metab ii: exam 3

what are micelles

• lipids arranged in a spherical form in aqueous solution

• contains free fatty acids, cholesterol, & fat soluble vitamins

• do not contain proteins

• requires bile acids for fat emulsification

what are chylomicrons

• lipoprotein particles containing triglycerides, phospholipids, cholesterol, & proteins

• formed in the enterocyte

• contain lipoproteins that mediate transport & uptake in tissues

how are fats metabolized

• all fats are absorbed via micelles in small intestine

• enterocyte produces chylomicrons containing all dietary fats & fat soluble vitamins

• during transport of chylomicrons to the liver: LPL digests TGs releasing FFAs to tissues

• this process reduces size of chylomicrons producing chylomicron remnants
  (CM-R)

• CM-R are taken by the liver → liver produces VLDLs → VLDLs are digested by LPL → forms LDL → LDLs are taken up by peripheral tissues

chylomicrons are produced in:

1. the blood stream

2. the enterocytes

3. the liver

4. in the lumen of the small intestine from dietary fats

the enterocytes

how are fats (dietary fat, TGs, cholesterol, & fat-soluble vitamins) absorbed in small intestine

• absorbed in micelles

• micelles are formed with bile acids & taken into enterocyte by NPC1, SR-BI, CD36

• inside enterocyte: fats are taken into chylomicron → CM are secreted into lymphatic vessels

what are the functions of CM

• transport dietary fats & TGs from small intestine to liver

• CM are rich in TGs

• contains all fat soluble vitamins from diet

LPL produces:

1. free fatty acids

2. cholesterol

3. HDL

4. chylomicron remnants

5. VLDL remnants

free fatty acids

how do CM get absorbed in blood circulation & form CM remnants

• after lymphatic vessels: CM reach blood circulation

• CM travel through blood vessel (which have LPL)

• LPL digests TGs and forms free FAs

• FFAs can be used by peripheral tissues & can be stored in adipose tissue

• after digestion by LPL: CM are reduced in size & become CM remnants

how do CM get absorbed in liver

• CM remnants are taken up by the LDL receptor (LDL-R)

• the receptor binding to CM-R are internalized in vesicles that fuse w/ lysosomes

• lysosomes contain digestive enzymes that degrade all proteins of the particle → release FFAs & fat soluble vitamins into the liver

how does the liver produces VLDLs

• fats & fat soluble vitamins are assembled into VLDLs

• in circulation: VLDLs are digested by LPL becoming VLDL remnants

  • VLDLs are rich in TGs

how are VLDLs absorbed in peripheral tissues

• VLDLs & VLDL remnants are taken up by peripheral tissues using VLDL receptor (VLDL-R)

• receptor binding to VLDL are internalized & all content is released into cells

VLDL contains:

1. triglycerides

2. all fat soluble vitamins

3. vitamin E & K

4. vitamin D & A

5. carotenoids

triglycerides

how are VLDLs converted in LDLs

• VLDL remnants can be taken up by cells or be converted to LDL

• LPL takes more TG from VLDL remnants until the particle becomes LDL

  • LDLs are rich in cholesterol

• LDL takes cholesterol to peripheral tissues

describe VLDL → LDL & what happens to LDL

• VLDLs converted to VLDL-Rs

• VLDL-Rs converted into LDL

• VLDL & VLDL-R can be internalized via VLDL receptors

• LDL can be internalized using LDL receptors

  • VLDL, VLDL-R, & LDL taken to peripheral tissues

LDLs are produced by the following mechanism:

1. synthesized in the liver from endogenous cholesterol

2. produced from HDL

3. produced by digestion of VLDLs via LPL

4. produced in the small intestine from dietary cholesterol

• produced by digestion of VLDLs via LPL

what is reverse cholesterol transport

transport excess cholesterol from peripheral tissues to the liver for excretion via HDL

describe reverse cholesterol transport

• cholesterol is taken from peripheral tissues by HDLs

• HDLs are formed by ApoA1 (secreted by the liver)

• HDL precursors goes to peripheral tissues

• cholesterol is excreted from tissues via exporter ABCA1

• HDL loads the cholesterol becoming mature HDL

• mature HDL goes to liver & interacts with SR-BI receptor

• the cholesterol is transported to liver leaving HDL empty → becomes immature HDL again

