biochem exam 4 Flashcards
where do LCFAs come from?
released from adipocytes then taken up and converted to acetyl CoA and make NADH and FADH2
how are LCFAs transported?
because they are insoluble, they must be bound to fatty acid binding proteins for transport
what is the significance of serum albumin?
it transports LCFA and can bind up to 6 FA chains
has non-specific binding capacity for several hormones and drugs
how can fatty acids enter cells?
via saturable binding and free diffusion
saturable binding means that a binding protein or receptor can only bind a limited amount of ligand or substrate until all available binding sites are occupied
what happens once the fatty acids have entered the cells?
they are bound to fatty-acid binding proteins that facilitates their transport to the mitochondria, ER, and or peroxisomes
explain fatty acid activation
FA must be activated to ACYL-CoA DERIVATIVES which is facilitated by acyl-CoA synthetase
FA attacks a phosphate from ATP making fatty acyl AMP (via fatty acyl CoA synthetase) and pyrophosphate (hydrolysis of pyrophosphate is favorable which drives this reaction forward) –> CoASH binds to the fatty acid, releasing the bound AMP via another fatty acyl CoA synthetase –> makes a FATTY ACYL CoA molecule
because AMP is generated, reaction uses equivalent of 2 ATP
what is significant about fatty acyl-coA synthetase?
there are at least 4 isoforms that have different affinities for FA of different chain lengths, located in different membranes in cell
VLC, LC, MC, SC
what are the fates of activated fatty acyl-CoA?
it can be converted into ENERGY (via beta-oxidation and ketogenesis), STORAGE (TG), and MEMBRANE LIPIDS (phospholipids and sphingolipids)
where are the locations of the acyl-CoA synthetase when converting fatty acyl-CoA into energy?
mainly in the mitochondria and peroxisomes
- PEROXISOMAL and ER acyl-CoA synthetase recognizes VLCFA
- MITOCHONDRIAL as well as ER acyl-CoA synthetases in all tissues recognize LCFA (located on the outer membrane)
- MCFA acyl-CoA synthase is found in the MITOCHONDRIAL MATRIX of many cell types
- ACETYL-CoA synthetase for SCFA is found in the CYTOSOL of many cell types
explain transport of FA into the mitochondria
acyl-CoA synthetase will activate FA using CoA and ATP, releasing AMP and PPi –> fatty acyl-CoA is transported from the cytosol into the outer mitochondrial membrane –> carnitine:palmitoyl-transferase I (CPTI) cleaves CoA off and binds a carnitine making FATTY ACYLCARNITINE –> fatty acylcarnitine can cross the inner mitochondrial membrane into the matrix via carnitine:acylcarnitine translocase (secondary active transport, antiport; RATE LIMITING STEP) –> CPTII cleaves off the carnitine (transported back to the intermembrane space by carnitine:acylcarnitine translocase for use by CPTI) and rebinds the CoA making fatty acyl-CoA that can now undergo beta-oxidation
where is carnitine found?
in many dietary sources like RED MEAT and can be synthesized from LYSINE by the body
deficiencies are RARE
what happens when there’s genetic defects in CPTI and CPTII?
impairs transporter that facilitates entry of carnitine into muscle cells = PRIMARY CARINITINE DEFICIENCY will cripple FA metabolism
defect in CPTI will cause build up of fatty acyl-CoA in the cytosol and intermembrane space, unable to bind carnitine and convert it to fatty acylcarnitine (build up of fatty acy-CoA may stimulate lipogenesis and can lead to fatty liver disease)
defect in CPTII will cause build up of fatty acylcarnitine in the matrix, unable to cleave carnitine and make fatty acyl-CoA for beta-oxidation, also decreases the amount of carnitine to be used by CPTI (can lead to hypoglycemia)
what are the consequences of L-carnitine and choline?
