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

Genetic Of Non-alcoholic Fatty Liver Disease Flashcards

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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
Q

What is ApoB100?

A

Apolipoprotein B protein

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26
Q

What is the function of ApoB100?

A

This protein is a building block of very low-density lipoproteins (VLDLs)

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27
Q

What is MTT?

A

Mitochondrial (mt-) tRNA

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28
Q

What is the function of MTT?

A

Gene mutations are an important cause of human morbidity.

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29
Q

What genes are responsible for the oxidation of fatty acids in the pathogenesis of NAFLD?

A

PPAR-alpha

CPT1

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30
Q

What is PPAR-alpha?

A

Peroxisome proliferator-activated receptor

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31
Q

What is the function of PPAR-alpha?

A

Regulates the expression of genes involved in fatty acid beta-oxidation and is a major regulator of energy homeostasis.

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32
Q

What is CPT1?

A

Carnitine palmitoyltransferase I

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33
Q

What is the function of CPT1?

A

An enzyme which helps the body convert fat to energy.

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34
Q

What are the 2 types of oxidation the fatty acids undergo in order to be ‘burned’ within the adipose tissue?

A

Mitochondrial

-OR-

Peroxisomal followed by Microsomal

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35
Q

What is the product of the oxidation of fatty acids during the pathogenesis of NAFLD?

A

Acetyl CoA

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36
Q

How is the Acetyl CoA removed out the adipose tissue?

A

Krebs Cycle.

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37
Q

What is SREBP1 responsible for in De Novo lipogenesis?

A

Increase in insulin

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38
Q

What is ChREBP responsible for in De Novo lipogenesis?

A

Increase in glucose

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39
Q

What is KHK responsible for in De Novo lipogenesis?

A

Increase in fructose

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40
Q

What kind of lipolysis is present in hepatic lipid metabolism in NASH pathogenesis?

A

De Novo

Adipose

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41
Q

What does adipose lipolysis during hepatic lipid metabolism in NASH pathogenesis increase the volume of?

A

Circulating fatty acids.

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42
Q

What does an increase in circulating fatty acids during Hepatic Lipid Metabolism in NASH Pathogenesis lead to?

A

An increase in hepatocyte-free fatty acid reflux.

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43
Q

What enzyme converts acetyl-CoA to Mal-CoA?

A

Acetyl-CoA carboxylase (ACC)

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44
Q

What is used to convert Mal-CoA to hepatocyte free fatty acid flux during Hepatic Lipid Metabolism in NASH Pathogenesis?

A

FAS

SCD1

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45
Q

What is SCD1?

A

Stearoyl-CoA desaturase enzyme

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46
Q

What is the function of SCD1?

A

Converts saturated fatty acids into monounsaturated fatty acids

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47
Q

What is FAS?

A

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
Q

What does an increase in hepatocyte free fatty acid fluid lead to?

A

Oxidation and an increase in lipotoxic intermediates.

49
Q

What enzyme assists the oxidation of fatty acids during Hepatic Lipid Metabolism in NASH Pathogenesis?

A

CPT1

50
Q

What is the problem with Mal-CoA?

A

It inhibits the production of CPT1 which prevents oxidation.

51
Q

Why is oxidation during Hepatic Lipid Metabolism in NASH Pathogenesis dangerous?

A

Reactive Oxygen Species lead to ER stress and apoptosis.

This leads to the NASH state

52
Q

What kinds of lipotoxic intermediates are there?

A

Phosphatidic acid

Lysophospahtidic acid

Lysophosphatidyl choline

Ceramides

Diacylglycerols

53
Q

What kinds of things cause the NASH state?

A

Lipotoxicity

Mitochondrial Damage

Oxidative Stress

ER Stress

Inflammation

Necrosis & Apoptosis

54
Q

What is a HSC cell?

A

Hematopoietic stem cell

55
Q

What is fibrogenesis?

A

Fibrogenesis is the production or development of fibres or fibrous tissue.

