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Medical Biochemistry and Pathophysiology > Week 7D: Liver Metabolism > Flashcards

Week 7D: Liver Metabolism Flashcards

HC 46, 47

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USMLE® Step 1 flashcards
1
Q

HC46: Lymph from capillaries

A

Capillary bed > blood plasma from arteriole to interstitial space and re-uptake in venule
> excess fluid and macromolecules drain into permeable lymphatic capillaries

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2
Q

Where do the lymph circulation flow to?

A

The subclavian vein to flow into blood

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3
Q

Lymphatic capillaries are derived from … cells

A

Venous endothelial cells

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4
Q

Lacteal

A

Blunt ended lymphatic vessel in villus of intestine
> drainage dietary lipids in intestine
> villi: large surface, quick and much uptake
> excess liquid collection
> excess liquid pushes it down into the lymph

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5
Q

Oil red O staining

A

After olive oil diet to mice
> little lipid accumulation in lamina propria: efficient transport through the lymph

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6
Q

Button junctions

A

Specialized, discontinuous junction between lacteal endothelial cells with open and closed regions
> allows chylomicron uptake (made in enterocytes)
> lipid through lymph, it cannot enter the blood stream directly

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7
Q

Junctions in endothelial cells and collecting lymphatics

A

Zipper junctions > tightly seal the ECs > no passage chylomicrons

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8
Q

Villi lengths in intestines

A

Duodenum > jejunum > ileum

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9
Q

Advantage chylomicrons to lymph

A

Gets to heart as first organ
> needs fats for energy (much energy needed): beta oxidation
> uses more fat than glucose
> high energy macronutrients

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10
Q

Reaction lymph capillaries to Vascular Endothelial Growth Factor (VEGF)

A

Lymph angiogenic signal transduction
> to express proteins to make zipper junctions
> stepwise proteolytic activation VEGF-A and binding VEGFR-2: pathway to zipper junctions

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11
Q

VEGF signalling in lacteals

A

VEGF binds to decoy (NRP1/FLP1) RTK on blood EC > limit VEGF binding to VEGFR-2 > resulting in discontinuous button junctions
-Waste of signal: no formation zipper junctions

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12
Q

Transition of button-to-zipper junctions

A

Inducible genetic deletion of decoy Nrp1/Flt1 increase bioavailability of VEGF and signalling through VEGFR-2.
> zippering up the lacteal junctions: prevent chylomicron uptake

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13
Q

Lipid droplet organelle: protein function

A

Regulate size and fusion etc
> on the outside layer

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14
Q

Lipid droplets in muscle

A

-Intramyocellular lipid storage
-Dynamic organelles
-Coated with proteins for regulation
-Independent or bound to mitochondria (couple to beta oxidation)

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15
Q

Core content of lipid droplets

A

TAGs and cholesterol ester (CE) > neutral lipids: hydrophobic

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16
Q

Outer layer lipid droplet

A

Monolayer phospholipids

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17
Q

Proteins on membrane lipid droplets from lipid metabolism

A

Lypolysis enzymes
> ATGL: adipose triglyceride lipase (TAG>DAG)
> HS lipase: hormone sensitive lipase
> Monoglyceride lipase
-Activated in glucagon/adrenalin signalling

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18
Q

Lipid synthesis and storage in liver

A

Temporary storage in liver lipid droplets and then to make VLDL or degrade in beta-oxidation

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19
Q

LC3 and lipid droplet

A

Receptor on phagosome > can bind lipases for complete degradation of lipid droplets through autophagy

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20
Q

After activation of lipids when entering the cell (Acyl-CoA), the only fate is not beta oxidation (committed step is transport in mitochondrion), other fates?

A

Storage in lipid droplet
> secretion as VLDL (liver)
> signalling: via PPARs
> make complex lipids in ER

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21
Q

Biogenesis lipid droplets > where?

A

Organized by proteins in ER > between two monolayers of ER
> cholesterol synthesis also in ER

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22
Q

What is done with DAGs and cholesterol in ER membrane to store them between the monolayers of the bilayer?

