasm
-the NADPH for FA Synthesis generated by the pentose phosphate pathway and from recycling of
oxaloacetate produced by citrate lyase; oxaloacetate  pyruvate by reduction to malate by NADdependent malate dehydrogenase and oxidation/decarboxylation of malate to pyruvate by NADPdependent malate dehydrogenase (malic enzyme)
-pyruvate that is formed by malic enzyme is reconverted back to citrate
-the NADPH that is generated by malic enzyme, along with NADPH generated glucose-6-phosohate and
gluconate-6-phosphate dehydrogenases in pentose phosphate pathway is used for reduction reactions
that occur on fatty acid synthase complex
-generation of cytosolic acetyl-CoA from pyruvate is stimulated by elevated insulin/glucagon ratio* after
carb meal; insulin activates pyruvate dehydrogenase by stimulating the phosphatase that
dephosphorylates the enzyme to an active form
-synthesis of malic enzyme, glucose-6-phosphate dehydrogenase, and citrate lyase is induced by high
insulin/glucagon ratio
-ability of citrate to accumulate and leave mitochondrial matrix for synthesis of fatty acids is attributable
to allosteric inhibition of isocitrate dehydrogenase by high energy levels within matrix
Conversion of Acetyl CoA to Malonyl CoA – cytosolic ACoA  malonyl-CoA, which is the immediate
donor of 2C units that are added to growing fatty acid chain on fatty acid synthase
-acetyl-CoA carboxylase adds a carboxyl group to acetyl CoA in a reaction requiring biotin and ATP
-**Acetyl-CoA carboxylase is the RATE-LIMITING STEP of fatty acid synthesis
-regulated by phosphorylation, allosteric modification, and induction/repression of synthesis
-citrate ACTIVATES ACoA carboxylase by polymerizing the 4 subunits of the enzyme
-Palmitoyl CoA, produced from palmitate (end product of fatty acid synthase) INHIBITS ACoA
carboxylase
-phosphorylation by AMP Kinase INHIBITS enzyme in fasting state
Fatty Acid Synthase Complex – sequentially adds 2 carbon units from malonyl CoA to growing fatty acyl
chain to form palmitate
-each addition of 2C unit, growing chain undergoes two reduction reactions requiring NADPH
-Fatty acid synthase is a large enzyme of 2 identical subunits; each has catalytic activities and an acyl
carrier protein (ACP)
-ACP contains phosphopantetheine derived from CoA
-initial step of fatty acid synthesis, an acetyl moiety is transferred from acetyl coA to ACP
phosphopantetheinyl group of one subunit and then to cysteinyl sulfhydryl group of other subunit
-malonyl CoA attaches to ACP phosphopantetheinyl sulfhydryl group, and the acetyl + malonyl moieties
condense and release a CO2, creating a 4 carbon β-ketoacyl chain attached to ACP
-3 reactions REDUCES 4C keto group to an alcohol, then removes H2O to form double bond, and then
reduction of double bond; NADPH provides reducing equivalents
-RESULT is that acetyl group is elongated by 2 carbons
-4C fatty acyl chain is transferred to cysteinyl sulfhydryl group and again condenses with a malonyl
group; this sequence is repeated until the chain is 16 CARBONS in length, at which point palmitate is
released; palmitate is elongated and desaturated to produce many other fatty acids
-in liver, palmitate and other FA are converted to triacylglycerols and packaged into VLDL
-in the liver, oxidation of new fatty acids back to acetyl CoA via β-oxidation is prevented by malonyl CoA
-**Malonyl-CoA INHIBITS carnitine: palmitoyl transferase I (the enzyme responsible for
transport of long-fatty acids into mitochondria**
-Malonyl CoA levels are elevated when acetyl CoA carboxylase is activated, and thus fatty acid
oxidation is inhibited while fatty acid synthesis is proceeding
Elongation of Fatty Acids – after synthesis, palmitate is activated to form palmitoyl-CoA and other long
chain fatty acids can be elongated 2 CARBONS AT A TIME by reactions in the ER
-Malonyl-CoA serves as 2C donor, and NADPH provides the reducing equivalents
-these reactions are similar to those of fatty acid synthesis except that the fatty acyl chain is attached to
a COENZYME A and not phosphopantetheinyl residue of ACP