comes from RED MEAT and can be metabolized by gut microbes to make trmethylamine (TMA) which can be inhibited by antibiotics and allicin (from garlic)
if not inhibited, it will eventually lead to decreases reverse cholesterol transport (RCT) = develop hypercholesterolemia and decrease bile acid synthesis (more cholesterol build up in the body since bile acid is the body’s main source of ridding itself of cholesterol) –> increases risks of atherosclerosis
what is the beta-oxidation spiral?
beta-carbon is oxidized to a carbonyl after the alpha-beta bond is cleaved, producing acetyl CoA
process occurs many times to produce many acetyl-CoA from even-chain-length FA
ex: palmitoyl CoA (16C) makes 8 acetyl CoA
describe the process of beta-oxidation spiral
- fatty acyl CoA undergoes OXIDATION via acyl-CoA DH, making FADH2 (transfers e- to ETC without dissociating from acyl-CoA DH)
- fatty acyl CoA now has a double bond between the alpha and beta carbons = fatty enoyl CoA which undergoes HYDRATION via enoyl CoA hydratase
- beta-hydroxy acyl CoA is formed and undergoes OXIDATION via beta-hydroxy acyl-CoA DH using NAD+ and making NADH (enters ETC)
- beta-keto acyl-CoA is formed and undergoes THIOLYSIS via beta-keto thiolase, using CoASH to make fatty acyl-CoA (can re-enter beta-oxidation) and acetyl CoA (enters TCA or used for synthesis of KB)
what is special about acyl-CoA DH?
there are 4 isozymes of acyl-CoA DH, each with a different substrate specificity
- VLCAD
- LCAD
- MCAD
- SCAD
what is the last step of the beta-oxidation spiral?
the beta-keto fatty acyl-CoA = acetoacetyl-CoA which is important in CATABOLISM of some amino acids and in the SYNTHESIS of KB and CHOLESTEROL
acetoacetyl-CoA can be converted to acetyl CoA, but if the acetyl CoA concentrations are high, the reaction can be reversed by THIOLASE to make acetoacetyl-CoA which can be converted into acetoacetate (KB) –> can be used in fasting and starved state by muscles and brain
what is significant about odd-chain-length FAs?
undergoes multiple rounds of beta-oxidation, resulting in the formation many molecules of acetyl-CoA and one molecule of PROPIONYL-CoA
why is propionyl CoA important? explain this process
propionyl CoA can be converted into succinyl CoA which can enter the TCA cycle (anaplerotic process)
propionyl CoA is converted to D-methylmalonyl Coa via PROPIONYL CoA CARBOXYLASE (uses biotin as a cofactor to transfer CO2 of HCO3- as carboxylate group)
D-methylmalonyl CoA is epimerized via methylmalonyl Coa to L-methylmalonyl CoA
L-methylmalonyl CoA is converted to succinyl CoA via methylmalonyl CoA MUTASE (uses B12 to facilitate radical rearrangement, this enzyme is one of two B12 dependence enzymes in body)
explain unsaturated FAs
beta-oxidation of unsaturated FAs requires assistance of two enzymes = enoyl CoA isomerase and 2,4-dienoyl CoA reductase (also uses NADPH)
basically requires more enzymes for beta-oxidation
most dietary fatty acids are…
long chain
as are the FAs synthesized from excess fuel by the liver and stored in adipocytes
what are other types of dietary fatty acids?
