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Genetics and Human Disease > Genetic Of Non-alcoholic Fatty Liver Disease > Flashcards

Genetic Of Non-alcoholic Fatty Liver Disease Flashcards

1
Q

What is the increasing risk factor for non-alcoholic fatty liver disease?

A

Worldwide obesity.

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2
Q

How is non-alcoholic fatty liver disease a multi-system disease?

A

Affect the pancreas, blood vessels, heart, kidney and the liver.

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3
Q

What is the basic mechanism behind the progression of non- alcoholic fatty liver disease?

A

Obesity → metabolic stress → inflammation & fibrogenesis

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4
Q

What is stage 1 of NAFLD?

A

Steatosis, a harmless build-up of fat.

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5
Q

What is stage 2 of NAFLD?

A

Steatohepatitis or NASH, a more serious build-up, the liver is inflamed.

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6
Q

What is stage 3 of NAFLD?

A

Fibrosis, a hyperinflammation causing scar tissue around the liver and nearby blood vessels.

BUT the liver is still functional.

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7
Q

What is stage 4 of NAFLD?

A

Cirrhosis, liver shrinks, scarred and lumpy. Liver failure and cancer.

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8
Q

What increased the risk of NAFLD?

A

Obesity

Diabetes

Underactive thyroid

High cholesterol

Age

Smoking

Metabolic syndrome

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9
Q

How does the prevalence of NAFLD increase with weight?

A

Increases by around 30% from lowest to highest weight bracket.

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10
Q

What is the cause of death with NAFLD?

A

Usually don’t die from liver disease but from other complications, mostly Cardiovascular Diseases.

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11
Q

Why is studying NAFLD so important?

A

Cases have increased 10 times within 10 years and liver free for transplant are staying the same.

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12
Q

What starts the pathogenesis of NAFLD?

A

An increase in insulin during peripheral insulin resistance means more fat is released.

Dietary intake.

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13
Q

Where is more fat released during the pathogenesis of NAFLD?

A

Adipose (Fat) tissue.

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14
Q

What form is the excess fat from adipose tissue reabsorbed?

A

Fatty acids

Carbohydrates.

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15
Q

What happens when the excess fat from adipose tissue is absorbed as a carbohydrate?

A

De novo synthesis into fatty acids.

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16
Q

What genes cause the de novo synthesis of fatty acids from carbohydrates during pathogenesis of NAFLD?

A

ChREBP

SREBP-1c

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17
Q

What is ChREBP?

A

Carbohydrate response element binding protein

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18
Q

What is the role of ChREBP?

A

Transcription factor that regulates de novo lipogenesis in the liver in response to elevated glucose.

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19
Q

What is SREBP-1c?

A

Sterol regulatory element-binding protein-1c

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20
Q

What is the role of SREBP-1c?

A

Transcription factor that regulates lipid synthesis by regulating the expression of lipid metabolism genes

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21
Q

What are the 2 ways fatty acids are removed from the adipose tissue during the pathogenesis of NAFLD?

A

Esterification

Oxidation

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22
Q

What happens when the fatty acids in adipose is esterified?

A

Turns to triglyceride and exported out.

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23
Q

What does the triglyceride exported out during the pathogenesis of NAFLD become outside the tissue?

A

VLDL which is a low-density lipoprotein.

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24
Q

What genes are responsible for exporting the triglycerides out of adipose tissue?