A

Esterification to TAGs or CEs > hydrophilic environment
> also a lot of proteins make it into monolayer of lipid droplet

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23
Q

Major steps lipid droplet biogenesis

A

-Nucleation
-Growth
-Budding

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24
Q

Membrane proteins from lipid droplets derived from…

A

ER membrane
> or made in cytosol and adhesion later

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25
Q

Lipid droplet nucleation

A

Synthesis lipids in ER > aggregate to form lens-like structure between ER membrane leaflets

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26
Q

SEIPIN function

A

Protein that forms ring in ER cytosolic leaflet
> keep lipids together > allows monolayer to bud, otherwise spontaneous reformation bilayer

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27
Q

Similarities and differences lipoproteins and lipid droplets

A

-Both consist of lipophilic core with TAGs and CEs surrounded by phospholipid monolayer
-Lipoproteins decorated by defined set of apolipoproteins that bind to the surface via amphipathic alpha-helices and beta-strands
-Lipid droplet proteome is highly diverse and dynamic for fusion, growth, shrinkage and fission: more organization

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28
Q

Budding lipid droplet

A

Proteins in ER membrane involved
> Sterol esterified to esterified sterol (CE) and Glycerol-3-P to TAG
> SEIPIN oligomer associates and forms pore around the neck of the buds with the help of other proteins

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29
Q

Class I and Class II proteins of lipid droplet

A

Class I proteins: inserted into ER and trafficked from ER to nascent lipid droplets
Class II proteins: inserted into lipid droplets directly from cytosol

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30
Q

What happens in lipid droplet biogenesis when Seipin KO

A

You can make lens-like structure, but budding cannot happen

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31
Q

Seipin disrupts which forces?

A

Hydrophobic forces in lipid droplet budding are blocked. These forces interfere with formation monolayer

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32
Q

Multiple functions Seipin, also in growth

A

Seipin
> stabilizes structure by surrounding neck of forming lipid droplet
> neutral lipids are channeled into nascent lipid droplet core: growth
> phospholipids are supplied from cytosolic leaflet of ER membrane

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33
Q

Dynamic size lipid droplet

A

-Shrinkage when TAGs or CEs are used > increased protein density > the weakest bound proteins will dissociate first to compensate
-At cytosolic side ER: proteins for lipid droplets are synthesized

34
Q

With which organelles does the lipid droplet interact?

A

Mitochondria, peroxisomes, lysosomes, ER

35
Q

Types of milk secretion in mammary glands

A

Lipid droplets in mammary gland
> pathway milk secretion involves merocrine and apocrine secretion

36
Q

Merocrine secretion

A

Exocytosis via vesicles

37
Q

Apocrine secretion

A

Secretion via lipid droplets: apical cytosol buds of surrounded by plasma membrane
> Total of monolayer (lipid droplet) + Bilayer (PM) = three membranes

38
Q

What give milk white appearance

A

Light reflected back because three layers around lipid droplets: a lot of membranes with proteins

39
Q

Holocrine secretion (does not occur in mammary gland!!)

A

Entire cell disintegrates > contents released

40
Q

Pathway milk secretion during lactation

A

1: merocrine secretion: exocytosis milk proteins, lactose, calcium and other soluble components
2: apocrine secretion of milk fat globules with formation lipid droplets that move to apical side of cytoplasm for budding of surrounded by PM
3: vesicular transcytosis of proteins such as immunoglobin from intersitial space to lumen
4: transporters for direct transfer of monovalent ions, water and glucose

41
Q

Difference lipid droplets and lipid globules

A

Globules are very large and droplets smaller

42
Q

HC47: Where placement lipid droplets in muscle fibers?