some fatty acids synthesized in EXTRAHEPATIC TISSUES are VLC, MC, or SC and DO NOT FOLLOW STANDARD PATHWAY FOR DEGRADATION/BETA OXIDATION
explain oxidation of SCFAs
they are more WATER SOLUBLE than LCFAs so they are not stored in the adipose tissue but are rather transported directly to the liver (recall that they can enter directly into circulation) or other organs for oxidation
SCFAs are produced primarily by fermentation of DIETARY FIBER by gut microbes (acetate, propionate, butyrate)
- provide health benefits by stimulation immune system and improving metabolic health (anti-diabetes, anti-obesity)
- also primary fuel source for COLONOCYTES (also decreases local inflammation) and can be oxidized by the liver)
SCFAs DO NOT RELY ON CARNITINE TRANSPORT
explain oxidation of MCFAs
also water soluble
MCFA enter the mitochondria via MONOCARBOXYLASE TRANSPORTER then are activated by fatty acyl-CoAs and undergo beta-oxidation (dairy and coconut and palm oils are rich in MCFAs)
acyl-CoA synthetase (in mitochondrial matrix) that recognize MCFAs also recognize other compounds (including several pharmaceutical drugs) that contain CARBOXYL GROUPS –> synthetase forms CoA thioesters, CoA esters converted to acylglycines and excreted
carboxyl –> thioester (via MC acyl-CoA synthetase using CoASH and ATP, releasing AMP and PPi) –> acylglycine (via glycine N-acyltransferase, using glycine and releasing CoASH)
ALTERNATIVE ROUTE IF CPTII IS IMPAIRED
What happens when there’s a disorder in beta-oxidation?
can cause accumulation of acylcarinitines and acylglycines (from MCFAs) in the serum or urine
acylglycine produced by glycine N-acyltransferase
acylcarnitine produced by reverse of CPTII
both reactions are reversible
disorders that cause an increase in mitochondrial [fatty acyl-CoA] will drive formation of fatty acylcarnitines and acylglycines, freeing CoASH for other uses in the cell (primarily TCA where it can be used to make succinyl CoA)
what other organelles can fatty acids be oxidized in?
unusual fatty acids and hydrophobic xenophobics (containing carboxyl groups) are metabolized in cellular PEROXISOMES or in the ER
what kind of fatty acid oxidation do peroxisomes catalyze?
peroxisomes catalyze alpha and beta oxidation
they contain acyl-CoA synthetase that recognizes VLCFA, LCFA, and PHYTANIC ACIDS
fatty acids can be oxidized or used in the synthesis of plasmalogens (class of glycerophospholipids that are important for maintaining cell function and protecting against oxidative damage)
what kind of fatty acid oxidation does the ER catalyze?
ER contains enzymes that catalyze omega-oxidation
they contain acyl-CoA synthetase that recognizes LCFA (which undergo omega-oxidation) or are used in the synthesis of membrane phospholipids or TG
method is used when there are disorders in beta-oxidation
what is the order of substances in the cholesterol synthesis pathway?
acetyl CoA –> acetoacetyl CoA –> HMG CoA –> mevalonate –> activated isoprenes (isopentyl PP and dimethylallyl PP) –> squalene (geranyl PP and farnesyl PP) –> lanosterol –> cholesterol
how does peroxisomal beta-oxidation differ from mitochondrial?
- carnitine is not needed for transport across the membrane
- the electron acceptor for the first step is MOLECULAR OXYGEN
- it is regulated only by SUBSTRATE AVAILABILITY
HOWEVER, acetyl CoA, SCFA CoA, and MCFA CoA are all converted to carnitine derivatives before moving into the mitochondria for completion of oxidation (SCFA CoA and MFCA CoA transferred via COT - octanoyltransferase to SCFA-carnitine and MCFA-carnitine, acetyl CoA transferred via CAT - carnitine acetyltransferase to acetyl-carnitine)
what catalyzes the first step in peroxisomal beta oxidation?