• HDL goes back to peripheral tissues to get more cholesterol

  • HDL is rich in cholesterol

• HDL takes cholesterol from peripheral tissues to liver & interacts with SR-BI

• HDL releases cholesterol in the liver → used for synthesis of bile acids/excreted in bile

what is the function of chylomicrons

transport dietary fats & cholesterol from intestine to tissues

what is the function of VLDLs

transport of endogenous fats (TGs) & cholesterol from liver to tissues

what is the function of LDL

transport of endogenous cholesterol from liver to tissues

what is the function of HDL

transport of endogenous cholesterol from tissues to liver

HDLs are produced in (choose all that apply):

1. the liver

2. the kidneys

3. peripheral tissues

4. the small intestine

• the liver

• peripheral tissues

• small intestine

describe vitamin E:

• forms of vitamin

• best source

• RDA

• functions

• 8 different forms (“vitamers)

• tocopherols & tocotrienols

• only alpha tocopherol has biological activity

• in the liver: alpha-TTP takes only alpha tocopherol into VLDLs

• best source: wheat germ oil

• RDA: 15 mg/day

• naturally occurring sources are better than supplements

• stored in membranes & acts as an antioxidant for lipids

• reduces lipid peroxidation

what diseases are associated with vitamin e

• defect in the alpha-TTP gene: causes ataxia with vitamin E deficiency

  • affects motor control & movement

  • symptoms: slurred speech (dysarthria), difficulty coordinating movements (ataxia), numbness in the hands & feet (peripheral neuropathy), & vision loss

• deficiency causes hemolytic anemia

• toxicity causes reduced vitamin K absorption

  • causes excessive bleeding

how is vitamin e absorbed in small intestine

• same pathway as all fats

  • (form micelles w/ bile acids & transported to small intestine via NPC1, SR-BI, & CD36 transporters)

• secreted from enterocytes via chylomicrons

• small intestine produces ApoA1 & HDL

• HDL gets cholesterol & vitamin e from enterocytes

• CM & HDLs are transported to liver

• LDL has highest vitamin e content

what happens to vitamin e at apical & basolateral membranes of small intestine

• apical:

  • lipid uptake

  • receptors: SR-BI, NPC1, CD36

• basolateral:

  • excretion of chylomicrons in secretory vesicles

  • cholesterol efflux via ABCA1 transporters into HDL particles

• only liver & small intestine produce ApoA1 & HDLs

how is vitamin e taken to liver

• chylomicron remnants, HDLs, & LDLs deliver vitamin e to liver

• uptake of chylomicrons by receptors (like LDL-R)

• hepatic alpha-tocopherol transfer protein (alpha-TTP) mediates the loading of RRR-a-tocopherol (active form) into VLDLs

  • aTTP protects alpha-tocopherol from degradation

• all other vitamers are metabolized & excreted in feces (bile) or in urine

• liver produces VLDLs & HDL containing vitamin e

the molecule involved in the targeting of vitamin e to VLDL is:

1. alpha-TTP

2. LPL

3. Apo-A1

4. LDL-R

alpha TTP

what are:

• reactive oxygen species (ROS) & superoxide dismutase

• & how is H2O2 destroyed

• superoxide anion (one extra electron), very reactive

• superoxide dismutase (SOD): converts superoxide into H2O2

  • H2O2 can generate hydroxyl radical

  • H2O2 can also generate hypochlorous acid (HOCl)

• H2O2 is destroyed by peroxidase enzyme

  • glutathione peroxidase (GPx)

  • peroxiredoxins (Prx)

  • catalase

what is lipid peroxidation

• polyunsaturated fatty acids (PUFAs) react with O2 or are attached by free radicals → generates lipid radicals & lipid peroxides

• these molecules interact with the surrounding PUFAs propagating the oxidation of the cell membrane → membrane ruptures inducing ferroptosis (a regulated form of cell death caused by lipid peroxidation)

how does vitamin e protect from lipid peroxidation

• vitamin e eliminates the lipid radical producing a lipid peroxide

  • lipid peroxide is then eliminated by glutathione peroxidase

• vitamin e becomes oxidized & is regenerated by vitamin c

• vitamin c becomes oxidized to DHA

• DHA is regenerated by DHA reductase using glutathione

• glutathione becomes oxidized to GSSG

• GSSG is regenerated by glutathione reductase using NADPH

• final product = reduced vitamin e, c, glutathione, & NADPH

vitamin e eliminates lipid radicals by:

1. donating electrons to lipid radical producing a lipid peroxide

2. converting the lipid radical back to its original state

3. eliminating the lipid radical from the membrane

4. inducing the synthesis of new lipids

donating an electron to the lipid radical producing a lipid peroxide

describe vitamin a:

• forms

• carotenoids

• best source

• RDA

• forms:

  • retinol

  • retinal: 11-cis-retinal (night vision)

  • retinoic acid: gene expression

  • retinyl esters: storage mainly in liver in stellate cells

• carotenoids:

  • vitamin a precursors (alpha & beta carotene)

  • all other carotenoids are antioxidants

• RDA: 900 microgram/day

• best sources:

  • liver - vitamin a

  • red/orange fruits & vegetables - carotenoids

what other vitamin deficiencies/toxicities are associated with vitamin a

• vitamin e toxicity: inhibits conversion of beta carotene to retinol

• vitamin a toxicity: reduces vitamin k absorption causing excessive bleeding

• carotenoid toxicity: reduces vitamin e absorption causing hemolytic anemia

• zinc deficiency: causes night blindness due to reduced regeneration of rhodopsin

what does vitamin a deficiency cause

• reduces iron uptake in RBCs causing iron-deficiency anemia

• night blindness

• bitot’s spot (eye)

• anorexia

what does an increase/deficiency in each vitamin cause:

• vitamin e

• vitamin a

• b-carotene

• toxicity of vitamin a or e → decreased vitamin k absorption → decreased blood coagulation → increased bleeding

• toxicity of b-carotene → decreased vitamin e → hemolytic anemia

  • can also cause jaundice

• deficiency of vitamin a → decreased iron absorption → iron deficiency anemia

• deficiency of zinc → decreased rhodopsin regeneration → night blindness

what happens to retinyl esters inside enterocytes

• retinyl esters (storage form) → retinol + carotenoids (by esterase) → form micelles → transported to small intestine

• retinol → retinol-CRBP (by CRBPII) → CRBP-retinyl palmitate (by LRAT) → chylomicrons

  • carotenoids directly converted to chylomicrons in SI

• chylomicrons exit SI → CM-R (digested by LPL) → transported to liver

  • only retinyl esters can go into chylomicrons

what happens to b-carotene inside enterocytes

• retinyl esters → retinol + carotenoids (by esterase) → forms micelles → transported to small intestine

• b-carotene in SI → 2x retinal → CRBP-retinal (by CRBPII) → CRBP-retinol (by retinal reductase {requires NADH}) → CRBP-retinyl palmitate (by LRAT) → forms chylomicrons

  • retinal → also converted to retinoic acid → retinoic acid leaves SI + binds to albumin → transported to liver

• chylomicrons leave SI → transported to liver

• retinol + retinal can bind CRBP

the correct order for the formation of retinoic acid from b-carotene is from b-carotene to:

1. retinol → retinal → retinoic acid

2. retinal → retinyl ester → retinoic acid

3. retinyl ester → retinol → retinoic acid

4. retinal → retinoic acid

retinal → retinoic acid

describe transport out of SI for vitamin a & carotenoids

• CM for retinyl esters & carotenoids → transported out of enterocyte to lymphatic vessels

• HDL for retinol → transported out of enterocyte to bloodstream

• retinoic acid binding to albumin → transported out of enterocyte to bloodstream

how do carotenoids act as antioxidants

• b-carotene → 2x retinal (by BCO1) → 2x retinol

• carotenoids → apo-carotenes → Nrf2 → antioxidant enzymes

  • carotenoid function as antioxidants: eliminate lipid radicals & singlet oxygen

what is Nrf2

• a transcription factor

• master regulator of antioxidant enzymes (i.e. GPxs, SDOs, etc)

how is vitamin a absorbed in the liver

• chylomicron remnants enter liver → retinyl esters → retinol (via CRBPII) → CRBP-retinol → CRBP-retinal (via retinal dehydrogenase) → retinoic acid → retinoic acid-CRABP (via CRABP)

  • CRBP-retinol → Holo-RBP (via RBP) → Holo-RBP exits liver

the synthesis of holo-rbp from b-carotene is as follows:

• chylomicron remnants enter liver → retinyl esters → retinol (via CRBPII) → CRBP-retinol → Holo-RPB (via RPB) → Holo-RPB exits liver

list transporter for each vitamin in small intestine & liver:

• retinyl esters

• carotenoids

• retinol

• retinioic acid

• carotenoids

• small intestine:

  • chylomicrons: retinyl esters & carotenoids

  • HDLs: retinol

  • retinoic acid

• liver

  • VLDL: carotenoids

  • holo-rbp-ttr-t4 trimolecular complex: retinol

how does retinoic acid play a role in gene expression

retinol → enters trimolecular complex → transported to SI (by STRA6) → retinol CRBP → retinal CRBP → retinoic acid CRABP → RAR-RXR & DNA → gene expression

what is the rhodopsin cycle

• rhodopsin → opsin + cis-retinal → opsin+ trans-retinal → opsin + trans-retinal → rhodopsin + cis-retinal (then to rhodopsin) → opsin + cis-retinal

describe vitamin d:

• forms

• RDA

• best source

• absorption & transport (brief)

• forms

  • D2 & D3 from the diet and D3 from the skin

  • synthesized from 7-dehydrocholesterol (cholesterol derivative) in the skin

  • activation in the liver (25-hydroxylation) & in the kidney (1 hydroxylation)

  • 1,25-OH vitamin D or calcitriol is the active form

  • low calcium increases serum PTH which increases expression of 1-hydroxylase to increase calcitriol synthesis

  • calcitriol is a hormone - binds to VDR & regulates gene expression

  • skin is the major source of vitamin d

• RDA

  • 15 microgram/day

• best source:

  • fatty fish & cod liver oil

• absorption & transport: follows fat absorption up to the liver

what diseases are associated with vitamin d

• vitamin d/calcium deficiency:

  • rickets (children)

  • osteomalacia (adults)

• vitamin d deficiency:

  • hypercalcemia

  • calcification of soft tissues (kidney/liver/blood vessels)

  • hypertension

how is vitamin d metabolized

• from sun (uvb): 7-dehydrocholesterol → vitamin D3

• from diet: foods/supplements → vitamin D3 (by vitamin d3 binding protein)

  • vitamin D3 → calcidiol (25-hydroxyvitamin D) in liver (by 25-hydroxylase) → calcitriol (1a-25-hydroxyvitamin D3) in kidneys (by 1a-hydroxylase) → tissues (brain, bones, kidneys, chief cells) (by vitamin d receptor)

    • calitriol → also converted to inactive metabolites (by 24-hydroxylase)

  • tissues + metabolites induces degradation of vitamin d

how is vitamin d activation regulated

• uptake of 25-OH D in the kidney & other tissues is upregulated by an increased concentration of PTH

• PTH is secreted when calcium + phosphorous concentrations are low

• PTH increases the synthesis of 1 hydroxylase in the kidney which produced 1,25-OH D

• hypocalcemia stimultes the production of PTH to increase Ca+ levels by:

  • increasing Ca+ resorption in bones

  • increasing Ca+ resorption in kidneys

  • increasing 1,25-OH D in kidneys which increases Ca+ absorption in SI

how does vitamin d regulate its own synthesis

• calcitriol increases FGF23 secretion from bone

• FGF23 inhibits 1-hydroxylase enzyme in kidneys reducing calcitriol formation

• calcitriol inhibits secertion of PTH

explain 1,25-OH D deficiency vs 1,25-OH D excess

• deficiency:

  • stimulates synthesis of 1 hydroxylase in the kidneys increasing synthesis of the active form

• excess:

  • inhibits synthesis of 1 hydroxylase reducing the synthesis of the active form of vitamin d

  • stimulates expression of 24 hydroxylase that inactivates vitamin d producing 24,25-OH & 1,24,25-OH vitamin d that are excreted

excessive PTH production can cause osteoporosis because:

1. PTH reduces the levels of osteoblasts

2. PTH increases osteoclasts degrading bones

3. PTH inhibits calcitriol reducing calcium absorption

4. PTH competes with calcitriol in the bones

PTH increases osteoclasts degrading bones

what is the function of calcitriol in bones

• calcitriol increases the transcription of RANKL in osteoblasts (genomic)

• RANKL interacts with receptor RANK in the surface of immature osteoclast precursors inducing diferentiation to osteoclast (maturing osteoclasts via signal transduction)