A

At specific locations: in mitochondrial network: efficient shuttling of FAs to mitochondria
> first lipolysis to FAs

43
Q

Muscle fuels

A

Glucose, lipids, ketone bodies

44
Q

Muscle fibers and organization lipid droplets

A

Type I: slow twitch, mitochondria dependent, high use oxygen and myoglobin, lots of lipid droplets
Type II: fast twitch, less mitochondria, anaerobic glycolysis, less lipid droplets

45
Q

Lipid droplets in muscle in trained state

A

Fat stored in more and smaller lipid droplets connected to (more) mitochondria

46
Q

Lipid droplets in muscle of T2DM patient

A

Change organization
> less association with mitochondria

47
Q

Lipid droplet organization in liver

A

Multiple contact points to orchestrate lipid metabolism

48
Q

Lipid droplets to feed VLDL

A

Start with ApoB100: synthesis on RER
> protein for secretion of VLDL enters lumen ER
Droplets via secretory pathway: vesicles to Golgi to exocytosis of the vesicle with the VLDL particle inside it
> lipid droplets need to associate with ER to feed VLDL (in hepatocytes with lots of TAGs)

49
Q

Other association lipid droplets in liver beside ER for VLDL feeding

A

Mitochondria or autophagosome

50
Q

Which transporters transport FFAs into hepatocytes

A

CD36 and FATP
> FFAs in blood bound to serum albumin

51
Q

High uptake FFAs by liver when…

A

Fasting
> from adipocytes

52
Q

Obesitas glucose and insulin levels and result for beta cells

A

Same patterns as healthy
> during night, higher blood glucose
> Insulin levels (C-peptide) way higher in obese than healthy, to keep blood glucose levels at lower levels
> overactive beta cells
-Make sulfide bonds to cleave C-peptide, make H2O2 (hydrogen peroxide)
-Beta cells are compensating > insulin resistance.

53
Q

Insulin receptor activation

A

Conformational change after binding insulin: from inverted-V conformation to T-conformation
> insulin receptor synthesized as one large protein: cleaved to alpha and beta parts
> receptor: heterotetramer: two alpha and beta from two insulin receptor primary products
> In inverted-V conformation: no trans-autophosphorylation, tyrosine kinase domains (beta) lay far apart
> T-conformation, tyrosine kinase domains in close proximity: trans-autophosphorylation and fully active tyrosine kinases: signal transduction

54
Q

PKB activation

A

Insulin receptor binds IRS which binds PI3K which makes PIP3 from PIP2
PDK1 and PKB bind PIP3 in membrane
> PDK1 active: phosphorylation and activation PKB by PDK1
> dissociation active PKB/Akt

55
Q

Insulin resistance in obesity

A

TAGs stored in lipid droplets (used for VLDL for example)
> TAGs made from DAG from Glycerol-3-P and 2 FAs
> accumulation TAGs: accumulation second messenger DAG
> DAG activates PKC theta (muscle) and epsilon (liver) isotypes
> PKC (serine/threonine kinase) phosphorlates threonine in activation loop of insulin receptor (where normally trans-autophosphorylation)
> phosphate group with negative charge and water shell prevents normal phsophorylation (not removed)
> some (20%) of insulin receptors not activated upon binding insulin

56
Q

Result insulin resistance

A

-Hyperinsulinemia, hyperglycemia, hypertriglyceridemia
-Liver
> Higher gluconeogenesis (more signals glucagon)
> higher FA and fat syntesis (fatty liver)
-Adipose tissue
> Lower glucose uptake (no GLUT4)
> Higher lipolysis: more effect glucagon
-Skeletal muscle
> lower glucose uptake
> more FA uptake and fat storage

57
Q

Obesitas to T2DM

A

Obesitas
> insulin resistance and hyperinsulinemia
> exhaustion pancreatic beta cells
> T2DM

58
Q

Exhaustion beta cells

A

Insulin release after increased glucose production, but eventually beta cells die due to oxidative stress because overhours to make insulin in obesity (then hyperglycemia chronically).
> body cannot make insulin anymore

59
Q

Reversible part in onset T2DM

A

Before the beta cell dysfunction
> reversible with life style changes
> genes in beta cells determine ‘survival’ after irreversible state: how long can beta cells make excessive insulin > after that: T2DM

60
Q

Liver functional unit

A

Lobule

61
Q

Lobule structural organisation

A

Portal triad: portal vein, hepatic artery and bile duct
> Between hepatocytes (at basal membrane) there are little vessels with loose endothelial cells and Kupffer cells lining within for blood flow towards central vein: sinusoids
> at apical membranes: bile canaliculli for bile flow towards bile duct