FAD-containing oxidase (gives its 2 H2 from FADH2 to O2) that transfers electrons to O2 and forms H2O2
The VLCFA CoA is transported into the peroxisome; it produces H2O2 (via the process above), NADH (which goes to the malate-aspartate shuttle), acetyl CoA, SFCA CoA, and MCFA CoA
explain the methods of regulation of beta oxidation
- FA are released from adipocytes in response to hormones (glucagon, epinephrine, adrenocorticotropic) that signal fasting or increased demand (like exercising or under stress)
- CPT I is INHIBITED BY MALONYL CoA (synthesized from acetyl CoA via acetyl-CoA carboxylase - ACCase –> inhibited by phosphorylation by AMP-dependent protein kinase in muscles and cells, activated by insulin), ACCase catalyzes the first step in FATTY ACID SYNTHESIS, inhibition of CPTI by malonyl Coa prevents simultaneous synthesis and degradation of FA
- when ATP/ADP is HIGH, NADH/NAD+ and FADH2/FAD also HIGH –> disfavor oxidative processes like beta-oxidation (because you already have a lot of energy, don’t want to make more)
why is peroxisomal alpha oxidation used?
it is important for the metabolism of PHYTANIC ACID (degradation product of chlorophyll found in TISSUES of herbivores and dairy products)
beta-oxidation of phytanic acids are NOT POSSIBLE because the presence of a methyl group of the beta carbon, sterically hindering it
it stops the beta-oxidation at beta-hydroxy DH
explain how peroxisomal alpha oxidation occurs?
phytanic acid hydroxylase introduces hydroxyl group on the alpha carbon (with no methyl group) –> then oxidizes the hydroxyl to a ketone and the bond between the two carbonyl carbons is broken
product = PRISTANIC ACID, which can now undergo beta oxidation –> producing many molecules of acetyl CoA, propionyl CoA, and isobutyryl CoA
why is omega-oxidation important?
process occurs in the ER and is only a minor physiological relevance
it is important when DISORDERS OF BETA OXIDATION are present, causing intracellular levels of fatty acids to increase
what are ketone bodies synthesized from?
acetyl CoA in the liver during fasting and starved state
fast progresses –> amount of free fatty acids in serum increases because of increased lipolysis, liver converts some of these FA to KB
after a few days, muscle stops using KB, increasing their concentration, high enough for the brain to use
what occurs in omega-oxidation?
free fatty acids in the ER are oxidized at the methyl end, producing a DICARBOXYLIC ACID which can be further metabolized by beta-oxidation in the MITOCHONDRIA
medium-chain water-soluble dicarboxylic acids may be ELIMINATED, eventually showing up in urine (if this shows up in urine, it indicates that there’s too much FA or beta-oxidation is impaired)
what is acetyl CoA converted to for metabolism KB?
acetoacetate and beta-hydroxybutyrate which can enter circulation and converted back into acetyl CoA for use in the TCA of extrahepatic tissues
beta-hydroxybutyrate ratios are always higher than acetoacetate (especially in a state where [NADH] levels are high because it will reduce the acetoacetate to beta-hydroxybutyrate)
what is omega-oxidation catalyzed by?
a MIXED FUNCTION OXIDASE that requires O2 and NADPH
the FA is oxidized to an alcohol, alcohol is oxidized to an aldehyde via alcohol DH, aldehyde is oxidized to a carboxylic acid via aldehyde DH —> makes dicarboxylic acid on both ends of FA
describe synthesis of ketone bodies
made when [acetyl CoA] is high
Two acetyl CoA is converted to acetoacetyl CoA via THIOLASE –> HMG-CoA via HMG CoA synthase –> acetoacetate via HMG CoA lyase –> beta-hydroxybutyrate and acetone when NADH/NAD+ is high then acetoacetate will be reduced to beta-hydroxybutyrate and both are released into circulation
some acetoacetate will undergo SPONTANEOUS DECARBOXYLATION to form acetone
how is beta oxidation regulated?