56
Q

What causes an activated HSC to fibrogenesis?

A

TGF-beta-1

TIMP1

57
Q

What is TGF-Beta-1?

A

Transforming growth factor beta 1

58
Q

What is the function of TGF-Beta-1?

A

Regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors.

59
Q

What is TIMP1?

A

An inhibitory molecule that regulates matrix metalloproteinases (MMPs), and disintegrin-metalloproteinases (ADAMs and ADAMTSs).

60
Q

Is NAFLD reversible?

A

Although scarring is irreversible you can set the progression back and heal your liver through a healthy lifestyle.

61
Q

What is the affect of moderate alcohol consumption on NAFLD progression?

A

Increases it drastically.

62
Q

What kinds of studies prove that genetic factors do contribute to inter-individual variation of NAFLD progression?

A
  • Familial aggregation
  • Inter-ethnic differences in susceptibility
  • Twin studies
63
Q

How were twin trials arranged for NAFLD?

A

60 twins, 42MZ and 18DZ

64
Q

What were the results of twin trial for NAFLD?

A

95% heritability for risk

65
Q

What kinds of genes cause the transition between a normal liver and steatosis?

A

Genes related to Insulin Resistance and/or Lipid Metabolism

Genes related to Lipotoxicity & Oxidative Stress

66
Q

What kinds of genes cause the transition between steatosis to steatohepatitis?

A

Genes related to Inflammation and Immune activation

67
Q

What kinds of genes cause the transition between steatosis to steatohepatitis?

A

Genes related to Inflammation and Immune activation

68
Q

What kinds of genes cause the transition between steatohepatitis and cirrhosis?

A

Genes related to Senescence or Cell Death (Apoptosis and Necrosis)

Genes related to Fibrogenesis & Collagen Turnover

69
Q

Which gene via GWAS was proved to be related to Insulin Resistance and/or Lipid
Metabolism?

A

GCKR

70
Q

What is GCKR?

A

Glucokinase regulatory protein

71
Q

Which gene via GWAS was proved to be related to Lipotoxicity & Oxidative Stress?

A

PNPLA3

72
Q

What is PNPLA3?

A

Adiponutrin

73
Q

Which gene via GWAS was proved to be related to Inflammation and Immune activation?

A

TM6SF2

74
Q

What is TM6SF2?

A

Transmembrane 6 superfamily 2

75
Q

Which gene via GWAS was proved to be related to Senescence or Cell Death (Apoptosis and Necrosis?

A

MBOAT7

76
Q

What is MBOAT7?

A

Membrane-bound O-acyltransferase domain-containing protein 7

77
Q

Which gene via GWAS was proved to be related to Fibrogenesis & Collagen Turnover?

A

HSD17B13

78
Q

What is HSD17B13?

A

7β-Hydroxysteroid dehydrogenase type 13

79
Q

What is the mechanistic effect of the PNPLA3(l148M) variant?

A

Encodes Adiponutrin

Composed of Ser-46 and Asp-166

Doesn’t affect the catalytic site.

80
Q

What effect does recombinant l148M PNPLA3 have on acylgylcerol hydrolase activity in vitro?

A

Reduces it

81
Q

What happens when you purify I148M adiponutrin?

A

Reduced enzymatic activity

82
Q

What is the effect of I148M on VLDL?

A

Reduces secretion of VLDL secretion in vitro and in vivo.

83
Q

What is the effect of l148M on lipid remodelling?

A

Alters it, causing lipid accumulation on lipid droplets.

84
Q

What happens when l148M is overexpressed in vivo?

A

Steatosis

85
Q

How does adiponutrin affect TAG synthesis?

A

Adiponutrin has lysophosphatidic acid acetyltransferase activity increased by I148M to increase TAG synthesis.

86
Q

What happens when PNPLA3 is lost in the body?

A

Do not promote steatosis

Increase ALT/AST levels.