-Major conversion is Palmitoyl CoA  Stearyl CoA
-very long chain fatty acids are also produced, particularly in the brain
Desaturation of Fatty Acids – involves O2, NADH, and cytochrome b5
-reaction occurs in ER and results in oxidation of fatty acid and NADH
-***most common desaturations involve placement of double bond between C9 and 10 in conversion of
palmitic acid to palmitoleic acid (16:1, Δ9) and conversion of stearic acid  oleic acid (18:1, Δ9)
-carbons 5 and 6 are also able to be desaturated
-polyunsaturated fatty acids w/ double bonds, 3C from methyl end (ω3 fatty acids) and 6C from the
methyl end (ω6 fatty acids) are required for eicosanoid synthesis
-humans cannot synthesize these; must be present in diet
-we obtain ω6 and ω3 from dietary plant oils from linoleic acid (ω6) and α-linoleic acid (ω3)
-these two acids are considered ESSENTIAL fatty acids for human diet
-linoleic acid converted  arachidonic acid used for prostaglandins and other eicosanoids
-Elongation of α-linoleic acid produces eicosapentaenoic acid more eicosanoids
-plants can synthesize these fatty acids; fish oils contain both ω3 and ω6 fatty acids, particularly EPA,
and docosahexaenoic acid
-arachidonic acid may be an essential fatty acid, though it is a ω6 fatty acid and can be synthesized from
linoleic acid
-linoleic acid is required for 2 reasons in diet:
1. precursor of arachidonic acid from which eicosanoids are produced
2. covalently binds another fatty acid attached to cerebrosides in skin, forming an unusual lipid
(acylglucosylceramide) that helps make skin impermeable to water and may help explain the
red, scaly dermatitis and other skin problems associated with dietary deficiency of essential
fatty acids
-*gene for glycerol kinase is on X chromosome close to DMD gene, codes for Dystrophin; and NROB1
gene, which codes for DAX1; DAX1 is important for development of adrenal gland, pituitary,
hypothalamus, and gonads
-complex glycerol kinase deficiency results from deletion of X chromosome which deletes
glycerol kinase gene WITH NROB1 and/or DMD; patient exhibits adrenal insufficiency,
hyperglycerolemia, or Duchenne muscular dystrophy
-*Abetalipoproteinemia – caused by lack of microsomal triglyceride transfer protein (MTP) results in the
inability to assemble both chylomicrons in the intestine and VLDL in the liver
Synthesis of Triacylglycerols and VLDL Particles – in liver and adipose, triacylglycerols are produced by a
pathway containing phosphatidic acid intermediate, which is also a precursor of glycerolipids in cell
membranes and blood lipoproteins
-sources of glycerol 3-phosphate, which provides the glycerol moiety for triacylglycerol synthesis is
DIFFERENT for liver and adipose
-in LIVER, glycerol-3-phosphate is produced from phosphorylation of glycerol by glycerol kinase
or from reduction of DHAP from glycolysis
-Adipose lacks glycerol kinase and can only produce glycerol 3-phosphate from DHAP; thus
adipose can store fatty acids only when glycolysis is activated in the fed state
-In both liver and adipose, triacylglycerols are produced in pathway where glycerol-3-phosphate reacts
with fatty acyl-CoA to form phosphatidic acid
-dephosphorylation of phosphatidic acid  diacylglycerol which reacts with ACoA  triacylglycerol
-triacylglycerol produced in smooth ER is packaged w/ cholesterol, phospholipids, and proteins  VLDL
-microsomal triglyceride transfer protein (MTP) is required for VLDL/chylomicron assembly
-**Major protein of VLDL is apoB-100 (one long apoB-100 wound through surface of VLDL)
-apoB-100 is encoded by same gene as apoB-48 of chylomicrons, but just shorter product due to
RNA editing
-VLDL is processed in golgi and secreted into blood by liver; the fatty acid residues of triacylglycerols are
ultimately stored in triacylglycerols of adipose cells
-VLDL molecules are denser than chylomicrons because they contain lower % of triglycerides
-VLDL first synthesized in nascent form, and then acquire apoproteins CII and E from HDL particles to
become mature VLDL particles
Fate of VLDL Triglyceride – Lipoprotein lipase (LPL), which is attached to basement membrane