- by the RATE OF RELEASE of fatty acids from adipocytes
- by the RATE OF TRANSPORT of fatty acylcarnitines into the mitochondria
- by intracellular NADH/NAD+ and FADH2/FAD ratios
what enzyme does the liver lack that prevents it from using KB as a fuel source?
succinyl CoA:acetoacetate CoA transferase
explain oxidation of ketone bodies
in extrahepatic tissues (NOT RBC) that lack mitochondria –> beta-hydroxybutyrate and acetoacetate are converted back to acetoacetyl CoA and then acetyl CoA
BETA-HYDROXYBUTYRATE to ACETOACETATE via beta-hydroxybutyrate DH (using NAD+ and making NADH for ETC) –> ACETOACETATE to ACETOACETYL CoA via succinyl CoA:acetoacetate CoA transferase - uses a succinyl CoA and makes succinate which costs an ATP (LIVER LACKS THIS ENZYME which is why it can not use KB for fuel) –> ACETOACETYL CoA to 2 ACETYL CoAs via thiolase
how is KB synthesis regulated?
- decreased insulin/glucagon ratio (MORE GLUCAGON = fasting or stress) = increased availability of FA for beta-oxidation in liver
- decreased insulin/glucagon ratio = inactivation of ACCase (phosphorylated) and decrease [malonyl CoA] –> activating CPTI for mitochondrial beta-oxidation
- [ATP] increases because of flux through beta-oxidation, [NADH/NAD+] also increase = SLOW beta-oxidation and TCA causing build-up of MALATE (favors reverse rxn of OAA to malate) which can be exported to the cytosol for gluconeogenesis
- [acetyl CoA] increases due to inability to enter TCA –> drives ketone synthesis of KB
where are FA synthesized?
mainly in the liver, can also occur in adipocytes and lactating mammary glands
glycolysis generates acetyl CoA for FA synthesis and the glycerol backbone for synthesizing TG from FA chains (acetyl CoA can also be generated from excess AA)
pyruvate –> acetyl CoA and OAA make citrate that can leak out of mitochondria into the cytosol and be converted to acetyl CoA then malonyl CoA via ACCase (using NADPH) then palmitate and lastly, FA CoA which combines with glycerol 3-P from DHAP in glycolysis to make TG that are incorporated into VLDL and secreted
where does FA synthesis occur?
in the cytosol but the acetyl CoA needed for this process is generated in the mitochondria HOWEVER acetyl CoA is transported to the cytosol as CITRATE
pyruvate converted to OAA (via pyruvate carboxylase using B7) and acetyl CoA (via pyruvate DH) –> both combine to form citrate –> citrate leaks out to cytosol where citrate lyase converts it to OAA (gets recycled) and acetyl CoA (can be used for FA synthesis)
why is the malic enzyme important?
it generates most of the NADPH needed for FA synthesis (rest comes from PPP)
it is involved in the OAA recycling process to pyruvate (cytosolic malate DH using NADH to convert OAA to malate)
what must acetyl Coa be converted to FIRST to enter FA synthesis?
it must be converted to MALONYL CoA via ACCase using B7 and ATP
malonyl CoA will allow the use of FA synthase
what is the rate-limiting step in FA synthesis?
acetyl CoA to malonyl CoA by ACCase
what stimulates the conversion of acetyl CoA to malonyl CoA?
the elevation of insulin/glucagon ratio
insulin activates the pyruvate DH, which induces citrate lyase and malic enzyme (produces NADPH) –> also activates ACCase to convert acetyl CoA to malonyl CoA
high energy = citrate accumulates because isocitrate DH is inhibited by NADH
explain the regulation of ACCase
insulin activates PP1 which dephosphorylates ACCase to its active form (citrate also activates ACCase)
AMP-dependent protein kinase phosphorylates ACCase to its inactive form due to feedback inhibition of palmitoyl CoA (if there’s too much palmitoyl Coa = enough energy has been produced, no need to make more)
what is FA synthase?
a homodimeric protein with multiple active sites
growing FA chain is linked to the acyl carrier protein (ACP) via a phosphopantetheinyl arm (B5), passing the substrate from one active site to the next
how is the FAS cycle initiated?