No affect TG hydrolysis of hepatic steatosis/injury.

87
Q

What is PNPLA3 l148M effect on diacylglycerol hydrolase?

A

Reduces its activity.

87
Q

What happens when mutant PNPLA3 l148M is overexpressed but the wild type is not?

A

Does not promote steatosis.

88
Q

The PNPLA3l148M variant has a dominant-negative effect what does that mean?

A

The non-functioning protein must be expressed.

89
Q

Where does the PNPLA3 l148M Variant accumulate?

A

Lipid Droplet

90
Q

How does the PNPLA3 l148M accumulate?

A

Evading ubiquitination.

91
Q

Why is ubiquitination important for PNPLA3 l148M?

A

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
Q

Is wild type or mutant PNPLA3 more abundant?

A

The mutant despite similar mRNA levels.

93
Q

Is wild type or mutant PNPLA3 more resilient to autophagy?

A

Wild type

94
Q

What is autophagy?

A

Consumption of the body’s own tissue as a metabolic process occurring in starvation and certain diseases.

95
Q

What interaction is required for the mutant PNPLA3 to have an effcet?

A

CGI-58 with PNPLA3

96
Q

What does the interaction of PNPLA3 and CGI-58?

A

Lipid droplet depletion in cultures cells.

97
Q

What is the effect of the mutant type PNPLA3 on CGI-58?

A

Further enhances CGI-58 affinity, reducing availability oF CGI-58 to co-activate ATGL.

98
Q

Which out of ATGL and CGI-58 has a higher affinity to PNPLA3?

A

CGI-58

99
Q

What is ATGL?

A

Adipose triglyceride lipase

100
Q

What is the mechanism of wild-type PNPLA3?

A

PNPLA3WT ubiquitylated and degraded

Lower PNPLA3 WT abundance

CGI-58 cofactor activates ATGL

Greater Lipolysis & Lipophagy

LD degradation

101
Q

What is the mechanism of mutant PNPLA3 l148M?

A

PNPLA3I148M resistant to ubiquitylation

Greater PNPLA3 I148M abundance

PNPLA3I148M binds CGI-58

ATGL lacks CGI-58 cofactor

Less Lipolysis & Lipophagy

102
Q

What is the function of PNPLA3 on Hepatic stem cells?

A

PNPLA3 is required for HSC activation and its genetic variant I148M potentiates the pro-fibrogenic features of HSCs

103
Q

What is TM6SF2?

A

A regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content.

104
Q

Where is TM6SF2 expressed?

A

Liver and small intestine.

105
Q

What is the problem with TM6SF2 E167K variant?

A

Alters lipid processing in both liver and small intestine leading to increased ER stress

106
Q

What is the function of TM6SF2 IN VLDL assembly?

A

Required to mobilize neutral lipids

107
Q

What is the issue with TM6SF2 variants?

A

Affect protein stability.

108
Q

What is the advantage of the loss of function splice variant?

A

Protective against raised ALT/AST, NASH, Cirrhosis & HCC

109
Q

What is HSD17B13?

A

A lipid droplet–associated retinol dehydrogenase that associates with NAFLD histology.

110
Q

What are the 4 principles of treatment for NAFLD?

A
  1. Target the ‘Obesogenic’ Lifestyle
  2. Target the Metabolic Syndrome
  3. Target the liver disease
  4. Minimise down-stream complications such as HCC
111
Q

What is the pathophysiological process for the normal liver stage?

A

Targets related to Insulin Resistance or Lipid Metabolism

Lipotoxicity & Oxidative Stress

112
Q

What is the pathophysiological process for the steatosis stage?

A

Targets related to Inflammation and Immune activation

113
Q

What is the pathophysiological process for the steatohepatitis stage?

A

Targets related to Cell Death

114
Q

What is the pathophysiological process for the cirrhosis stage?

A

Targets related to Fibrogenesis & Collagen Turnover

115
Q
A

Genetics and Human Disease (16 decks)

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