NAFLD Genetics Flashcards by Anna Safrankova

What is nafld

Excess liver fat

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What are the progression steps

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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What is steatohepatitis

Steatosis and necroinflammation

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Is it high prevalence

Yes and increasing

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When does mortality occur

Late fibrosis or mainly due to other conditions eg chd

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What 2 ways does fat get in

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

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Where becomes insulin resistant and why

Muscles, periphery and fat stores

Because increased insulin release from diet desensitises

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What gets disinhibited due to insulin resistance in adipose tissue

HLA hormone sensitive lipase

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What does this do

Allows fa flow from adipose tissue

Due to increased lipolysis

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Why does liver still make more and more fa

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

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What gets overwhelmed first

Esterification

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What 3 types of oxidation are there

Peroxisomal b-oxidation
Microsomal omega
Mitochondrial b oxidation

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What do they all produce

Ros

Causes oxidative stress, damage and apoptosis of cells

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

Mal-coa

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How

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

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

Lipotoxic intermediates like ceramides from the alternative oxidation paths

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What do all of these with ROS also cause overtime

NASH

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How does bacteria trans locate to liver making nash worse

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

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What bacterial things can cause nash

Lps through inflammasome activation/PAMPS

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What cells allow for fibrosis to occur

Hsc

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What sorts of things activate them

Lps, tgfb1, il17a,il6

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What do they do

Lay down scar tissue eg col type 1

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

How does regression of fibrosis occur

Mmps and hsc quiescence/apoptosis

Which 3 ways do you study genetics of nafld

Twin studies
Family aggregation studies
Inter ethnic differences in susceptibility

Which are highest and lowest at risk

Hispanic highest Afro Caribbean lowest

What did twin studies find heritability of steatosis and fibrosis

Around 50%

Which gene is the most studied associated with nafld

Pnpla3

What is the variant of it

I148M

What does this help to explain

Inter ethnic differences by 70%

How is it an example of gene x environment

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

Other than steatosis what other risk does it cause

Hcc and advanced fibrosis

What does it usually do

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

Where does the variant affect

Next to catalytic site affecting how substrate reaches catalytic site

What sorts of things does it do which causes steatosis

Reduced vldl release Reduced fattt acid hydrolysis Increased TG accumulation

Why is there more pnpla3 protein with this variant

Stops ub proteasomes deg of it

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

Ccl5, gm-csf, il8, tgfb

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

Macrophages

What thing which causes hsc wuisceince is down regulated

Ppar-y

What receptor signalling is downregulated which usually stops fibrogenesis from hsc

Retinoid x as retinol levels decreased

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

Atgl (a tg hydrolase)

How

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

What does tm6sf2 do

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

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

Because reduced vldl/tg plasma release

Does the variant affect expression of tm6sf2

Yes

How is vldl usually formed

In er tg and apoB assembly with mttp help Then cop II transport to Golgi where further lipidsrion ocxurs

Where is tm6sf2 thought to be important

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

Is hsd17b13 protective and of what

Yes Of nash, cirrhosis and overall nafld risk

What other variants injury is mitigated with this hsd17 variant

I148m

How is it found protective

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

What 4 ways can you treat nafld

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

Which antioxidant vitamin used to treat Nash

Vitamin e

What does simtuzimab target

Loxl2 which cross links collagen

What sort of personalised medicine is there which knocks down pnpla3

Silencing with antisense oligonucleotides