begins with covalent attachment of ACETYL group from acetyl CoA to a CYSTEINE residue
- acetyl group from acetyl CoA is transferred to active site cysteine residue (first attaches to pantetheinyl arm then gets transferred to cysteine residue)
- malonyl CoA transfers its malonyl group (3 carbon, 1 is carboxylate) to pantetheinyl arm of ACP after acetyl group is transferred
- malonyl CoA undergroes beta-DECARBOXYLATION (of the carboxylate), leaving the alpha-carbanion that will attach to the cysteine-linked acetyl group making a BETA-KETOACYL GROUP (move it to the P arm, leaving the cysteine residue free)
explain the reduction of the beta-ketoacyl group
after the malonyl CoA is decarboxylated, it attaches the cysteine-linked acetyl group to the P arm, creating the beta-ketoacyl group (leaving the cysteine residue free)
this beta-ketoacyl group undergoes three reactions to be reduced to an alkane (reverse of beta-oxidation)
- beta-keto group is reduced, using NADPH, to an alcohol
- alcohol is dehydrated, forming double bond (alkene)
- double bond is reduced to an alkane
this FA chain is then transferred to the cysteine residue –> this whole process is then repeated until palmitate (C16) is formed, and then THIOESTERASE hydrolyzes the FA chain from ACP (P arm)
what inhibits CPTI?
malonyl CoA (product of ACCase)
prevents wasteful cycling of newly synthesized FA chains into mitochondria for beta-oxidation and facilitates transport of FA into mitochondria when ACCase activity is low
why is elongation of FA chain needed?
FAS only produces palmitate (16C), and some tissues need longer FA for their own use
explain the process of elongation of the FA chain
FAS produces palmitate, which can be activated by palmitoyl Coa and elongated in the ER using the same reactions as the ones that catalyze FAS in the cytosol (acetyl group attaches, malonyl group attaches, decarboxylation, beta-ketoacyl group, formation of palmitate)
HOWEVER, enzymes ELONGASES are not part of multifunctional complex and FA chain remains attached to CoA instead of being transferred around
what are the predominantly produced FA in the liver?
palmitate and stearate
palmitoyl CoA is reduced to an alcohol, alcohol reduced to alkene, alkene is reduced to alkane, producing stearoyl CoA
why is elongation important for the brain and lactating mammary glands?
the brain contains additional elongation capacities to produce NEURON-SPECIFIC LIPIDS
lactating mammary glands contain SOLUBLE THIOESTERASE that terminate the FAS reaction sequence early, generating SC and MC FA for milk
explain the process of desaturation
desaturation is the introduction of double bonds into fatty acid chains
this process is catalyzed by desaturases (members of mixed function oxidases like omega-oxidation) and occurs in the ER, REQUIRES O2 and NADH
saturated fatty acyl-CoA and NADH reduces O2 to 2H2O (O2 is an oxidizing agent that is reduced to water), producing a monounsaturated fatty acyl-CoA
what carbons does desaturation occur at?
carbons 9, 6, or 5
what FA cannot be synthesized by the body?
linoleic acid (omega 6) = important for synthesis of ARACHIDONIC ACID (precursor of eicosanoid hormones)
alpha-linolenic acid (ALA or omega 3) = important for synthesis of EPA (another precursor of eicosanoid hormones)
these are essential fatty acids that need to be obtained through our diet since the body CANNOT synthesize them because of where double bonds can be made
where do linoleic acid and ALA come from?
produced by plants and are obtained in diet primarily in VEGETABLE OILS (linoleic acid) and LEAFY GREENS, and FISH OILS (ALA)
where are TGs synthesized?
in the liver and adipocytes started with glycerol 3-P from glycerol via glycerol kinase and from DHAP in glycolysis
unlike intestinal epithelial cells which start with 2-MG (pancreatic lipase)
how is glycerol 3-P made in adipocytes?
during the fed state, glucose is taken into adipocytes by GLUT4 (stimulated by insulin) and used to generate DHAP, which is then reduced to glycerol 3-P
LACK GLYCEROL KINASE
how is glycerol 3-P made in hepatocytes?