A

MTT

ApoB100

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25
What is ApoB100?
Apolipoprotein B protein
26
What is the function of ApoB100?
This protein is a building block of very low-density lipoproteins (VLDLs)
27
What is MTT?
Mitochondrial (mt-) tRNA
28
What is the function of MTT?
Gene mutations are an important cause of human morbidity.
29
What genes are responsible for the oxidation of fatty acids in the pathogenesis of NAFLD?
PPAR-alpha CPT1
30
What is PPAR-alpha?
Peroxisome proliferator-activated receptor
31
What is the function of PPAR-alpha?
Regulates the expression of genes involved in fatty acid beta-oxidation and is a major regulator of energy homeostasis.
32
What is CPT1?
Carnitine palmitoyltransferase I
33
What is the function of CPT1?
An enzyme which helps the body convert fat to energy.
34
What are the 2 types of oxidation the fatty acids undergo in order to be 'burned' within the adipose tissue?
Mitochondrial -OR- Peroxisomal followed by Microsomal
35
What is the product of the oxidation of fatty acids during the pathogenesis of NAFLD?
Acetyl CoA
36
How is the Acetyl CoA removed out the adipose tissue?
Krebs Cycle.
37
What is SREBP1 responsible for in De Novo lipogenesis?
Increase in insulin
38
What is ChREBP responsible for in De Novo lipogenesis?
Increase in glucose
39
What is KHK responsible for in De Novo lipogenesis?
Increase in fructose
40
What kind of lipolysis is present in hepatic lipid metabolism in NASH pathogenesis?
De Novo Adipose
41
What does adipose lipolysis during hepatic lipid metabolism in NASH pathogenesis increase the volume of?
Circulating fatty acids.
42
What does an increase in circulating fatty acids during Hepatic Lipid Metabolism in NASH Pathogenesis lead to?
An increase in hepatocyte-free fatty acid reflux.
43
What enzyme converts acetyl-CoA to Mal-CoA?
Acetyl-CoA carboxylase (ACC)
44
What is used to convert Mal-CoA to hepatocyte free fatty acid flux during Hepatic Lipid Metabolism in NASH Pathogenesis?
FAS SCD1
45
What is SCD1?
Stearoyl-CoA desaturase enzyme
46
What is the function of SCD1?
Converts saturated fatty acids into monounsaturated fatty acids
47
What is FAS?
The Fas receptor is a death receptor on the surface of cells that leads to programmed cell death if it binds its ligand, Fas ligand (FasL)
48
What does an increase in hepatocyte free fatty acid fluid lead to?
Oxidation and an increase in lipotoxic intermediates.
49
What enzyme assists the oxidation of fatty acids during Hepatic Lipid Metabolism in NASH Pathogenesis?
CPT1
50
What is the problem with Mal-CoA?
It inhibits the production of CPT1 which prevents oxidation.
51
Why is oxidation during Hepatic Lipid Metabolism in NASH Pathogenesis dangerous?
Reactive Oxygen Species lead to ER stress and apoptosis. This leads to the NASH state
52
What kinds of lipotoxic intermediates are there?
Phosphatidic acid Lysophospahtidic acid Lysophosphatidyl choline Ceramides Diacylglycerols
53
What kinds of things cause the NASH state?
Lipotoxicity Mitochondrial Damage Oxidative Stress ER Stress Inflammation Necrosis & Apoptosis
54
What is a HSC cell?
Hematopoietic stem cell
55
What is fibrogenesis?
Fibrogenesis is the production or development of fibres or fibrous tissue.
56
What causes an activated HSC to fibrogenesis?
TGF-beta-1 TIMP1
57
What is TGF-Beta-1?
Transforming growth factor beta 1
58
What is the function of TGF-Beta-1?
Regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors.
59
What is TIMP1?
An inhibitory molecule that regulates matrix metalloproteinases (MMPs), and disintegrin-metalloproteinases (ADAMs and ADAMTSs).
60
Is NAFLD reversible?
Although scarring is irreversible you can set the progression back and heal your liver through a healthy lifestyle.
61
What is the affect of moderate alcohol consumption on NAFLD progression?
Increases it drastically.
62
What kinds of studies prove that genetic factors do contribute to inter-individual variation of NAFLD progression?
* Familial aggregation * Inter-ethnic differences in susceptibility * Twin studies
63
How were twin trials arranged for NAFLD?
60 twins, 42MZ and 18DZ
64
What were the results of twin trial for NAFLD?
95% heritability for risk
65
What kinds of genes cause the transition between a normal liver and steatosis?
Genes related to Insulin Resistance and/or Lipid Metabolism Genes related to Lipotoxicity & Oxidative Stress
66
What kinds of genes cause the transition between steatosis to steatohepatitis?
Genes related to Inflammation and Immune activation
67
What kinds of genes cause the transition between steatosis to steatohepatitis?
Genes related to Inflammation and Immune activation
68
What kinds of genes cause the transition between steatohepatitis and cirrhosis?
Genes related to Senescence or Cell Death (Apoptosis and Necrosis) Genes related to Fibrogenesis & Collagen Turnover
69
Which gene via GWAS was proved to be related to Insulin Resistance and/or Lipid Metabolism?
GCKR
70
What is GCKR?
Glucokinase regulatory protein
71