62
Q

Gradient oxygen and metabolites in lobule

A

Portal triad to central vein
> high oxygen and nutrients to lower

63
Q

Metabolic zoning of lobule

A

From high oxygen zone towards portal triad: Zone 1, and gradient to central vein to Zone 2 and Zone 3

64
Q

Function space between endothelial cells lining sinusoids: liver sinusoidal endothelial cells (LSECs)

A

A lot of molecules, like chylomicrons and LDL can pass

65
Q

Resident macrophages in liver

A

Kupffer cells

66
Q

Quiescent stellate cells (qHSCs)

A

Produce collagen
> wrong collagen in injured liver > activation stellate cells: fibrosis: collagen on wrong positions, cells die and spaces filled in with scar tissue

67
Q

Basal membrane of hepatocytes (face sinusoids) contain

A

Microvilli

68
Q

Injured liver structure

A

Hepatocytes lose microvilli and finally their function, associated with ECM deposition from activated hepatic stellate cells (aHSCs) favoring progression to cirrhosis and finally hepatocellular carcinoma

69
Q

Hepatic stellate cells are located at …

A

Space of Disse: between hepatocytes and liver sinusoidal endothelial cells (LSECs)

70
Q

Collagen fibers in healthy vs injured liver

A

Healthy: collagen IV and VI > provide perfect scaffold for architecture and function of space of Disse
Injured: collagen is replaced with colalgen I and III fibers, fibrotic fibers

71
Q

Bile salt function

A

Emulsifier of fats in intestinge
> surface active molecules
> amphipathic: hydrophobic and hydrophilic site
> like cholate
> solubilize large fat globules to small fat droplets with hydrophilic outside made up by the bile salts

72
Q

Pancreatic lipase activation

A

Activated by co-lipase
> Co-lipase binds only to lipid droplets when there are bile salts there
> Co-lipase connects pancreatic lipase with lipid droplets
> breakdown TAGs to MAG and 2 FAs
> uptake by enterocytes

73
Q

Bile acid formation, structure substrate and product

A

From cholesterol (C27) to bile acids (C24)
> remove three carbons to make for example cholate
> cholesterol is very hydrophobic but weakly amphipathic
> cholate is very amphipathic

74
Q

Committed step bile acid formation

A

Hydroxylation cholesterol at 3, 7, and 12 alpha carbon atoms
> by CYP enzyme: make hydroxyl 7a carbon (committed step)

75
Q

Second part bile acid formation in the ….

A

Peroxisomes

76
Q

Peroxisomal steps bile acid formation

A

Oxidation > hydration > oxidation > thiolysis (release propionyl-CoA)
(like the beta-oxidation cycle!)

77
Q

Glycocholate and taurocholate are conjugated bile salts of cholate, name their characteristics

A

Unconjugated cholate: pKa around 6, more in protonated form in duodenum (pH around 6) as bile acid > pKa is larger than pH
-Glycocholate: pKa: 4
-Taurocholate: pKa: 2 > deprotonated form mostly, negative charge, micelles easier formed in emulsifying

78
Q

Bile salt is the acid/alkaline form

A

alkaline

79
Q

Which form, bile salts or bile acids can solubilize the cells (dangerous)?

A

Bile acids > mostly protonated
> neutral, no charge and amphipathic > can enter cell > deprotonated in cell (pH 7.2 in cell) > detergent: solubilize the cell

80
Q

Bile acid form of cholate (bile salt)

A

Cholic acid

81
Q

Biliary bicarbonate umbrella theory

A

Secretion of bicarbonate (HCO3-) to protect hepatocytes and cholangiocytes from cytotoxic effects of cholic acid (unconjugated bile acid)
> deprotonating the bile acids (cholic acid) and keep them in bile salt form (cholate)

82
Q

Bile salts recycling

A

Enterohepatic circulation
> bile salts synthesized in liver, stored in gallbladder, secreted in duodenum, reabsorbed in terminal ileum and returned to liver by portal blood

Medical Biochemistry and Pathophysiology (16 decks)

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