proteoglycans of capillary endothelial cells, cleaves triacylglycerols in both VLDL and chylomicrons to
form fatty acids and glycerol
-aproprotein CII, obtained from HDL, activates LPL
-low Km of muscle LPL allows muscle to use fatty acids of VLDL/chylomicrons as fuel even when
blood concentration of these lipoproteins is low
-adipose LPL has high Km and is most active after a meal, when blood levels of lipoproteins high
-fate of VLDL after triglyceride removal is generation of intermediate-density lipoprotein (IDL),
which can further lose triglyceride to become LDL
-*Familial Combined Hyperlipidemia (FCH) – abnormalities in lipoprotein profiles and may involve
genetic increase in production of apoprotein B-100 to package more VLDL and increase blood VLDL
-depending on efficiency of lipolysis of VLDL by LPL, VLDL levels may be normal and LDL levels
may be elevated, or both may be elevated
-*In alcoholism, NADH levels in liver are elevated, which inhibit oxidation of fatty acids; fattey acids are
reesterified to glycerol 3-phosphate in liver  triacylglycerols  VLDL = increased VLDL in alcoholics
Storage of Triacylglycerols in Adipose Tissue – after meal, triacylglycerol stores of adipose increases;
adipose synthesize LPL and secrete it into capillaries of adipose tissue when insulin/glucagon is high
-enzyme digests triacylglycerols of both chylomicrons and VLDL
-fatty acids enter adipose cell and are activated  fatty acyl CoA, which reacts with glycerol 3phosphate to form triacylglycerol by the same pathway in the liver
-because adipose lacks glycerol kinase and cannot use glycerol produced by LPL, glycerol travels back to
liver, which it uses to synthesize more triacylglycerol; in adipose, glycerol-3-phosphate is from glucose
-in addition to stimulating synthesis and release of LPL, insulin stimulates glucose metabolism in adipose
and leads to activation of PFK-1 by activating kinase activity of PFK-2, which increased F-2,6-BP
-insulin also stimulates dephosphorylation of pyruvate dehydrogenase so that pyruvate
produced by glycolysis can be oxidized in TCA cycle
-lastly, insulin stimulates conversion of glucose  fatty acids in adipose, although liver is main site
-*fatty acids for VLDL synthesis may be obtained from blood or may be synthesized from glucose
-major source of fatty acid of VLDL triacylglycerol in healthy humans is EXCESS GLUCOSE
-in diabetes mellitus, fatty acids mobilized from adipose triacylglycerols in excess of oxidative
capacity of tissues are a major source of fatty acid reesterified in liver to VLDL triacylglycerols
-these people have elevated blood triacylglycerols
-*because fatty acids of adipose triacylglycerols are from both chylomicrons and VLDL, we produce our
major fat stores from both dietary fat (produces chylomicrons) and dietary sugar (produces VLDL)
Release of Fatty Acids From Adipose Tissue – during fasting, decrease of insulin and increase of
glucagon cause cAMP levels to rise in adipose cells, stimulating lipolysis
-protein kinase A phosphorylates hormone-sensitive lipase to produce a more active form of enzyme
-hormone-sensitive lipase, also known as triacylglycerol lipase, cleaves fatty acid from triacylglycerol
-then, other lipases complete lipolysis, and fatty acids/glycerol are released into blood
-fatty acids travel in blood complexed to albumin, enter cells of muscle and other tissues and are
oxidized to CO2 and H2O to produce energy
-during prolonged fasting, ACoA produced by ß-oxidation of fatty acids in liver is converted to ketone
bodies and are released into the blood
-glycerol from lipolysis is used for gluconeogenesis in liver during fasting as a source of carbon
Regulation of Fatty Acid Release by Glyceroneogenesis – fatty acids in adipocyte are also used to
resynthesize triacylglyceride as a mechanism to limit fatty acid release into circulation
-resynthesis of triglycerides depends on adequate supply of glycerol-3-phosphate, which is dependent
on adipose glyceroneogenesis (synthesis of new glycerol)
