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

Week 7D: Liver Metabolism Flashcards

HC 46, 47

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
Lipid droplet nucleation
Synthesis lipids in ER > aggregate to form lens-like structure between ER membrane leaflets
26
SEIPIN function
Protein that forms ring in ER cytosolic leaflet > keep lipids together > allows monolayer to bud, otherwise spontaneous reformation bilayer
27
Similarities and differences lipoproteins and lipid droplets
-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
28
Budding lipid droplet
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
29
Class I and Class II proteins of lipid droplet
Class I proteins: inserted into ER and trafficked from ER to nascent lipid droplets Class II proteins: inserted into lipid droplets directly from cytosol
30
What happens in lipid droplet biogenesis when Seipin KO
You can make lens-like structure, but budding cannot happen
31
Seipin disrupts which forces?
Hydrophobic forces in lipid droplet budding are blocked. These forces interfere with formation monolayer
32
Multiple functions Seipin, also in growth
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
33
Dynamic size lipid droplet
-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
With which organelles does the lipid droplet interact?
Mitochondria, peroxisomes, lysosomes, ER
35
Types of milk secretion in mammary glands
Lipid droplets in mammary gland > pathway milk secretion involves merocrine and apocrine secretion
36
Merocrine secretion
Exocytosis via vesicles
37
Apocrine secretion
Secretion via lipid droplets: apical cytosol buds of surrounded by plasma membrane > Total of monolayer (lipid droplet) + Bilayer (PM) = three membranes
38
What give milk white appearance
Light reflected back because three layers around lipid droplets: a lot of membranes with proteins
39
Holocrine secretion (does not occur in mammary gland!!)
Entire cell disintegrates > contents released
40
Pathway milk secretion during lactation
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
Difference lipid droplets and lipid globules
Globules are very large and droplets smaller
42
HC47: Where placement lipid droplets in muscle fibers?
At specific locations: in mitochondrial network: efficient shuttling of FAs to mitochondria > first lipolysis to FAs
43
Muscle fuels
Glucose, lipids, ketone bodies
44
Muscle fibers and organization lipid droplets
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
Lipid droplets in muscle in trained state
Fat stored in more and smaller lipid droplets connected to (more) mitochondria
46
Lipid droplets in muscle of T2DM patient
Change organization > less association with mitochondria
47
Lipid droplet organization in liver
Multiple contact points to orchestrate lipid metabolism
48
Lipid droplets to feed VLDL
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
Other association lipid droplets in liver beside ER for VLDL feeding
Mitochondria or autophagosome
50
Which transporters transport FFAs into hepatocytes
CD36 and FATP > FFAs in blood bound to serum albumin
51
High uptake FFAs by liver when...
Fasting > from adipocytes
52
Obesitas glucose and insulin levels and result for beta cells
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
Insulin receptor activation
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
PKB activation
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
Insulin resistance in obesity
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
Result insulin resistance
-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
Obesitas to T2DM
Obesitas > insulin resistance and hyperinsulinemia > exhaustion pancreatic beta cells > T2DM
58
Exhaustion beta cells
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
Reversible part in onset T2DM
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
Liver functional unit
Lobule
61
Lobule structural organisation
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
Gradient oxygen and metabolites in lobule
Portal triad to central vein > high oxygen and nutrients to lower
63
Metabolic zoning of lobule
From high oxygen zone towards portal triad: Zone 1, and gradient to central vein to Zone 2 and Zone 3
64
Function space between endothelial cells lining sinusoids: liver sinusoidal endothelial cells (LSECs)
A lot of molecules, like chylomicrons and LDL can pass
65
Resident macrophages in liver
Kupffer cells
66
Quiescent stellate cells (qHSCs)
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
Basal membrane of hepatocytes (face sinusoids) contain
Microvilli
68
Injured liver structure
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
Hepatic stellate cells are located at ...
Space of Disse: between hepatocytes and liver sinusoidal endothelial cells (LSECs)
70
Collagen fibers in healthy vs injured liver
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
Bile salt function
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
Pancreatic lipase activation
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
Bile acid formation, structure substrate and product
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
Committed step bile acid formation
Hydroxylation cholesterol at 3, 7, and 12 alpha carbon atoms > by CYP enzyme: make hydroxyl 7a carbon (committed step)
75
Second part bile acid formation in the ....
Peroxisomes
76
Peroxisomal steps bile acid formation
Oxidation > hydration > oxidation > thiolysis (release propionyl-CoA) (like the beta-oxidation cycle!)
77
Glycocholate and taurocholate are conjugated bile salts of cholate, name their characteristics
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
Bile salt is the acid/alkaline form
alkaline
79
Which form, bile salts or bile acids can solubilize the cells (dangerous)?
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
Bile acid form of cholate (bile salt)
Cholic acid
81
Biliary bicarbonate umbrella theory
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
Bile salts recycling
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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