phosphorylating glycerol using glycerol kinase (not expressed in adipocytes) or from glucose via DHAP
explain the process of synthesis of TAG
begins with glycerol 3-P which combines with 2 FA CoA (FA chains MUST be activated to acyl-CoAs prior to addition to the glycerol backbone, chains may be NEWLY SYNTHESIZED OR BE EXCESS CHAINS BROUGHT TO THE LIVER FROM ADIPOCYTES) –> produces phosphatidic acid (intermediate common to synthesis of TAGs and glycerophospholipids) –> removal of phosphate group makes diacylglycerol –> addition of FA CoA makes TAG which can be released from the liver as VLDL or stored in adipocytes
explain synthesis of VLDL
synthesis of VLDL is similar to chylomicrons; major DIFFERENCE is that ApoB-100 is the apoprotein (not ApoB-48)
Apoproteins are synthesized in the RER with the help of MTP (recall that a deficiency in MTP leads to abetalipoproteinemia), small aggregates of apoproteins, phospholipids, and TAGs are formed
apoprotein complexes move to GOLGI APPARATUS where additional TAG and other lipids are added to form VLDL
Apoprotein made in the RER, moves to golgi apparatus, secreted from golgi as secretory vesicle, and releases VLDL into circulation (needs ApoCII and ApoE to become mature)
how are TAGs stored in adipocytes?
both chylomicrons and VLDL become mature due to the addition of ApoCII and ApoE; ApoCII stimulates LPL which breaks down mature chylomicrons and VLDL to make FA (stored in adipocytes and myocytes) and glycerol (returned to liver)
In fed state –> chylomicrons and VLDL will be delivering FA to adipocytes and myocytes, TAGs hydrolyzed then chylomicrons become chylomicron remnants and VLDL becomes IDL (VLDL remnants)
Recall
- ApoCII activates LPL
- LPL expression and secretion is UPREGULATED by INSULIN (because in fed state you want to break down TG to FA for storage in different tissues)
- adipocytes make glycerol 3-P from glucose (not from DHAP because they can’t use glycerol kinase)
how are FAs released from adipocytes?
hydrolysis of TAG is regulated by HORMONE SENSITIVE LIPASE
hormone-sensitive lipase is activated by phosphorylation catalyzed by PKA; active in fasting state when insulin/glucagon ratio is LOW (high insulin/glucagon = dephosphorylation of hormone-sensitive lipase); PHOSPHORYLATED FORM IS ACTIVE
low insulin/glucagon ratio will activate adenylyl cyclase to convert ATP to cAMP, which will activate PKA to phosphorylate hormone-sensitive lipase to its active form, allowing hydrolysis of TGs (along with other lipases) to 3 FA chains that bind to SERUM ALBUMIN and are transported to tissues while the glycerol is returned to the liver
explain impaired metabolism of Type I diabetes
lack insulin due to the destruction of pancreatic beta cells = failure to release insulin which results in failure of glucose uptake of muscle adipose tissue (mimics STARVED state)
brain will not need KB because there’s enough glucose in the blood to supply its energy, KB will accumulate = DKA
Glut 4 is impaired because there is no insulin to stimulate its activity of transferring glucose into tissues/cells, glucose will accumulate in the blood, leading to HYPERGLYCEMIA (also because of gluconeogenesis due to starved state)
describe the process of acquiring Type I diabetes
exposure to a virus or toxin may begin the process of beta cell destruction in individuals with a genetic predisposition
beta cell destruction will progress over time, leading to decreased production of insulin
insulin production falls below threshold, type 1 diabetes symptoms begin to appear
explain impaired metabolism of Type II diabetes
insulin response is adequate enough because beta cells are still producing insulin, the body is just resistant to it = can prevent massive release of free FA from adipocytes so DKA is rare
HOWEVER, high [glucose] in acute states result in HYPEROSMOLARITY
insulin resistance = there will be more glucose than normal in serum because they’re not being transported into adipocytes and myocytes –> this leads to hyperglycemic and hyperosmolar state (HHS)
insulin resistance is often accompanied by obesity but not always (resistance can also arise from genetics, sedentary lifestyle, and aging)
how can you differentiate between type I and type II diabetes?