-in adipocyte, hormone-sensitive lipase initiates conversion of triglyceride  glycerol and 3 fatty acids
-glycerol is sent to liver, but within adipocyte, glycerol-3-phosphate is synthesized from carbons of AA,
lactate, or pyruvate by phosphoenolpyrucate carboxykinase (PEPCK), which is induced by cAMP levels
-elevated cAMP occur in response to glucagon or epinephrine, two signals that indicate that adipocyte
should release FA into circulation; pyruvate formed in adipocyte from lactate is converted to
oxaloacetate by pyruvate carboxylase
-oxaloacetate is converted to phosphoenolpyruvate (PEP) by PEPCK, and the PEP follows
gluconeogenesis to DHAP, which is then reduced to glycerol-3-phosphate
-glycerol-3-phosphate is used to reesterify free FA before they leave adipocyte, to modulate free
FA release by the fat cells
Metabolism of Glycerophospholipids and Sphingolipids – fatty acids from diet or glucose are precursors
of glycerophospholipids and sphingolipids, major components of the cell membrane
-glycerophospholipids also components of blood lipoproteins, bile, and lung surfactant
-they are also the source of polyunsaturated fatty acids (arachidonic acid  eicosanoids)
-have glycerol as their backbone
-ether glycerophospholipids differ from other glycerophospholipids in that the alkyl or alkenyl
chain is joined to C1 of glycerol by an ether rather than an ester
-Ether lipids: plasmalogens and platelet activating factor (PAF)
-sphingolipids are important in signal transduction and forming myelin sheath around nerves
-sphingosine provides backbone for sphingolipids, DERIVED FROM SERINE
Synthesis of Phospholipids Containing Glycerol
Glycerophospholipids – initial steps are similar to triacylglycerol synthesis: Glycerol-3-phopshate + 2
fatty acids  phosphatidic acid, and two mechanisms are used to add head group to molecule
-A head group is a chemical group like choline or serine attached to carbon 3 of glycerol that contains
hydrophobic groups (fatty acids) at positions 1 and 2; head groups are hydrophilic
-all head groups contain free OH group used to link phosphate on carbon 3 of glycerol backbone
1. Mechanism 1 of Head Attachment – phosphatidic acid is cleaved by phosphatase to form
diacylglycerol (DAG), which then reacts with activated head group
a. In synthesis of phosphatidylcholine, a choline is activated by combining with CTP to
form CDP-choline; phosphocholine is transferred to C3 of DAG, and cytidine
monophosphate (CMP) is released
b. Phosphatidylethanolamine is produced by similar reaction with CDP-ethanolamine
c. Interconversions occur between phospholipids
i. Phosphotidylserine produced by reaction with ethanolamine from
phosphatidylethanolamine in exchange for serine, and can be reconverted back
ii. Phosphtidylcholine can also be made by methylation of
phosphatidylethanolamine
-phosphatidylcholine (lecithin) is not required in diet because it can be synthesized by the body;
deficiencies in phosphatidylcholine is only observed in patients with total parenteral nutrition (TPN)
where patient is supported only by intravenous feeding; causing fatty livers due to decreased ability to
synthesize phospholipids for VLDLs
2. Mechanism 2 of Head Attachment – phosphatidic acid reacts with CTP to form CDP-DAG, which can
react with phosphatidylglycerol to produce cardiolipin or with inositol  phosphatidylinositol
a. Cardiolipin is component of inner mitochondrial membrane
b. Phosphatidylinositol can be phosphorylated to PIP2, a hormone component of
membranes
Ether Glycerolipids – synthesized from glycolytic intermediate DHAP; a fatty acyl-CoA reacts with C1 of
DHAP to form an ester; this fatty acyl group is exchanged for fatty alcohol, produced by reduction of a
fatty acid; an ether linkage is formed
-keto group of C2 of DHAP is reduced and esterified to fatty acid; and addition of head group proceeds
in same format as before
-formation of double bond between C1 and 2 of alkyl group produces a plasmalogen
-ethanolamine plasmalogen is found in myelin and choline plasmalogen in heart
-PAF is similar to choline plasmalogen except that acetyl group replaces fatty acyl group at C2 of
