NAFLD Genetics Flashcards
What is nafld
Excess liver fat
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
What is steatohepatitis
Steatosis and necroinflammation
Is it high prevalence
Yes and increasing
When does mortality occur
Late fibrosis or mainly due to other conditions eg chd
What 2 ways does fat get in
De novo lipogenesis in liver or through diet/fa flow from adipose tissue
Where becomes insulin resistant and why
Muscles, periphery and fat stores
Because increased insulin release from diet desensitises
What gets disinhibited due to insulin resistance in adipose tissue
HLA hormone sensitive lipase
What does this do
Allows fa flow from adipose tissue
Due to increased lipolysis
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
What gets overwhelmed first
Esterification
What 3 types of oxidation are there
Peroxisomal b-oxidation
Microsomal omega
Mitochondrial b oxidation
What do they all produce
Ros
Causes oxidative stress, damage and apoptosis of cells
What in the lipogenesis cycle can inhibit mt b oxidation whcih is the best one to use
Mal-coa
How
Inhibits cpt1 which is an enzyme used to import fat into mt for b oxidation
What builds up which causes things like er stress, mitochondrial dysfunction and necrosis
Lipotoxic intermediates like ceramides from the alternative oxidation paths
What do all of these with ROS also cause overtime
NASH
How does bacteria trans locate to liver making nash worse
Gut permeability and flow through the portal vein from gut to liver
What bacterial things can cause nash
Lps through inflammasome activation/PAMPS
What cells allow for fibrosis to occur
Hsc
What sorts of things activate them
Lps, tgfb1, il17a,il6
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