• activated osteoclasts secrete HCl, alkaline phosphatase, & collagenases that eat away the bone releasing calcium + phosphorous

summarize vitamin d metabolism

describe vitamin k

• forms

• RDA

• best source

• overview of absorption & transport

• forms

  • K1 (phylloquinone) & K2 (menaquinone), K3 (synthetic form)

  • K1 found in liver

  • K2 found in peripheral tissues

• RDA:

  • 80 micrograms/day

• best source:

  • K1: green veggies

  • K2: animal sources + gut bacteria

• absorption & transport

  • follows fat absorption up to liver

  • in liver: vitamin k goes to VLDLs

  • stored in cell membranes

what are the functions of vitamin k

• k1: activates coagulation factors in liver

• k2: activates osteocalcin in bones & MGP in blood vessels

• vitamin d increases calcium absorption & k2 mediates binding of calcium to bone

  • k2 inhibits binding of calcium to blood vessels

where does each vitamin start & end up:

• vitamin a, d, e, & k

• vitamin a: small intestine → chylomicrons → liver → holo-rbp → trimolecular complex

• vitamin d: small intestine → chylomicrons → liver (25-OH-DBP) → kidney → 1,25-OH-DBP

  • skin → D-DBP → liver (25-OH-DBP) → kidneys → 1,25-OH-DBP

• vitamin e & k: small intestine → chylomicrons → liver → VLDL

what is the vitamin k cycle

• for activation vitamin k is first reduced by vitamin k reductase

• reduced vitamin k works on the carboxylation of glutamic acid on target proteins

• after carboxylation reaction vitamin k is oxidized forming vitamin k epoxide

• enzyme epoxide reductase regenerates vitamin k & new cycle begins

what is vitamin k mediated carboxylation

• damaged blood vessel: injury to vessel lining triggers the release of clotting factors

• formation of platelet plug: vasoconstriction limits blood flow + platelets form a sticky plug

• development of clot: fibrin strands adhere to the plug to form an insoluble clot

explain primary vs secondary hemostasis

• coagulation factors are produced in the liver where k1 is stored

• primary hemostasis: regulated by activation + aggregation of platelets → creates an unstable plug

• secondary hemostasis: coagulation creates a stable fibrin mesh

  • extrinsic pathway or initiation is mediated by the external damage to the vessel → endothelial cells secrete tissue factor (TF)

  • intrinsic pathway or amplification is activated by internal damage to the endothelium that amplifies the clotting response

explain fibrinolysis

• coagulation cascade from hemolysis requires calcium → calcium binds to carboxylated glutamic acid

• fibrinolysis: degradation of fibrin mesh to dissolve the clot (from hemolysis)

  • endothelial cells release tissue plasminogen activator (t-PA) into clot

  • t-PA converts plasminogen into plasmin

  • plasmin degrades fibrin

what genetic diseases are associated with vitamin k

• hemophilia (increased bleeding)

  • a bleeding disorder caused by a mutation in coagulation factors (factor VIII, IX, & XI)

  • more common in men

• hereditary thrombophilia (increased coagulation)

  • factor V leiden - a mutation that makes factor V resistant to inhibition increasing blood clotting

• protein C & protein S deficiency (increased coagulation)

  • these proteins reduce clotting - its deficiency increases clotting

what disease are associated with vitamin k deficiency

• vitamin k deficiency bleeding (VKDB) in infants:

  • a severe + life threatening bleeding disorder in newborns & young infants due to insufficient vitamin k at birth

  • preventable with a vitamin k shot given to newborns

• in adults:

  • reduced coagulation & excessive bleeding

• long term deficiency

  • osteoporosis (reduced ostecalcin activity)

  • cardiovascular disease (reduced MGP activity), increased arterial stiffness + calcification, increased risk of heart disease

what are the causes of each anemia:

1. hemolytic

2. pernicious

3. megaloblastic

4. microcity hypochromic

5. iron deficiency

• hemolytic

  • vitamin e deficency

  • carotenoid toxicity

• pernicious

  • caused by lack of intrinsic factor (B12 injection)

• megaloblastic macrocytic

  • caused by B9 or B12 deficiency

  • treated with B12 and/or folate supplement

• microcity hypochromic

  • vitamin B6 deficiency reduces heme synthesis

• iron deficiency

  • vitamin a deficiency