lack of insulin due to destruction of beta cells (type I) and still production of insulin from beta cells but the body is insulin resistant (type II)
type I = DKA
type II = hyperosmolar state (or HHH), very strong genetic predisposition
Cholesterol is a precursor for…
steroid hormones (including vitamin D) and bile salts
where is cholesterol obtained and synthesized?
it is obtained from the diet and synthesized in the cytosol and ER of ALL CELL TYPES (all cells have capacity to make cholesterol)
what is the “central hub” of cholesterol metabolism?
the liver
- it processes lipoproteins that carry cholesterol to and from extrahepatic tissues
- synthesizes large quantities of cholesterol for export to other tissues, and bile salts to aid digestion
- excretes cholesterol, bile salts, and phospholipids to intestine (only route for elimination of cholesterol in the body - through feces)
what is important about tissues that produce and excrete steroid hormones?
they require a LARGE quantity of cholesterol (since they are derivatives of cholesterol)
like adrenal glands, testes, and ovaries
what is the common dietary form of cholesterol? and what happens to them?
cholesterol esters that are hydrolyzed by pancreatic esterase prior to uptake of cholesterol and fatty acid by enterocytes
enterocytes also absorb cholesterol released in bile
how is cholesterol absorbed from the intestinal lumen?
through a DIFFUSION-CONTROLLED PROCESS
absorption is inhibited by soluble dietary fibers (because they slow down absorption) and EZETIMIBE or Zetia which inhibits the transporter that moves cholesterol into the liver
how are excess cholesterol and plant sterols eliminated?
unwanted or excess cholesterol and plant sterols can be eliminated from enterocytes and back into the lumen by ABCG5 and ABCG8 (members of ATP-Binding Cassette transporter family)
deficiencies in these transporters results in ELEVATION OF SERUM CHOLESTEROL (hypercholesterolemia) AND PLANT STEROLS (aka phytosterolemia) –> because the transporters are not functioning, they’re not eliminating cholesterol from the serum, causing it to build up and absorption
plant sterols are said to be good because they can help prevent absorption of cholesterol by competing with the transporter, similar effects to EZETIMIBE
why are ABC transporters important?
they play key roles in hepatic drug metabolism and drug resistance in bacteria and cancer cells (resistance to chemotherapy), they also function to just transport things outside of cell (to remove)
recall, this is similar to how we mark drugs for export by adding glycine and glucuronate
how is cholesterol synthesized (basics)?
cholesterol can be synthesized from acetyl-CoA in ALL cells
liver, intestine, adrenal cortex, and reproductive have most active synthesis
cholesterol molecule is highly reduced, requiring NADPH from PPP and malic enzyme
synthesis of cholesterol occurs in CYTOPLASM and will require transport of acetyl-CoA across the mitochondrial membrane in the form of CITRATE
what is the first step of cholesterol synthesis?
begins with synthesis of MEVALONATE from acetyl-CoA
high [acetyl CoA] drives the reaction of beta-oxidation in reverse to make acetoacetyl CoA –> then via HMG CoA synthase (CYTOSOLIC isoform is important in synthesis of cholesterol, MITOCHONDRIAL synthase is important in synthesis of KB), HMG CoA is made –> HMG CoA reductase makes mevalonate (uses 2NADPH and release
statins inhibit HMG CoA reductase = interferes with cholesterol synthesis by decreasing the synthesis of cholesterol because they can’t make mevalonate to continue the process (statins also increase the number of LPL receptors expressed since there is less cholesterol, LPL will decrease cholesterol even more by removing it)