Which gene via GWAS was proved to be related to Lipotoxicity & Oxidative Stress?
PNPLA3
72
What is PNPLA3?
Adiponutrin
73
Which gene via GWAS was proved to be related to Inflammation and Immune activation?
TM6SF2
74
What is TM6SF2?
Transmembrane 6 superfamily 2
75
Which gene via GWAS was proved to be related to Senescence or Cell Death (Apoptosis and Necrosis?
MBOAT7
76
What is MBOAT7?
Membrane-bound O-acyltransferase domain-containing protein 7
77
Which gene via GWAS was proved to be related to Fibrogenesis & Collagen Turnover?
HSD17B13
78
What is HSD17B13?
7β-Hydroxysteroid dehydrogenase type 13
79
What is the mechanistic effect of the PNPLA3(l148M) variant?
Encodes Adiponutrin Composed of Ser-46 and Asp-166 Doesn't affect the catalytic site.
80
What effect does recombinant l148M PNPLA3 have on acylgylcerol hydrolase activity in vitro?
Reduces it
81
What happens when you purify I148M adiponutrin?
Reduced enzymatic activity
82
What is the effect of I148M on VLDL?
Reduces secretion of VLDL secretion in vitro and in vivo.
83
What is the effect of l148M on lipid remodelling?
Alters it, causing lipid accumulation on lipid droplets.
84
What happens when l148M is overexpressed in vivo?
Steatosis
85
How does adiponutrin affect TAG synthesis?
Adiponutrin has lysophosphatidic acid acetyltransferase activity increased by I148M to increase TAG synthesis.
86
What happens when PNPLA3 is lost in the body?
Do not promote steatosis Increase ALT/AST levels. No affect TG hydrolysis of hepatic steatosis/injury.
87
What is PNPLA3 l148M effect on diacylglycerol hydrolase?
Reduces its activity.
87
What happens when mutant PNPLA3 l148M is overexpressed but the wild type is not?
Does not promote steatosis.
88
The PNPLA3l148M variant has a dominant-negative effect what does that mean?
The non-functioning protein must be expressed.
89
Where does the PNPLA3 l148M Variant accumulate?
Lipid Droplet
90
How does the PNPLA3 l148M accumulate?
Evading ubiquitination.
91
Why is ubiquitination important for PNPLA3 l148M?
Ubiquitylation and proteasomal degradation are the major catabolic pathway for PNPLA3. Wild Type is efficiently ubiquitylated and rapidly degraded PNPLA3 I148M is not and so accumulates on lipid droplets.
92
Is wild type or mutant PNPLA3 more abundant?
The mutant despite similar mRNA levels.
93
Is wild type or mutant PNPLA3 more resilient to autophagy?
Wild type
94
What is autophagy?
Consumption of the body’s own tissue as a metabolic process occurring in starvation and certain diseases.
95
What interaction is required for the mutant PNPLA3 to have an effcet?
CGI-58 with PNPLA3
96
What does the interaction of PNPLA3 and CGI-58?
Lipid droplet depletion in cultures cells.
97
What is the effect of the mutant type PNPLA3 on CGI-58?
Further enhances CGI-58 affinity, reducing availability oF CGI-58 to co-activate ATGL.
98
Which out of ATGL and CGI-58 has a higher affinity to PNPLA3?
CGI-58
99
What is ATGL?
Adipose triglyceride lipase
100
What is the mechanism of wild-type PNPLA3?
PNPLA3WT ubiquitylated and degraded Lower PNPLA3 WT abundance CGI-58 cofactor activates ATGL Greater Lipolysis & Lipophagy LD degradation
101
What is the mechanism of mutant PNPLA3 l148M?
PNPLA3I148M resistant to ubiquitylation Greater PNPLA3 I148M abundance PNPLA3I148M binds CGI-58 ATGL lacks CGI-58 cofactor Less Lipolysis & Lipophagy
102
What is the function of PNPLA3 on Hepatic stem cells?
PNPLA3 is required for HSC activation and its genetic variant I148M potentiates the pro-fibrogenic features of HSCs
103
What is TM6SF2?
A regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content.
104
Where is TM6SF2 expressed?
Liver and small intestine.
105
What is the problem with TM6SF2 E167K variant?
Alters lipid processing in both liver and small intestine leading to increased ER stress
106
What is the function of TM6SF2 IN VLDL assembly?
Required to mobilize neutral lipids
107
What is the issue with TM6SF2 variants?
Affect protein stability.
108
What is the advantage of the loss of function splice variant?
Protective against raised ALT/AST, NASH, Cirrhosis & HCC
109
What is HSD17B13?
A lipid droplet–associated retinol dehydrogenase that associates with NAFLD histology.
110
What are the 4 principles of treatment for NAFLD?
1. Target the ‘Obesogenic’ Lifestyle 2. Target the Metabolic Syndrome 3. Target the liver disease 4. Minimise down-stream complications such as HCC
111
What is the pathophysiological process for the normal liver stage?
Targets related to Insulin Resistance or Lipid Metabolism Lipotoxicity & Oxidative Stress
112
What is the pathophysiological process for the steatosis stage?
Targets related to Inflammation and Immune activation
113
What is the pathophysiological process for the steatohepatitis stage?
Targets related to Cell Death
114
What is the pathophysiological process for the cirrhosis stage?
Targets related to Fibrogenesis & Collagen Turnover
115

Genetics and Human Disease (16 decks)

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