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Genetics Of Complex Disease > NAFLD Genetics > Flashcards

NAFLD Genetics Flashcards

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1
Q

What is nafld

A

Excess liver fat

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2
Q

What are the progression steps

A

Normal to steatosis (fat accumulation)

Long term fat deposition = steatohepatitis/NASH

This can lead to cirrhosis scarring

This can lead to hepatocellular carcinoma

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3
Q

What is steatohepatitis

A

Steatosis and necroinflammation

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4
Q

Is it high prevalence

A

Yes and increasing

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5
Q

When does mortality occur

A

Late fibrosis or mainly due to other conditions eg chd

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6
Q

What 2 ways does fat get in

A

De novo lipogenesis in liver or through diet/fa flow from adipose tissue

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7
Q

Where becomes insulin resistant and why

A

Muscles, periphery and fat stores

Because increased insulin release from diet desensitises

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8
Q

What gets disinhibited due to insulin resistance in adipose tissue

A

HLA hormone sensitive lipase

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9
Q

What does this do

A

Allows fa flow from adipose tissue

Due to increased lipolysis

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10
Q

Why does liver still make more and more fa

A

From glucose and the insulin stimulates it which it isn’t resistant to in the circulation

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11
Q

What gets overwhelmed first

A

Esterification

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12
Q

What 3 types of oxidation are there

A

Peroxisomal b-oxidation
Microsomal omega
Mitochondrial b oxidation

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13
Q

What do they all produce

A

Ros

Causes oxidative stress, damage and apoptosis of cells

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14
Q

What in the lipogenesis cycle can inhibit mt b oxidation whcih is the best one to use

A

Mal-coa

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15
Q

How

A

Inhibits cpt1 which is an enzyme used to import fat into mt for b oxidation

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16
Q

What builds up which causes things like er stress, mitochondrial dysfunction and necrosis

A

Lipotoxic intermediates like ceramides from the alternative oxidation paths

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17
Q

What do all of these with ROS also cause overtime

A

NASH

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18
Q

How does bacteria trans locate to liver making nash worse

A

Gut permeability and flow through the portal vein from gut to liver

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19
Q

What bacterial things can cause nash

A

Lps through inflammasome activation/PAMPS

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20
Q

What cells allow for fibrosis to occur

A

Hsc

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21
Q

What sorts of things activate them

A

Lps, tgfb1, il17a,il6

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22
Q

What do they do

A

Lay down scar tissue eg col type 1

Also stimulate more inflammation via Icam/vcam lymphocyte recruitment and cytokine release

23
Q

How does regression of fibrosis occur

A

Mmps and hsc quiescence/apoptosis

24
Q

Which 3 ways do you study genetics of nafld

A

Twin studies
Family aggregation studies
Inter ethnic differences in susceptibility

25
Q

Which are highest and lowest at risk

A

Hispanic highest

Afro Caribbean lowest

26
Q

What did twin studies find heritability of steatosis and fibrosis

A

Around 50%

27
Q

Which gene is the most studied associated with nafld

A

Pnpla3

28
Q

What is the variant of it

A

I148M

29
Q

What does this help to explain

A

Inter ethnic differences by 70%

30
Q

How is it an example of gene x environment

A

Increased risk of the gene if you’re a higher bmi

31
Q

Other than steatosis what other risk does it cause

A

Hcc and advanced fibrosis

32
Q

What does it usually do

A

Encode adiponutrin which affects how lipids are formed and metabolised and associates with lipid droplets

33
Q

Where does the variant affect

A

Next to catalytic site affecting how substrate reaches catalytic site

34
Q

What sorts of things does it do which causes steatosis

A

Reduced vldl release
Reduced fattt acid hydrolysis
Increased TG accumulation

35
Q

Why is there more pnpla3 protein with this variant

A

Stops ub proteasomes deg of it

36
Q

Which cytokines/chemokines which are profibrogenic or pro inflammatory does it increase exp of

A

Ccl5, gm-csf, il8, tgfb

37
Q

What cells were seen to be enhanced in migration with the variant

A

Macrophages

38
Q

What thing which causes hsc wuisceince is down regulated

A

Ppar-y

39
Q

What receptor signalling is downregulated which usually stops fibrogenesis from hsc

A

Retinoid x as retinol levels decreased

40
Q

Which enzyme is blocked for lipolysis and lipophagy by the pnpla3 variant

A

Atgl (a tg hydrolase)

41
Q

How

A

More pnpla3 due to less ub degradation binds more cgi-58, a cofactor needed for atgl

42
Q

What does tm6sf2 do

A

Regulate liver fat metabolism, tg secretion, lipid droplet content/size

43
Q

How does the variant show reduced cvd risk if you have the minor allele e167k

A

Because reduced vldl/tg plasma release

44
Q

Does the variant affect expression of tm6sf2

A

Yes

45
Q

How is vldl usually formed

A

In er tg and apoB assembly with mttp help

Then cop II transport to Golgi where further lipidsrion ocxurs

46
Q

Where is tm6sf2 thought to be important

A

Between er and Golgi or at Golgi for mroe lipidsrion (unknown)

47
Q

Is hsd17b13 protective and of what

A

Yes

Of nash, cirrhosis and overall nafld risk

48
Q

What other variants injury is mitigated with this hsd17 variant

A

I148m

49
Q

How is it found protective

A

Reduced exp of pro inflam/profibrogenic cytokines and collagen
Increased phoshilipids too

50
Q

What 4 ways can you treat nafld

A

Target obesity

Treat the metabolic syndrome eg IR/dyslipidemia (where lipids accumulation in liver causes pushed out into plasma = cvd etc)

Target nash

Target hcc

51
Q

Which antioxidant vitamin used to treat Nash

A

Vitamin e

52
Q

What does simtuzimab target

A

Loxl2 which cross links collagen

53
Q

What sort of personalised medicine is there which knocks down pnpla3

A

Silencing with antisense oligonucleotides

Genetics Of Complex Disease (17 decks)

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