glycerol moiety
-PAD is released from phagocytic blood cells in response to stimuli to cause platelet
aggregation, edema, hypotension, and ellergic repsons
-plasmalogen synthesis occurs in PEROXISOMES, and in people with Zelleger Syndrome (defect in
peroxisome biogenesis), plasmalogen synthesis is compromised  can lead to death
Respiratory Distress Syndrome (RDS) – related to deficiency of substance known as lung surfactant;
-major constituents of surfactant are **dipalmitoylphosphatidylcholine**, phosphatidylglycerol,
apoproteins (Surfactant proteins SPA, SPB, and SPC), and cholesterol
-these components contribute to reduction in surface tension within alveoli of the lung to prevent their
collapse; premature infant has NOT begun to produce adequate amounts of surfactant
-without surfactant, lung collapses and 10x normal pressure is needed for reinflation
Degradation of Glycerophospholipids – phospholipases in cell membranes or lysosomes degrade
glycerophospholipids
-phospholipase A1 removes fatty acyl group of C1 of glycerol
-phospholipase A2 removes fatty acyl group of C2
-C2 is USUALLY an unsaturated fatty acid (frequently arachidonic acid)
-removed for synthesis of eicosanoids
-PLA2 provides major repair mechanism for membrane lipids damaged by oxidative free
radicals
-arachidonic acid can be peroxidatively cleaved in free radical reactions to
malondialdehyde, recognized by PLA2, which removes abnormality from membrane
-phospholipase C – bond joining carbon 3 of glycerol is cleaved by PLC, which is activated by
hormonal stimuli to hydrolyze PIP2 to produce DAG and IP3
-phospholipase D – cleaves bond between phosphate and head group to produce phosphatidic
acid and free OH of head group
Sphingolipids – serve in intercellular communication and as antigenic determinants of ABO blood group
-some are used as receptors by viruses and bacterial toxins
-synthesis of sphingolipids begins with formation of ceramide from condensation of serine + palmitoylCoA; very-long chain fatty acid (22C) forms an amide with amino group to form double bond = ceramide
-ceramide reacts with phosphatidylcholine  sphingomyelin, a component of myelin sheath
-ceramide also reacts with UDP-sugars to form cerebrosides, which contain 1 monosaccharide, usually
galactose or glucose
-galactocerebroside can react with PAPS to form sulfatides, major sulfolipids in the brain
-additional sugars may be added to ceramide to form globosides and gangliosides (addition of
N-acetylneuraminic acid)
-sphingolipids are degraded by lyosomal enzymes (deficiencies cause sphingolipidoses)
Adipocyte as an Endocrine Organ – adipose does more than store triglyceride, it is an endocrine organ
that secretes factors to regulate both glucose and fat metabolism: leptin + adiponectin
Leptin – leptin binds receptor linked to JAK, so leptin’s signal is transmitted by STAT factors
-leptin is released by adipocytes as their triglyceride levels increase, and binds to receptors in
hypothalamus, which leads to release of neuropeptides to signal cessation of eating
-giving leptin to leptin-deficient patients will result in weight loss
-giving leptin to OBESE patients DOES NOT TO ANYTHING
-believed to be a result of leptin resistance due to constant stimulation of leptin
receptors in obese individuals, leading to desensitization
-another possibility is that leptin-induced synthesis of factors that block leptin-induced
signal transduction
-leptin induces synthesis of SOCS3, a factor that antagonizes STAT activation; long term leptin
stimulation may lead to constant expression of SOCS3, resulting in diminished cellular response to leptin
Adiponectin – most abundant hormone secreted by adipocyte; and is secreted as adipocyte gets larger
-reduced secretion of adiponectin may be linked to development of insulin resistance in obesity
-adiponectin will bind either of two receptors (AdipoR1 and AdipoR2), which initiate cascade resulting in
activation of AMP-activated protein kinase (AMPK) and activation of nuclear transcription factor PPAR-a
-in muscle, AMPK leads to enhanced fatty acid oxidation and glucose uptake
-in liver, activation of AMPK also leads to enhanced fatty acid oxidation
-AMPK activation in liver and muscle leads to reduction of blood glucose and free fatty acids
-as adipocytes increase in size, less adiponectin is released, and as obesity occurs, it is more difficult for
circulating fatty acids and glucose to be used by tissues; and so elevated glucose and fat are seen in
circulation of obese patients
-activation of PPAR-a leads to enhanced fatty acid oxidation by liver and muscle
-PPAR-a is target of fibrate group of lipid-lowering drugs, and activation leads to increased
transcription of genes involved in FA transport, energy uncoupling, and FA oxidation
-Thiazolidinedione antidiabetic drugs such as pioglitazone is used to control type II diabetes by binding
and activating PPAR-G in adipose and leads to increased adiponectin synthesis and release, aiding in
reducing circulating fat and glucose levels
Metabolic Syndrome – in obesity, adipocyte function is altered
-adiponectin lvls fall and reduced fatty acid oxidation occurs; release of free fatty acids is also increased
in large adipocytes because of high concentration of triglycerides
-this is coupled to perilipins in obese people
-perilipins are adipocyte phosphoproteins that bind to triacylglycerol droplets and regulate
accessibility of triglyceride to lipases
-decrease in perilipin synthesis leads to ENHANCED BASAL RATE OF LIPASES
-weight reduction results in decrease size of fat cells rather than decrease in number; after weight loss,
amount of LPL (an enzyme involved in transfer of fatty acid from blood triacylglycerols to the
triacylglycerol stores of adipocytes) increases
-mRNA for LPL also increases
-this all suggests that individuals who become obese early in life will have difficulty losing weight
and maintaining lower body adipose mass
-obesity and overeating are associated with damage to ventromedial or paraventricular nucleus
-anorexia is related to damage to lateral hypothalamus
-increased levels of nonesterified fatty acids (NEFAs, or free fatty acids) are seen in obesity and
associated with insulin resistance
-insulin resistance is a hallmark of type II diabetes
-as NEFA levels in circulation rise, muscle begins to use NEFA as energy source, which reduces
muscle glucose metabolism. This results in buildup of ACoA in mitochondria, export of citrate to
cytoplasm, and inhibition of PFK-1
-because glucose is not being metabolized, its uptake by muscle is reduced, which results in a
sign of insulin resistence
Metabolic Syndrome – OBESITY + INSULIN RESISTANCE + ALTERED BLOOD LIPID LEVELS
-diagnosis based on recommendations of some people who have power
-at least 3 criteria need to be met:
-increased waist circumference
-elevated triglycerides
-reduced HDL
-elevated blood pressure
-elevated fasting glucose
-people with metabolic syndrome are at risk for type II diabetes and cardiovascular disease
-characteristic of metabolic syndrome is insulin resistance, part of which is caused by altered insulin
release from B cells of pancreas under hyperlipidemic conditions
-glucose metabolized in pancreatic B cell to generate ATP, closing ATP K channels leading to
depolarization and activating voltage gated Ca channels to cause exocytosis of insulin
-islet cells express pyruvate carboxylase, but low levels of PEPCK
-NADPH is generated in cytosol of islets by malic enzyme and cytosolic isozyme of isocitrate
dehydrogenase, which uses NADP+ instead of NAD+
-some other crap blah blah blah
-When B cells are exposed to NEFA high levels, B- cell begins to oxidize fatty acids, which raises acetyl
CoA levels in B-cell mitochondria, leading to activation of pyruvate carboxylase and enhanced pyruvate
cycling, with significant increases in resting NADPH levels; this leads to blunted increases in NADPH
levels when glucose levels increase since pyruvate cycling is already high due to activation of pyruvate
carboxylase; thus, B cell releases less insulin in response to high blood glucose levels and contributes to
hyperglycemia